Tratamiento farmacológico para la atrofia muscular espinal tipos II y III
Resumen
Antecedentes
La atrofia muscular espinal (AME) es causada por una deleción homocigótica del gen de supervivencia de motoneuronas 1 (SMN1) en el cromosoma 5; o una deleción heterocigótica en combinación con una mutación (puntual) en el segundo alelo de SMN1. Lo anterior resulta en la degeneración de las células del cuerno anterior, lo cual da lugar a debilidad muscular progresiva. Los niños con AME tipo II no desarrollan la capacidad de caminar sin apoyo y tienen una esperanza de vida breve, mientras que los niños con AME tipo III desarrollan la capacidad de caminar y tienen una esperanza de vida normal. Ésta es una actualización de una revisión publicada por primera vez en 2009 y actualizada previamente en 2011.
Objetivos
Evaluar si el tratamiento farmacológico puede desacelerar o detener la progresión de la AME tipo II y III y evaluar si dicho tratamiento se puede administrar con seguridad.
Métodos de búsqueda
Se realizaron búsquedas en el Registro Especializado del Grupo Cochrane de Enfermedades Neuromusculares (Cochrane Neuromuscular Specialised Register), CENTRAL, MEDLINE, Embase y en las actas de congresos de la ISI Web of Science en octubre de 2018. En octubre 2018 también se realizaron búsquedas en dos registros de ensayos para identificar ensayos no publicados.
Criterios de selección
Se buscaron todos los ensayos aleatorizados o cuasialeatorizados que examinaban la eficacia del tratamiento farmacológico para la AME tipo II y III. Los participantes tenían que cumplir con los criterios clínicos y tener una deleción homocigótica o hemizigótica en combinación con una mutación puntual en el segundo alelo del gen SMN1 (5q11.2‐13.2) confirmada mediante un análisis genético.
La medida de resultado primaria fue el cambio en la puntuación de la discapacidad un año después del inicio del tratamiento. Las medidas de resultado secundarias en un año después del inicio del tratamiento fueron el cambio en la fuerza muscular, la capacidad para ponerse de pie o caminar, el cambio en la calidad de vida, el tiempo desde el inicio del tratamiento hasta la muerte o hasta la ventilación a tiempo completo, y los eventos adversos atribuibles al tratamiento durante el período del ensayo.
Las estrategias de tratamiento que incluyen el reemplazo del gen SMN1 con vectores virales están fuera del alcance de esta revisión, aunque se proporciona un resumen en el Apéndice 1. El tratamiento farmacológico para la AME tipo I es el tema de otra revisión Cochrane.
Obtención y análisis de los datos
Se siguió la metodología Cochrane estándar.
Resultados principales
Los revisores encontraron diez ensayos aleatorizados, controlados con placebo, de tratamientos para la AME tipos II y III para su inclusión en esta revisión, con 717 participantes. Se agregaron cuatro de los ensayos en esta actualización. Los ensayos investigaron la creatina (55 participantes), la gabapentina (84 participantes), la hidroxiurea (57 participantes), el nusinersén (126 participantes), la olesoxima (165 participantes), el fenilbutirato (107 participantes), la somatotropina (20 participantes), la hormona liberadora de tirotropina (TRH) (nueve participantes), el ácido valproico (33 participantes) y el tratamiento de combinación con ácido valproico y acetil‐L‐carnitina (ALC) (61 participantes). La duración del tratamiento fue de seis a 24 meses. Ninguno de los estudios investigó el mismo tratamiento y ninguno estuvo completamente libre de sesgo. Todos los estudios realizaron el cegamiento, la generación de la secuencia y el informe de los resultados primarios de forma adecuada.
Sobre la base de la evidencia de certeza moderada, el nusinersén intratecal mejoró la función motora (discapacidad) en los niños con AME tipo II, con una mejoría de 3,7 puntos en el grupo de nusinersén en la Hammersmith Functional Motor Scale Expanded (HFMSE; rango de puntuaciones posibles 0 a 66), en comparación con una disminución de 1,9 puntos en la HFMSE en el grupo de procedimiento simulado (p < 0,01; n = 126). En todas las escalas de la función motora utilizadas, las puntuaciones más altas indican una mejor función.
Sobre la base de la evidencia de certeza moderada de dos estudios, las siguientes intervenciones no tuvieron un efecto clínicamente importante sobre las puntuaciones de la función motora en la AME tipos II o III (o ambos) en comparación con placebo: creatina (cambio mediano 1 punto mayor, intervalo de confianza [IC] del 95%: ‐1 a 2; en la Gross Motor Function Measure [GMFM], escala 0 a 264; n = 40); y tratamiento de combinación con ácido valproico y carnitina (diferencia de medias [DM] 0,64, IC del 95%: ‐1,1 a 2,38; en la Modified Hammersmith Functional Motor Scale [MHFMS], escala 0 a 40; n = 61).
Sobre la base de la evidencia de certeza baja de otros estudios individuales, las siguientes intervenciones no tuvieron un efecto clínicamente importante sobre las puntuaciones de la función motora en la AME tipos II o III (o ambos) en comparación con placebo: gabapentina (cambio mediano de 0 en el grupo de gabapentina y ‐2 en el grupo de placebo en la SMA Functional Rating Scale [SMAFRS], escala 0 a 50; n = 66); hidroxiurea (DM ‐1,88, IC del 95%: ‐3,89 a 0,13 en la GMFM, escala 0 a 264; n = 57), fenilbutirato (DM ‐0,13, IC del 95%: ‐0,84 a 0,58 en la Hammersmith Functional Motor Scale [HFMS], escala 0 a 40; n = 90) y monoterapia con ácido valproico (DM 0,06, IC del 95%: ‐1,32 a 1,44 en la SMAFRS, escala 0 a 50; n = 31).
La evidencia de certeza muy baja indicó que las siguientes intervenciones tuvieron poco o ningún efecto sobre la función motora: olesoxima (DM 2; IC del 95%: ‐0,25 a 4,25 en la Motor Function Measure [MFM] D1 + D2, escala 0 a 75; n = 160) y somatotropina (cambio mediano a los tres meses 0,25 más alto, IC del 95%: ‐1 a 2,5 en la HFMSE, escala 0 a 66; n = 19). Un ensayo pequeño de la TRH no informó los efectos sobre la función motora y la certeza de la evidencia para otros resultados a partir de este ensayo fue baja o muy baja.
Se esperaban los resultados de nueve ensayos completados que investigaban la 4‐aminopiridina, la acetil‐L‐carnitina, la CK‐2127107, la hidroxiurea, la piridostigmina, el riluzol, el RO6885247/RG7800, el salbutamol y el ácido valproico que no estaban disponibles para el análisis en el momento de la redacción.
Hay varios ensayos y estudios actualmente en curso que están investigando estrategias de tratamiento distintas del nusinersén (p.ej. el aumento del SMN2 mediante moléculas pequeñas).
Conclusiones de los autores
El nusinersén mejora la función motora en la AME tipo II, sobre la base de evidencia de certeza moderada.
La creatina, la gabapentina, la hidroxiurea, el fenilbutirato, el ácido valproico y la combinación de ácido valproico y ALC probablemente no tienen un efecto clínicamente importante sobre la función motora en la AME tipos II o III (o ambos), sobre la base de evidencia de certeza baja, y la olesoxima y la somatropina también pueden tener poco o ningún efecto clínicamente importante, aunque la evidencia fue de certeza muy baja. Un ensayo de la TRH no midió la función motora.
PICO
Resumen en términos sencillos
Medicamentos para la atrofia muscular espinal tipos II y III
¿Cuál era el objetivo de esta revisión?
Esta revisión Cochrane tuvo como objetivo analizar los efectos de los fármacos sobre la atrofia muscular espinal (AME) tipos II y III en cuanto a la discapacidad, la fuerza muscular, la capacidad para estar de pie o caminar, la calidad de vida y el tiempo hasta la muerte o la ventilación a tiempo completo, dentro del año desde el inicio del tratamiento. También se deseaba identificar cualquier efecto perjudicial de los tratamientos durante el período del ensayo. Los autores de la revisión Cochrane recopilaron los estudios relevantes para responder a esta pregunta y encontraron 10 estudios.
Mensajes clave
El nusinersén administrado mediante inyección intratecal (en la columna vertebral) probablemente mejora la discapacidad en la AME.
La creatina, el fenilbutirato, la gabapentina, la hidroxiurea, el ácido valproico y el tratamiento de combinación con ácido valproico y acetil‐L‐carnitina probablemente no tienen ningún efecto clínicamente importante sobre la función motora (movimientos y acciones de los músculos) en la AME tipos II y III, sobre la base de la evidencia de ensayos únicos completados y publicados.
La olesoxima y la somatotropina subcutánea pueden tener poco o ningún efecto sobre la función motora en la AME, pero la confiabilidad de la evidencia fue muy baja. Un ensayo de la hormona liberadora de tirotropina (TRH, por sus siglas en inglés) intravenosa (en una vena) no midió la función motora y la confiabilidad de la evidencia fue muy baja. Ambos estudios tuvieron limitaciones en el diseño o la realización que podrían haber afectado los resultados.
¿Qué se estudió en la revisión?
Esta revisión es sobre medicamentos para la AME tipos II y III. Los síntomas de la AME aparecen por primera vez en la infancia y la adolescencia. La característica principal es el aumento de la debilidad muscular. Los niños con AME tipo II nunca podrán caminar sin apoyo, en general viven hasta la adolescencia o más, pero con una esperanza de vida reducida. La edad de aparición de la AME tipo II es entre los seis y los 18 meses. Los niños con AME tipo III caminarán de forma independiente pero pueden perder la capacidad de caminar en algún momento y tienen una esperanza de vida normal. La edad de inicio de la AME tipo III es después de los 18 meses.
¿Cuáles son los principales resultados de la revisión?
Se identificaron 10 ensayos que incluían a 717 participantes. Todos los ensayos compararon un medicamento con una sustancia inactiva (placebo) o un procedimiento falso (simulado). Los ensayos estudiaron la creatina oral (por boca) (55 participantes), la gabapentina oral (84 participantes), el fenilbutirato oral (107 participantes), la hidroxiurea oral (57 participantes), el nusinersén intratecal (126 participantes), la olesoxima oral (165 participantes), la somatotropina subcutánea (bajo la piel) (20 participantes), la TRH intravenosa (nueve participantes), el ácido valproico oral (33 participantes) o el tratamiento combinado con ácido valproico oral y acetil‐L‐carnitina (ALC) (61 participantes). La duración del tratamiento fue de seis a 24 meses.
El nusinersén tuvo un efecto beneficioso sobre la función motora en los pacientes con AME tipo II, en comparación con un procedimiento simulado. Probablemente no hubo efectos beneficiosos sobre la función motora en la AME tipos II/III para la creatina, la gabapentina, la hidroxiurea, el fenilbutirato, el ácido valproico o el tratamiento combinado con ácido valproico y ALC. La olesoxima y la somatotropina pueden no tener ningún efecto sobre la función motora. El ensayo pequeño de la TRH no evaluó la función motora y no proporcionó evidencia fiable sobre otros resultados. Se encontró que todos los estudios tuvieron limitaciones en el diseño o la realización que podrían haber afectado los resultados. Ocho estudios fueron financiados (parcialmente) por compañías farmacéuticas, ya sea suministrando el fármaco del estudio o proporcionando apoyo financiero de otra manera. En dos estudios que investigaron el nusinersén y la olesoxima, las compañías farmacéuticas participaron en el análisis y la presentación de los datos.
Se esperan los resultados de nueve ensayos completos que investigan la 4‐aminopiridina, la ALC, la CK‐2121707, la hidroxiurea, la piridostigmina, el riluzol, el RO6885247/RG7800, el salbutamol y el ácido valproico, que no estaban disponibles en el momento de la redacción.
¿Cómo de actualizada está esta revisión?
La evidencia está actualizada hasta octubre de 2018.
Authors' conclusions
Summary of findings
| Oral creatine compared to placebo for children with SMA types II and III | ||||||
| Patient or population: children with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with oral creatine | |||||
| Change in disability score | The median change in disability score was –1 | Median change 1 higher | — | 40 | ⊕⊕⊕⊝ | — |
| Change in total muscle strength (total muscle strength) | The mean change in total muscle strength was 2.42 pounds | MD 1.25 pounds lower | — | 22 | ⊕⊕⊝⊝ | Only participants aged ≥ 5 years. |
| Acquiring the ability to stand or walk | Not measured | |||||
| Change in quality of life | The median change in quality of life was 2 | Median change 7 lower | — | 38 | ⊕⊕⊝⊝ | Higher scores on the PedsQL indicate better quality of life. |
| Change in pulmonary function | The mean change in pulmonary function was –0.83 % predicted | MD 0.56 % predicted higher | — | 23 | ⊕⊕⊝⊝ | Only participants aged ≥ 5 years. |
| Time from beginning of treatment until death or full‐time ventilation | 1 death occurred in the placebo group in 28 participants (36 per 1000) | 0 deaths occurred in the treatment group among 27 participants (0 per 1000) | — | 40 | ⊕⊕⊕⊝ | — |
| Adverse events related to treatment | 571 per 1000 | 480 per 1000 (291 to 800) | 0.84 (0.51 to 1.4) | 40 | ⊕⊕⊝⊝ | There were 43 events in 16/28 participants in placebo group and 55 events in 13/27 participants treated with creatine. Adverse events were systematically, prospectively collected at every study visit. Adverse events included mainly respiratory infections. |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; GMFM: Gross Motor Function Measure; MD: mean difference; MHFMS: Modified Hammersmith Functional Motor Scale; MMT: Manual Muscle Testing; PedsQL: Pediatric Quality of Life Inventory; RCT: randomised controlled trial; RR: risk ratio; SMA: spinal muscular atrophy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level for imprecision because of the small sample size. | ||||||
| Oral gabapentin compared to placebo for adults with SMA types II and III | ||||||
| Patient or population: adults with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with oral gabapentin | |||||
| Change in disability score | The median change in the SMAFRS score was 0 in the gabapentin group (37 participants) and –2 in the placebo group (34 participants) | — | 66 | ⊕⊕⊝⊝ | Higher scores on the SMAFRS indicate better function. | |
| Change in muscle strength | The mean change in muscle strength was –2.2% | MD 3.3% higher | — | 50 | ⊕⊕⊝⊝ | — |
| Acquiring ability to walk | 0/35 participants in the placebo group developed the ability to walk at 9 or 12 months' follow‐up | 0/38 participants treated with oral gabapentin developed the ability to walk at 9 or 12 months' follow‐up | — | 73 | ⊕⊕⊝⊝ | — |
| Change in quality of life | The mean change in quality of life was –0.26% | MD 0.36% higher | — | 67 | ⊕⊕⊝⊝ | Higher scores on the mini‐SIP indicate poorer health status. |
| Change in pulmonary function | The mean change in pulmonary function was –2.9 % predicted | MD 1.1 % predicted lower | — | 65 | ⊕⊕⊝⊝ | Data from analysis of participants who completed ≥ 2 visits. |
| Time from beginning of treatment to death or full‐time ventilation | 0 reported deaths and 0 participants required full‐time ventilation | — | 84 | ⊕⊕⊕⊝ | — | |
| Adverse events related to treatment | Adverse events were reported to be infrequent and not statistically different between treatment groups. Numerical data on adverse events were not available. | — | 65 | ⊕⊕⊝⊝ | Adverse events were systematically, prospectively collected at every study visit. | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; MD: mean difference; mini‐SIP: mini‐Sickness Impact Profile; PedsQL: Pediatric Quality of Life Inventory; RCT: randomised controlled trial; RR: risk ratio; SMA: spinal muscular atrophy; SMAFRS: Spinal Muscular Atrophy Functional Rating Scale. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level for imprecision because the small sample size. | ||||||
| Oral hydroxyurea compared to placebo for children and adults with SMA types II and III | ||||||
| Patient or population: children and adults with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with oral hydroxyurea | |||||
| Change in disability score | The mean change in disability score was 2.02 | MD 1.88 lower | — | 57 | ⊕⊕⊝⊝ | Higher scores on the GMFM indicate better function. |
| Change in disability score | The mean change in disability score was 0.04 | MD 0.02 lower | — | 38 | ⊕⊕⊕⊝ | Only performed in non‐ambulatory participants. |
| Change in muscle strength | The mean change in muscle strength was –0.03 | MD 0.55 lower | — | 57 | ⊕⊕⊕⊝ | — |
| Acquiring the ability to stand or walk | Not measured | |||||
| Change in quality of life | Not measured | |||||
| Change in pulmonary function | The mean change in pulmonary function was –0.22 L | MD 0.01 L higher | — | 57 | ⊕⊕⊝⊝ | — |
| Time from beginning of treatment until death or full‐time ventilation | 1 participant died in the treatment group after 5 visits (after 8 months of treatment), due to respiratory complications. | — | 57 | ⊕⊕⊕⊝ | Also reported as the 1 serious adverse event. | |
| Adverse events related to treatment | All participants experienced adverse events. 129 events occurred in the 20 participants in the placebo group. 224 events occurred in the 37 participants in the hydroxyurea group. | — | 57 | ⊕⊕⊕⊝ | Adverse events were systematically, prospectively collected using a questionnaire at every study visit. Adverse events: laboratory disturbances (e.g. neutropenia, thrombocytopenia, high transaminases), respiratory complaint, gastrointestinal complaints, rash, neurological symptoms, unspecified. 1 participant died in the treatment group due to respiratory complications.d | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level for imprecision. CIs were very wide. | ||||||
| Intrathecal injected nusinersen compared to sham procedure for children with SMA type II | |||||||
| Patient or population: children with SMA type II | |||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | ||
| Risk with sham procedure | Risk with intrathecal injected nusinersen | ||||||
| Change in disability score | The mean change in HFMSE in the control group was –1.9 points | The mean change in HFMSE in the nusinersen‐treated group was 5.9 points higher than in the sham procedure group (3.7 higher to 8.1 higher) | MD 5.9 (3.7 to 8.1) | 126 | ⊕⊕⊕⊝ | ||
| Change in disability score (3 point‐change) | 262 per 1000 | 471 per 1000 (259 to 812) | RR 1.8 (0.99 to 3.1) | 126 | ⊕⊕⊕⊝ | 11/42 participants in the sham‐controlled group showed a 3‐point change on the HFMSE. 48/84 participants in the nusinersen group showed a 3‐point change on the HFMSE. | |
| Change in muscle strength | Not measured | ||||||
| Acquiring the ability to stand or walk | Acquiring the ability to stand | 1/42 children in the sham‐controlled group acquired the ability to stand alone. | 1/84 children treated with nusinersen acquired the ability to stand alone. | RR 0.5 (0.03 to 7.80) | 126 | ⊕⊕⊝⊝ | |
| Acquiring the ability to walk | 0/42 children in the sham‐controlled group acquired the ability to walk with assistance. | 1/84 children treated with nusinersen acquired the ability to walk with assistance. | RR 1.5 (0.06 to 36.1) | 126 | ⊕⊕⊝⊝ | ||
| Change in quality of life | Not measured | ||||||
| Change in pulmonary function | Not measured | ||||||
| Time from beginning of treatment until death or full‐time ventilation | Not measured | ||||||
| Adverse events related to treatment | 1000 per 1000 | 900 per 1000 | RR 0.9 (0.9 to 1.0) | 126 | ⊕⊕⊕⊝ | 78/84 (93%) participants treated with nusinersen experienced an adverse event, while 42/42 (100%) participants treated in the sham‐controlled group had any adverse event. Adverse events were systematically, prospectively collected at every study visit. Adverse events included proteinuria, hyponatraemia, transient low platelet counts, vasculitis, pyrexia, headache, vomiting, back pain and epistaxis. | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HFMSE: Hammersmith Functional Motor Measure Expanded; MD: mean difference; MHFMS: Modified Hammersmith Functional Motor Scale; MMT: manual muscle testing; RCT: randomised controlled trial; RR: risk ratio; SMA: spinal muscular atrophy; WHO: World Health Organization. | |||||||
| GRADE Working Group grades of evidence | |||||||
| a Downgraded one level for imprecision because of the small sample size. | |||||||
| Oral olesoxime compared to placebo for non‐ambulatory children and adolescents with SMA types II and III | ||||||
| Patient or population: non‐ambulatory children and adolescents with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with oral olesoxime | |||||
| Change in disability score | The mean change in disability score was –1.82 | MD 2 higher | — | 160 | ⊕⊝⊝⊝ | Higher scores on the MFM indicate better function. Combined analysis of participants assessed with MFM‐32 or MFM‐20. |
| Change in disability score | The mean change in disability score was –1.45 | MD 2.04 higher | — | 160 | ⊕⊝⊝⊝ | Higher scores on the MFM indicate better function. Combined analysis of participants assessed with MFM‐32 or MFM‐20. |
| Change in disability score | Study population | RR 1.43 | 160 | ⊕⊝⊝⊝ | Higher scores on the MFM indicate better function. Participants were classified as 'responders' in case MFM‐32 or MFM‐20 showed no change or better scores compared to baseline, and 'non‐responders'. | |
| 39 per 100 | 55 per 100 | |||||
| Change in disability score | The mean change in disability score was –1.72 | MD 0.94 higher | — | 160 | ⊕⊕⊝⊝ | Higher scores on the HFMS indicate better function.a |
| Change in muscle strength | Not measured | |||||
| Acquiring the ability to stand or walk | Not measured | |||||
| Change in quality of life | — | MD 0.25 | — | 108 | ⊕⊕⊝⊝ | Higher scores on the PedsQL indicate a better quality of life. Scores on participants aged > 5 years. |
| Change in pulmonary function | The mean change in pulmonary function was +6.16 % predicted | MD 1.88 % predicted lower | — | 102 | ⊕⊕⊝⊝ | — |
| Time from beginning of treatment until death or full‐time ventilation | 2 participants died; 1 with cardiac arrest (olesoxime group) and 1 with increased bronchial secretions (placebo group). Deaths were not deemed to be related to treatment. | — | 160 | ⊕⊕⊕⊝ | — | |
| Adverse events related to treatment | 1000 per 1000 | 950 per 1000 | RR 0.95 (0.91 to 0.99) | 165 | ⊕⊕⊕⊝ | 612 events occurred in 57 participants in the placebo group. 1104 events occurred in 108 participants in the olesoxime group. Adverse events were systematically, prospectively collected at every study visit. Adverse events: (upper) respiratory tract infection, gastroenteritis, influenza, vomiting, abdominal pain, diarrhoea, cough, pyrexia, pain in extremity, scoliosis, arthralgia, fall, headache. |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; HFMS: Hammersmith Functional Motor Score; MD: mean difference; MFM: Motor Function Measure; MMT: manual muscle testing; PedsQL: Pediatric Quality of Life Inventory; RCT: randomised controlled trial; RR: risk ratio; SMA: spinal muscular atrophy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level for indirectness because trial authors combined two different outcome measures (MFM‐32 and MFM20) to assess the primary outcome with no correction in analysis. | ||||||
| Oral phenylbutyrate compared to placebo for children with SMA type II | |||||||
| Patient or population: children with SMA type II | |||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | ||
| Risk with placebo | Risk with oral phenylbutyrate | ||||||
| Change in disability score | The mean change in disability score was 0.73 | MD 0.13 lower | ‐ | 90 | ⊕⊕⊝⊝ | Higher scores on the HFMS indicate better function. | |
| Change in muscle strength | Leg megascore | The mean change in muscle strength (leg megascore) was 3.22 N | MD 1.04 N higher | — | 70 | ⊕⊕⊝⊝ | Children aged > 5 years had additional assessment of muscle strength by myometry. |
| Arm megascore | The mean change in muscle strength (arm megascore) was –0.42 N | MD 1.98 N higher | — | 72 | ⊕⊕⊝⊝ | Children aged > 5 years had additional assessment of muscle strength by myometry. | |
| Acquiring the ability to stand or walk | Not measured | ||||||
| Change in quality of life | Not measured | ||||||
| Change in pulmonary function | The mean change in pulmonary function was –0.01 % predicted | MD 0.04 % predicted higher | — | 67 | ⊕⊕⊝⊝ | Children aged > 5 years had additional assessment of FVC. | |
| Time from beginning of treatment until death or full‐time ventilation | No deaths were reported. No data available on ventilation. | — | 107 | ⊕⊕⊝⊝ | — | ||
| Adverse events related to treatment | 994 per 1000 | 292 per 1000 (118 to 740) | RR 3.1 (1.25 to 7.84) | 107 | ⊕⊕⊕⊝ | 5/53 participants had ≥ 1 adverse events in the phenylbutyrate and placebo group. 19/54 participants had ≥ 1 adverse events in the phenylbutyrate group. Adverse events were systematically and prospectively collected at every study visit. Adverse events included rash, drowsiness with hallucinations, nausea and constipation. No full report on types of adverse events was available. 3 participants discontinued the trial because of severe drowsiness, rash or constipation.b | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||||
| GRADE Working Group grades of evidence | |||||||
| a Downgraded one level because of risk of bias. | |||||||
| Subcutaneous somatotropin compared to placebo for children and adults with SMA types II and III | |||||||
| Patient or population: children and adults with SMA types II and III | |||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | ||
| Risk with placebo | Risk with subcutaneous somatotropin | ||||||
| Change in disability score | The median change in disability score was –1.05 | Median change 0.25 higher | — | 19 | ⊕⊝⊝⊝ | Higher scores on the HFMSE indicate better function. | |
| Change in muscle strength | Upper limbs | The mean change in muscle strength (upper limbs) was 0.30 N | MD 0.08 N lower | — | 19 | ⊕⊕⊝⊝ | — |
| Lower limbs | The mean change in muscle strength (lower limbs) was 0.95 N | MD 2.23 N higher | — | 19 | ⊕⊕⊝⊝ | — | |
| Acquiring the ability to stand or walk | Not measured | ||||||
| Change in quality of life Follow‐up: 40 weeks | The trial report states that the trial found no significant differences in quality of life between the somatotropin‐treated group and the placebo group. | — | 19 | ⊕⊝⊝⊝ | |||
| Change in pulmonary function | The mean change in pulmonary function was –0.11 L | MD 0.22 L higher | — | 19 | ⊕⊕⊝⊝ | — | |
| Time from beginning of treatment until death or full‐time ventilation | No participant died or required full‐time ventilation in either group | — | 19 | ⊕⊕⊝⊝ | — | ||
| Adverse events related to treatment | 368 per 1000 | 578 per 1000 (278 to 1000) | RR 1.57 | 19 | ⊕⊕⊝⊝ | 23 adverse events occurred, 14 during somatotropin treatment and 9 during placebo treatment. Adverse events were systematically, prospectively collected at every study visit. Adverse events included headache, arthralgia, myalgia, oedema, elevated serum thyroid‐stimulating hormone and myalgia. | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||||
| GRADE Working Group grades of evidence | |||||||
| a Downgraded two levels due to risk of bias. HFMSE ranges were not available and because of the potential carry‐over effect due to the cross‐over design. | |||||||
| Intravenous thyrotropin releasing hormone compared to placebo for children with SMA types II and III | ||||||
| Patient or population: children with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with intravenous TRH | |||||
| Change in disability score | Not measured | |||||
| Change in muscle strength | The mean change in muscle strength was 0.48 pounds | MD 0.34 pounds higher | — | 9 | ⊕⊝⊝⊝ | — |
| Acquiring the ability to stand or walk | Not measured | |||||
| Change in quality of life | Not measured | |||||
| Change in pulmonary function | Not measured | |||||
| Time to death or full‐time ventilation | Not measured but no deaths reported | — | 9 | ⊕⊕⊝⊝ Lowa,b | — | |
| Adverse events related to treatment | No events in 3 participants treated with placebo | 12 events in 6 participants treated with TRH | — | 9 | ⊕⊝⊝⊝ | Adverse events included abdominal discomfort, flushing, nausea and vomiting. |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; SMA: spinal muscular atrophy; TRH: thyrotropin‐releasing hormone. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level for sample size. | ||||||
| Oral valproic acid + acetyl‐L‐carnitine compared to placebo for non‐ambulatory children with SMA types II and III | ||||||
| Patient or population: non‐ambulatory children with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with oral valproic acid + acetyl‐L‐carnitine | |||||
| Change in disability score | The mean change in disability score was 0.18 | MD 0.64 higher | — | 61 | ⊕⊕⊕⊝ | Higher scores on the MHFMS indicate better function. |
| Change in muscle strength | The mean change in muscle strength was –0.25 kg | MD 1.43 kg higher | — | 16 | ⊕⊕⊝⊝ | Only performed in participants aged > 5 years. |
| Acquiring the ability to stand or walk | Not measured | |||||
| Change in quality of life | The mean change in quality of life was 0.3 | MD 2.2 lower | — | 54 | ⊕⊝⊝⊝ | Higher scores on the PedsQL indicate better quality of life. Only 54 participants completed PedsQL at follow‐up. Characteristics of this subset are unknown. |
| Change in pulmonary function | No numerical data available for analysis | — | 24 | ⊕⊕⊝⊝ | Only performed in participants aged > 5 years. | |
| Time from beginning of treatment until death or full‐time ventilation | 0 deaths or no need for full‐time ventilation | — | 61 | ⊕⊕⊕⊝ | — | |
| Adverse events related to treatment | 581 per 1000 | 755 per 1000 (534 to 1000) | RR 1.32 (0.92 to 1.89) | 61 | ⊕⊕⊕⊝ | 18/31 participants in the placebo group had ≥ 1 adverse events. 23/30 participants in the valproic acid + acetyl‐L‐carnitine group had ≥ 1 adverse events. Adverse events were systematically, prospectively collected at every study visit. |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; MD: mean difference; MHFMS: Modified Hammersmith Functional Motor Scale; PedsQL: Pediatric Quality of Life Inventory; RCT: randomised controlled trial; SMA: spinal muscular atrophy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded for imprecision because the small sample size. | ||||||
| Oral valproic acid compared to placebo for ambulatory adults with SMA type III | |||||||
| Patient or population: ambulatory adults with SMA type III | |||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | ||
| Risk with placebo | Risk with oral valproic acid | ||||||
| Change in disability score | The mean change in disability score was –0.35 | MD 0.06 higher | — | 31 | ⊕⊕⊝⊝ | Higher scores on the SMAFRS indicate better function. | |
| Change in muscle strength | Arms | The mean change in muscle strength of arms was –0.01 N | MD 0.23 N lower | — | 30 | ⊕⊕⊝⊝ | — |
| Legs | The mean change in muscle strength of legs was 0.35 N | MD 0.37 N lower | — | 30 | ⊕⊕⊝⊝ | — | |
| Acquiring the ability to stand or walk | Not measured | ||||||
| Change in quality of life | The mean change in quality of life was 0.91 | MD 1.1 lower | — | 28 | ⊕⊕⊝⊝ | Higher score on the mini‐SIP indicates a poorer health status. | |
| Change in pulmonary function | The mean change in pulmonary function was 0.53% predicted | MD 1.24% predicted lower | — | 24 | ⊕⊕⊕⊝ | — | |
| Time from beginning of treatment until death or full‐time ventilation | No deaths or full‐time ventilation | — | 33 | ⊕⊕⊕⊝ | — | ||
| Adverse events related to treatment | 455 per 1000 | 364 per 1000 (200 to 655) | RR 0.80 (0.44 to 1.44) | 33 | ⊕⊕⊝⊝ | 96 adverse events occurred, 66 in the placebo group and 30 in the valproic acid group. Adverse events were systematically, prospectively collected at every study visit and included upper airway tract infection or symptoms, dizziness, headache, peripheral neuropathy, tremor, fatigue, pain, abdominal pain, nausea, vomiting, decreased platelet count, weight gain and alopecia.a,b | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; MD: mean difference; mini‐SIP: mini‐Sickness Impact Profile; MVICT: maximum voluntary isometric contraction testing; RCT: randomised controlled trial; SMA: spinal muscular atrophy; SMAFRS: Spinal Muscular Atrophy Rating Scale; TRH: thyrotropin‐releasing hormone. | |||||||
| GRADE Working Group grades of evidence | |||||||
| a Downgraded one level because of potential carry‐over effect due to the cross‐over design. | |||||||
Background
Description of the condition
Spinal muscular atrophy (SMA) is a neuromuscular disorder of childhood and adolescence with an annual incidence of 1 in 6000 to 1 in 12,000 people (Arkblad 2009; Cobben 2001; Nicole 2002). It is caused by degeneration of anterior horn cells in the spinal cord and characterised by progressive muscle weakness (Iannaccone 2001; Talbot 1999). Other parts of the peripheral nervous system such as the neuromuscular junction (NMJ), and possibly muscles and other organs, may also be affected (Braun 1995; Cifuentes‐Diaz 2002; Kariya 2008; Murray 2008).
SMA is an autosomal‐recessive disease caused by the homozygous deletion of the SMN1 gene, which has been mapped to chromosome 5q11.2‐13.3 (Brzustowicz 1990; Gilliam 1990; Lefebvre 1995; Melki 1990a; Melki 1990b). The deleted gene results in survival motor neuron (SMN) protein deficiency. Chromosome 5q11.2‐13.3 contains the duplicated SMN1 and SMN2 genes (Iannaccone 1998; Nicole 2002). The SMN1 and SMN2 genes are almost identical, but a crucial C to T nucleotide difference in exon 7 results in the exclusion of exon 7 from most SMN2 messenger ribonucleic acid (mRNA) copies (Lefebvre 1995; Lorson 1999). The functional SMN1 gene, which is transcribed into full‐length mRNA that produces the bulk of stable SMN protein, is lacking in people with SMA. The SMN2 gene, which is 80% to 90% transcribed into a truncated form lacking exon 7, only produces residual levels of full‐length SMN mRNA and protein (Cartegni 2006; Lorson 1999). The clinical severity of the disease is related to the number of copies of the SMN2 gene (Feldkotter 2002; Harada 2002; Piepers 2008; Swoboda 2005; Wadman 2017).
The cellular functions of the SMN protein are multiple (Sumner 2007), including ribonucleoprotein (RNP) assembly (Burghes 2009; Gendron 1999; Jablonka 2000; Lefebvre 1998; Pellizzoni 1998), motor axon outgrowth and axonal transport (McWhorter 2003; Rossoll 2003), protection against superoxide dismutase 1 (SOD1) toxicity (Zou 2007), endocytosis (Hosseinibarkooie 2016; Riessland 2017), and ubiquitin homeostasis (Wishart 2014).
Muscle weakness in SMA occurs predominantly in the axial and proximal muscle groups, with the lower limbs more affected than the upper limbs (Kroksmark 2001; Thomas 1994). In more severe cases of SMA, intercostal muscles are also weakened, usually with relative sparing of the diaphragm. Survival depends primarily on respiratory function and not necessarily on motor ability (Dubowitz 1995; Russman 1992; Talbot 1999). There is often a fine tremor in the fingers (Iannaccone 1998). Although the face is often spared, tongue fasciculations and facial weakness are not unusual findings (Iannaccone 1993). Cognitive function of people with SMA is normal (Iannaccone 1998; Thomas 1994). Electrophysiological examination shows denervation and reinnervation (Iannaccone 1998; Nicole 2002; Swoboda 2005).
Classification of SMA according to the International SMA Collaboration distinguishes five types (0 to IV), which are based on age of onset and maximal acquired motor function (Finkel 2015; Mercuri 2012; Munsat 1992). SMA types 0, I and IV represent the two ends of the spectrum of SMA, which are outside the scope of this review.
SMA type II is also known as intermediate SMA, juvenile SMA and chronic SMA. The age of onset is between six and 18 months. Children with SMA type II develop the ability to sit independently but are never able to walk without support. They often develop severe pulmonary and orthopaedic complications (Bertini 2005). The children generally survive beyond two years of age and usually live into adolescence or longer (Russman 1996; Zerres 1995; Zerres 1997).
SMA type III is known as Kugelberg‐Welander disease, Wohlfart‐Kugelberg‐Welander disease and mild SMA. The age of onset is after 18 months. Children with SMA type III develop the ability to walk independently at some time, although many lose this ability later in life. Most people with SMA type III have a normal life expectancy (Russman 1992; Zerres 1995; Zerres 1997). SMA type III is often further divided into SMA type IIIa (disease onset before 36 months of age) and SMA type IIIb (disease onset after 36 months of age) (Zerres 1995).
Description of the intervention
Drug treatment to modify the course of SMA types II and III is urgently needed. Management of SMA until recently has consisted of preventing or treating complications of the condition (Iannaccone 1998; Russman 2003; Finkel 2018; Mercuri 2018). Administration of agents capable of increasing the expression of SMN protein levels may improve the outcome in SMA (Feldkotter 2002; Gavrilina 2008; Lorson 1999). Transcriptional SMN2 activation, facilitation or correction of SMN2 splicing, translational activation and stabilisation of the full‐length SMN protein are possible therapeutic strategies for SMA. Other strategies are improvement of motor neuron viability by neuroprotective or neurotrophic agents (Lunn 2008; Thurmond 2008; Wirth 2006a). Recently, trials with splice‐site‐modulators (Chiriboga 2016; EMBRACE 2015; Finkel 2016; Finkel 2017 (ENDEAR); Mercuri 2018 (CHERISH); NCT01703988; NCT02052791; NCT02122952; NCT02268552; SHINE 2015), ribonucleic acid (RNA)‐degradation inhibitors (Butchbach 2010; Gogliotti 2013; van Meerbeke 2013), and compounds that replace the SMN1 gene have started (Appendix 1).
Various drugs that might slow down or cure SMA have been tested in open and (un)controlled studies of people with SMA types II and III, including thyrotropin‐releasing hormone (TRH) (Takeuchi 1994; Tzeng 2000), gabapentin (Merlini 2003; Miller 2001), phenylbutyrate (Mercuri 2004; Mercuri 2007; NPTUNE01 2007; STOPSMA 2007), creatine (Wong 2007), valproic acid (Conceicao 2010; JPRN‐JapicCTI‐163450 2016; Kissel 2014; Kissel 2011; NCT01671384; Saito 2014; SMART01; SMART02; SMART03; Swoboda 2009; Swoboda 2010), hydroxyurea (Chang 2002; Chen 2010; Liang 2008; NCT00568802), somatropin (Kirschner 2014), carnitine (Kissel 2014; Merlini 2007; Swoboda 2010), salbutamol (Giovannetti 2016; Khirani 2017; Kinali 2002; Morandi 2013; Pane 2008; Pasanisi 2014; Prufer de Queiroz Campos Araujo 2010; Tan 2011), riluzole (Abbara 2011; ASIRI 2008; Russman 2003), lamotrigine (Nascimento 2010), celecoxib (NCT02876094), olesoxime (Bertini 2017), SMN1 gene therapy (Mendell 2016; NCT02122952; Sproule 2016), SMN2 antisense oligonucleotides (ASO) (Chiriboga 2016; Mercuri 2018 (CHERISH); NCT01703988; NCT02052791; SHINE 2015), small molecules (JEWELFISH 2017; MOONFISH 2014; NCT02644668; SUNFISH 2016), and NMJ‐interactors (EMOTAS 2014; NCT01645787; SPACE).
Below we describe the working mechanisms, preclinical studies in SMA models, and results of studies and trials of the various drugs tested in people with SMA type II and III.
It was not clear on clinical grounds whether the patient populations in studies on coenzyme Q10, lithium carbonate and guanidine hydrochloride had a genetically confirmed diagnosis of SMA, partially because SMN gene analysis was not possible prior to 1991 (Angelini 1980; Folkers 1995; Il'ina 1980). Therefore, we have not discussed the therapeutic effects of these drugs.
In vitro and animal studies have found several other compounds to have an effect on SMN expression, but they are as yet untested in people with SMA. Therefore, they are outside the scoop of this review. See Appendix 2 for a brief description of these compounds.
SMN1 gene therapies are outside the scope of this review. We have added some information in Appendix 1 for overall completeness.
Antisense oligonucleotides
ASOs or 'morpholinos', are synthetic strands of nucleic acid that are able to interfere with (stimulate or inhibit) mRNA products of the target DNA sequence. In this way, ASOs can modify potential splice sites and interfere with splicing (Porensky 2013). Multiple ASOs for the SMN2 gene have been developed and investigated (Bogdanik 2015; Keil 2014; Nizzardo 2014; Osman 2014; Shababi 2012; Skordis 2003; Staropoli 2015; Zhou 2013; Zhou 2015). The intronic splice silencer in intron 7 of SMN2 is called nusinersen (formerly known as SMN Rx 39443, IONIS SMN Rx or ISIS‐SMN Rx). This compound specifically targets the splice silencer in intron 7 and ensures the inclusion of SMN2 exon 7, which results in increased SMN2 full‐length mRNA and protein production (Hua 2010). Nusinersen has subsequently demonstrated improved performance and survival in SMA animal models (Hua 2011; Passini 2011). Nusinersen is an intrathecally injected therapy.
Carnitine
L‐carnitine, an essential cofactor for the beta‐oxidation of long‐chain fatty acids, inhibits mitochondrial injury and apoptosis both in vitro and in vivo (Bigini 2002; Bresolin 1984). Acetyl‐L‐carnitine, the acetylated derivative of L‐carnitine, shows neuroprotective and neurotrophic activity in motor neuron cultures (Bigini 2002). L‐carnitine treatment restored the level of free carnitine in one animal model of SMA (Bresolin 1984).
Celecoxib
Treatment with celecoxib increased SMN RNA and protein levels in vitro and in models of severe SMA mice by activating the p38 pathway (Farooq 2013), and might have a neuroprotective effect by inhibition of glutamate release (Bezzi 1998). Glutamate is released after presynaptic depolarisation and if not efficiently cleared, leads to increased levels of free radicals, and potentially to degeneration of motor neurons (Bryson 1996).
Creatine
Creatine might have therapeutic benefit by increasing muscle mass and strength through its role as an energy shuttle between mitochondria and working musculature, and is thought to exert neuroprotective effects (Bessman 1981; Ellis 2004; Tarnopolsky 1999).
Gabapentin
Gabapentin has a neuroprotective role by diminishing the excitotoxicity of glutamate (Greensmith 1995; Merlini 2003; Taylor 1998).
Hydroxyurea
Hydroxyurea is a histone deacetylase inhibitor. Studies have suggested a therapeutic role for these agents in SMA, as they appear to activate SMN2 transcription (Darras 2007; Kernochan 2005; Wirth 2006b). In vitro, hydroxyurea increases SMN2 gene expression and production of SMN protein in cultured lymphocytes of people with SMA (Grzeschik 2005; Liang 2008).
Lamotrigine
Lamotrigine is a glutamate inhibitor and might prevent motor neuron death (Casanovas 1996).
Olesoxime
The experimental drug olesoxime (TRO19622) is thought to modulate the mitochondrial permeability transition pore (mPTP) opening, which might influence cell apoptosis of, for example, motor neurons (Bordet 2007; Bordet 2010).
Phenylbutyrate
Phenylbutyrate is a histone deacetylase inhibitor. In fibroblast cultures and leukocytes of people with SMA, phenylbutyrate increased SMN transcript expression (Also‐Rallo 2011; Andreassi 2004; Brahe 2005).
Valproate
Valproate is another histone deacetylase inhibitor that increases SMN protein in vitro by increasing transcription of SMN2 gene (Kernochan 2005; Weihl 2006). It also has an antiglutamatergic effect (Kim 2007). Valproate has been tested in various models of SMA and showed positive results on SMN expression in vitro (Brichta 2003; Brichta 2006; Sumner 2003) and in vivo (Piepers 2011).
Salbutamol
Some studies have documented positive effects of oral beta2‐adrenoceptor agonists on human skeletal muscle (Caruso 1995; Kindermann 2007; Mack 2014; Martineau 1992). Trials investigating effects of oral beta2‐adrenoceptor agonists in people with NMJ disorders have demonstrated improvement of motor function (Burke 2013; Liewluck 2011; Lorenzoni 2013; Rodríguez Cruz 2015). Since abnormal development of the NMJ and dysfunction of neuromuscular synaptic transmission occur in SMA (Braun 1995; Kariya 2008; Kong 2009; Murray 2008; Wadman 2012a), beta2‐adrenoceptor agonists might have an positive effect on muscles and NMJs in SMA. In fibroblasts of people with SMA, salbutamol increases the levels of SMN2 full‐length mRNA and the SMN protein (Angelozzi 2008). In 12 people with SMA types II and III who received six months of treatment with oral salbutamol, leukocytes showed a significant and constant increase in SMN2 full‐length transcript levels (Tiziano 2010).
Small molecules
RO6885247/RG7800
The small molecule RO6885247/RG7800 selectively modulates SMN2 splicing towards the inclusion of exon 7 and thereby stimulates production of full‐length SMN2 mRNA. Administration of RO6885247/RG7800 improves and almost rescues motor function and survival of SMA mice (Naryshkin 2014).
RO7034067/RG7916
The small molecule RO7034067/RG7916 modulates SMN2 splicing, but exact details of its structure and pharmacology are not available. One phase I trial with RO7034067/RG7916 combined with itraconazole in healthy volunteers showed a dose‐dependent increase of SMN2 mRNA transcripts, but results were only reported in a conference abstract, with further publication of data pending (NCT02633709; Sturm 2016).
CK‐2127107
CK‐2127107/CK‐107 (2‐aminoalkyl‐5‐N‐heteroarylpyrimidine) is a small‐molecule fast skeletal troponin activator candidate that has been tested in conditions of muscle weakness, fatigue and heart failure (Hwee 2015). It might have a beneficial effect in SMA because of muscle protection, increased muscle strength in skeletal muscle, and delay of onset and extent of muscle fatigue (Andrews 2018). One report of a phase I study in healthy men reported that the drug was well tolerated and there were no serious adverse events (Rudnicki 2016).
Somatropin
Somatropin, also called growth hormone or somatomedin C, is a small polypeptic hormone produced in the pituitary gland. It interacts with growth hormone receptors primarily in the muscles and liver, in which it induces insulin‐like growth factor‐1 (IGF‐1). Because of its primary role in liver and muscle metabolism, IGF‐1 seems to play an important role during muscle development and induces muscle regeneration after injury and denervation (Duan 2010). IGF‐1 stimulates myoblast and motor neuron proliferation, induces myogenic differentiation and generates myocyte hypertrophy in vitro and in vivo (Bosch‐Marcé 2011; Murdocca 2012). In vitro studies of motor neuron tissue cultures of rat spinal cord showed that IGF‐1 was one of the neuroprotective hormones that enhanced the survival of motor neurons and reduced their susceptibility to glutamate‐induced neurotoxicity (Corse 1999). One study showed that intracerebroventricular injections of IGF‐1 next to a SMN trans‐splicing RNA vector had a positive effect on disease severity and prolonged survival of severe SMA mice (Shababi 2011). One study showed that overexpression of IGF‐1 increased muscle mass, and that administration of a combination of IGF‐1 and trichostatin‐A improved survival and motor function in SMA mice (Bosch‐Marcé 2011). Biondi 2015 showed that underexpression of IGF‐1 receptors alone improved the motor function and the life span of SMA mice. Two studies investigated intracerebral injection of AVV‐IGF‐1 in SMA mice and showed variable results, with slightly improved motor function and survival due to prevention of muscle atrophy and preservation of NMJs (Tsai 2012; Tsai 2014).
Thyrotropin‐releasing hormone
The precise mechanism of action of TRH, a tripeptide produced by the hypothalamus, is unknown. It may have a neurotrophic effect on spinal motor neurons (Takeuchi 1994).
Riluzole
Riluzole is thought to have a neuroprotective effect on motor neurons by blocking the presynaptic release of glutamate. In a mouse model of SMA, riluzole attenuated disease progression (Haddad 2003).
Other neurotrophic factors
Other neurotrophic factors have been considered as potential therapies for motor neuron diseases (Apfel 2001). In a mouse model of SMA, cardiotrophin‐1 seemed effective in slowing down disease progression (Lesbordes 2003).
Neuromuscular junction interactors
Studies in SMN‐deficient mouse models of SMA have uncovered significant abnormalities in the morphology of the NMJ in SMA, in addition to the well‐known motor neuron degeneration (Braun 1995; Kariya 2008; Kong 2009; Murray 2008). Additionally, there was abnormal aggregation of acetylcholine receptors at the muscle endplates in people with SMA type I (Arnold 2004). Electrophysiological studies in people with SMA have shown neurophysiological alterations of the NMJ, which may correspond with the symptoms of fatigability (Dunaway 2014; Montes 2013; Wadman 2012a). Drugs such as pyridostigmine and neostigmine, which have an inhibitory effect on acetylcholinesterase, might directly interact with the NMJ and could improve its function. Other potential NMJ interactors are 3‐4 diaminopyridine (3‐4 DAP) and 4‐aminopyridine (4‐AP), which are potassium channel blockers that are presumed to prolong repolarisation and to facilitate the generation of the action potential at the NMJ.
Why it is important to do this review
There has been no treatment to slow progression or cure SMA types II or III (Bosboom 2009; Wadman 2012b).
Many studies have explored the effects of various drugs in SMA animal models or in people with SMA. Currently, several drugs and compounds tested in uncontrolled, unblinded and non‐randomised settings have shown possible positive effects on the course of SMA through neuroprotection (e.g. cardiotrophin‐1, creatine, gabapentin, lamotrigine and riluzole), induction of SMN2 activity (histone deacetylase inhibitors, e.g. valproic acid, phenylbutyrate and hydroxyurea), improvement of NMJ transmission (e.g. pyridostigmine), modification of SMN2 RNA (ASOs or small molecules, e.g. nusinersen), genetic restoration of the SMN1 gene using viral vectors, improvement of muscle metabolism and strength (e.g. creatine), and other (unknown) mechanisms (e.g. somatotropin, salbutamol, TRH). Overall, these studies provide conflicting evidence about the effects of these compounds on muscle strength, motor function and survival in SMA.
The number of studies and trials for drug treatment in SMA has expanded rapidly, which has created a need for a clear, thorough and systematic review of these trials and their results. We used Cochrane Systematic Review methods (Higgins 2011), and the GRADE approach (Atkins 2004), to review all randomised studies and trials on drug treatment in people with SMA types ii and III to analyse the effect of drug treatments on disability, muscle strength, ability to stand or walk, quality of life, time to death or full‐time ventilation and adverse events.
This is an update of a review first published in 2009 and first updated in 2012 (Bosboom 2009; Wadman 2012b). Drug treatment for SMA type I is the subject of a separate Cochrane Review (Wadman 2019).
Objectives
To evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely.
Methods
Criteria for considering studies for this review
Types of studies
All randomised or quasi‐randomised (alternate or other systematic treatment allocation) studies examining the effect of drug treatment designed to slow or arrest disease progression in children or adults with SMA types II and III. Placebo‐controlled cross‐over studies were also considered to be eligible for inclusion.
Types of participants
Children or adults with SMA types II and III fulfilling the criteria outlined in Table 1.
| Primary criteria |
| SMA type II: age of onset between 6 and 18 months and have been able to sit independently, but never been able to walk without assistance. SMA type III: age of onset after 18 months and has/had the ability to walk without assistance. |
| Genetic analysis to confirm the diagnosis, with deletion or mutation of the SMN1 gene (5q11.2‐13.3) |
| Supporting criteria |
| Symmetrical muscle weakness of limb and trunk. |
| Proximal muscles more affected than distal muscles and lower limbs more than upper limbs. |
| No abnormality of sensory function. |
| Serum creatine kinase activity ≤ 5 times the upper limit of normal |
| Denervation on electrophysiological examination, and no nerve conduction velocities < 70% of the lower limit of normal. No abnormal sensory nerve action potentials. |
| Muscle biopsy showing atrophic fibres of both types, hypertrophic fibres of one type (usually type I), and in chronic cases type grouping. |
| No involvement of the central neurological systems, such as hearing or vision. |
Types of interventions
Any drug treatment, alone or in combination, designed to slow or arrest the progress of the disease compared to placebo (or sham) treatment, with no restrictions on the route of administration.
Types of outcome measures
We assessed outcome measures within or up to one year after the onset of treatment and compared to baseline. This is a list of the outcomes of interest within whichever studies are included in the review; we did not use outcomes as criteria for including studies.
Primary outcomes
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Change in disability score (e.g. Gross Motor Function Measure (GMFM), Hammersmith Functional Motor Score (HFMS), Motor Function Measure (MFM) and SMA Functional Rating Scale (SMAFRS)) as determined by the original study authors.
Secondary outcomes
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Change in muscle strength (e.g. dynamometry, isometric strength testing, manual muscle testing (MMT) or Medical Research Council (MRC) score).
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Acquiring the ability to stand within one year after the onset of treatment.
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Acquiring the ability to walk or improvement of walking within one year after the onset of treatment.
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Change in quality of life as determined by quality of life scales.
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Change in pulmonary function (forced vital capacity (FVC) as a percentage of FVC predicted for height). This was not stated in the original protocol, but many trials included a measure of pulmonary function or the strength of respiratory muscles.
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Time from beginning of treatment until death or full‐time ventilation (a requirement for 16 hours of ventilation out of 24 hours regardless of whether this was with tracheostomy, a tube or mask).
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Adverse events attributable to treatment during the whole study period, separated into severe (requiring or lengthening hospitalisation, life threatening or fatal) and others.
Search methods for identification of studies
Electronic searches
We searched the following databases on 22 October 2018.
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Cochrane Neuromuscular Specialised Register (in the Cochrane Register of Studies (CRS); Appendix 3).
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Cochrane Central Register of Studies (CENTRAL) (in the Cochrane Register of Studies Online (CRSO); Appendix 4).
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MEDLINE (1991 to October week 43 2018; Appendix 5).
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Embase (1991 to October week 43 2018; Appendix 6).
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ISI Web of Science Conference Proceedings Citation Index (1991 to October 2018; Appendix 7).
We consulted the following registries on 22 October 2018 to identify additional trials that had not yet been published.
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clinical trials registry of the US National Institute of Health (www.clinicaltrials.gov; Appendix 8).
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the WHO international Clinical trials Registry (www.who.int/ictrp/en/; Appendix 9).
Searches were performed from 1991 onwards because at that time genetic analysis of the SMN1 gene became widely available and could be used to establish the diagnosis of SMA.
Searching other resources
We handsearched the reference lists of relevant cited studies, reviews, meta‐analyses, textbooks and conference proceedings to identify additional studies. We invite readers to suggest studies, particularly in other languages, that should be considered for inclusion.
Data collection and analysis
Selection of studies
For this updated review, two review authors (RW and AV) independently checked titles and abstracts obtained from literature searches to identify potentially relevant trials for full review.
We identified and excluded duplicates and collated multiple reports of the same study so that each study rather than each report was the unit of interest in the review.
From the full texts, two review authors (RW and AV) independently selected trials for inclusion that met the selection criteria. The review authors were not blinded to the trial author and source institution. The review authors resolved disagreement by reaching consensus. We presented an adapted PRISMA flowchart of study selection (Figure 1), and recorded details of excluded studies in the Characteristics of excluded studies table.
Study flow diagram.
Data extraction and management
Two review authors (RW and AV) independently extracted data using a specially designed data extraction form. We extracted study characteristics from included studies on study design and setting, characteristics of participants (SMA type and age), eligibility criteria, intervention details, the outcomes assessed, source(s) of study funding and any conflicts of interest among investigators and recorded them in the Characteristics of included studies table.
We obtained missing data from the trial authors or pharmaceutical company whenever possible.
Disagreement did not occur, but we would have resolved differences by reaching consensus or with third party adjudication, if necessary.
Assessment of risk of bias in included studies
The 'Risk of bias' assessment took into account allocation concealment, security of randomisation, participant blinding (parent blinding), blinding of outcome assessors, incomplete outcome data (including use of intention‐to‐treat (ITT) analysis), selective reporting and 'other bias'. We scored each 'Risk of bias' item according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), as 'low', 'high' or 'unclear'.
Statistical considerations involved a trade‐off between bias and precision. We assessed the risk of bias as 'unclear' when too few details were available to make a judgement of 'high' or 'low' risk, when the risk of bias was genuinely unknown despite sufficient information about the conduct of the study, or when an entry was not relevant to a study. All studies were described by a precise risk of bias.
Two review authors (RW and AV) independently graded the risk of bias in included studies. In the event of disagreement, the review authors reassessed studies and reached agreement by consensus.
Measures of treatment effect
We initially intended to analyse continuous outcomes using mean differences (MDs) with 95% confidence intervals (CIs) in the outcome measures with standard deviation (SD) to quantify the effects of the drug treatment (such as change in disability scores, MRC muscle strength, quality of life) and dichotomous outcomes using a risk ratio (RR) with 95% CIs (such as ability to stand or walk and adverse events). We reported median
For survival or time to full‐time ventilation, we would have reported results from Kaplan‐Meier survival analyses if data been presented in this way.
Unit of analysis issues
We took into account the level at which randomisation occurred in cross‐over trials. We did not anticipate finding cluster‐randomised trials and did not anticipate that multiple observations for the same outcome would occur in the included studies.
Where multiple trial arms were reported in a single trial, we would have included only the treatment arms relevant to the review topic. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) were combined in the same meta‐analysis, we would have followed the guidance in Section 16.5.4 of the Cochrane Handbook for Systematic Reviews of Interventions to avoid double‐counting (Higgins 2011). Our preferred approach would have been to perform a multiple‐treatments meta‐analysis using the indirect comparison method. In case of such analysis in the next update of this review, we will have expert statistical support, as well as subject expertise to analyse the data.
Cross‐over trials
If neither carry‐over nor period effects were present in cross‐over trials and individual participant data or the mean and SD (or standard error) of the participant‐specific differences between experimental intervention and control intervention measurements were available, we would have analysed continuous data using a paired t‐test in the two‐period, two‐intervention setting. The effect estimate would have been included in any meta‐analysis using the generic inverse variance function in Review Manager 5 (Review Manager 2014). In the absence of data for such an analysis, we would have analysed the treatment and placebo group as if they were parallel groups with the risk of a unit‐of‐analysis error. In the event of potential carry‐over or period effects, we would have analysed data from only the first period.
Dealing with missing data
We carefully evaluated important numerical data, such as the number of screened, randomised participants as well as ITT, as‐treated and per protocol populations. We investigated attrition rates (i.e. dropouts, losses to follow‐up and withdrawals), and critically appraised issues of missing data and imputation methods (e.g. last observation carried forward (LOCF)). In case of missing outcome data, we would have performed an ITT analysis. If SDs for outcomes were not reported, we would have imputed these values by assuming the SD of the missing outcome to be the mean of the SDs from studies where this information was reported (Higgins 2011).
Where there were missing data, we contacted the trial investigators, who provided additional data (Kirschner 2014; Kissel 2014; Miller 2001; Wong 2007).
Assessment of heterogeneity
In the event of substantial clinical, methodological or statistical heterogeneity, we would not have reported study results as the pooled effect estimate in a meta‐analysis. We would have identified heterogeneity by visual inspection of the forest plots and by using a standard Chi² test with a significance level of alpha = 0.1, in view of the low power of this test.
We would have examined heterogeneity using the I² statistic, which quantifies inconsistency across studies, to assess the impact of heterogeneity on the meta‐analysis.
We would have used the approximate guide to interpretation of the I² statistic as outlined in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions, as follows:
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0% to 40%: might not be important;
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30% to 60%: may represent moderate heterogeneity;
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50% to 90%: may represent substantial heterogeneity;
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75% to 100%: considerable heterogeneity.
Assessment of reporting biases
We reviewed and included studies from trial registries to assess the magnitude of publication bias (Appendix 8; Appendix 9). If trials were completed but not yet published, we tried to retrieve results by contacting the principal investigators of the trials.
Data synthesis
We would only have pooled results of studies with the same class of drug treatment.
We would have calculated MDs or RRs with corresponding 95% CI for the pooled data if studies were sufficiently comparable. For continuous outcomes measured using different but comparable scales, we would have calculated standardised mean differences (SMD) and 95% CI, taking care to ensure a consistent direction of effect. If data were not sufficiently comparable between studies, we would have used the standard Review Manager 5 generic inverse variance (GIV) analysis using treatment effect differences with their standard errors.
The review authors estimated differences in medians and CI for the median from participant‐level data from Miller 2001 and Wong 2007 using a Hodges‐Lehmann estimator.
We would have pooled survival data using the GIV approach. If studies to be pooled had different follow‐up periods, we would have used appropriate adjustments, if necessary Poisson regression allowing for the aggregate person‐time‐at‐risk in the study groups.
When Chi² analysis showed the data to be heterogeneous, we would have used a random‐effects model with a maximum likelihood estimation, carrying out a sensitivity analysis with a fixed‐effect model (Mantel‐Haenszel RR method). Formal comparisons of intervention effects according to risk of bias would have been done using meta‐regression. The major approach to incorporating 'Risk of bias' assessments would have been to incorporate and restrict meta‐analyses to studies at low (or lower) risk of bias.
'Summary of findings' tables
We created 'Summary of findings' tables using the following outcomes depending on the outcomes used in the included studies:
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change in disability score (e.g. GMFM, HFMS and MFM);
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change in muscle strength (e.g. dynamometry, isometric strength testing, MMT or MRC;
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acquiring the ability to stand or walk within one year after the onset of treatment;
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change in quality of life as determined by quality of life scales;
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change in pulmonary function (FVC; reported preferably as a percentage of FVC predicted for height or age (or both) or alternatively as total volume in litres);
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time from beginning of treatment until death or full‐time ventilation;
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adverse events (reported preferably as number of adverse events or alternatively as number of people with adverse events).
We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of a body of evidence (studies that contributed data for the prespecified outcomes). We used methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro GDT software (gradepro.org). We justified all decisions to down‐ or upgrade the certainty of studies using footnotes and made comments to aid reader's understanding of the review where necessary. Although studies might be graded as high risk in any of the GRADE domains, we would not have excluded the particular study.
Subgroup analysis and investigation of heterogeneity
We would have attempted to determine potential reasons for heterogeneity by examining individual study and subgroup characteristics.
We would have performed subgroup analyses as follows to explore the influence of the following factors (if applicable) on effect sizes:
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SMA type (II versus III);
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SMN2 copy number.
Subgroup analysis based on SMA type and SMN2 copy number is needed, since the subgroups contain a different disease course with potential, significant different effects from or interaction with the intervention.
We would have compared subgroups using the formal tests for subgroup differences in Review Manager 5 (Review Manager 2014).
Sensitivity analysis
We would have performed sensitivity analyses as follows to explore the influence of the following factors (if applicable) on effect sizes. We would have restricted the analysis:
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by taking into account risk of bias;
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to outlier studies (very long, very large, very short or very small) to establish the extent to which they dominated the results.
We would also have tested the robustness of the results by repeating the analysis using different measures of effect size (RR, odds ratios, etc.) and different statistical models (fixed‐effect and random‐effects models).
Non‐randomised evidence
We did not include non‐randomised studies in our review. In the Discussion section, we reviewed the results from open and uncontrolled studies.
Results
Description of studies
Results of the search
For this updated review, the numbers of new references found by the searches were: Cochrane Neuromuscular Specialised Register 67 (37 new), CENTRAL 173 (90 new), MEDLINE 676 (351 new), Embase 196 (123 new) and ISI Web of Knowledge 402 (277 new).
Studies with no published data yet, were named by their acronym, or after their trial register code (www.clinicaltrial.gov).
See Figure 1 for a flow diagram of the study selection process.
Included studies
Ten trials fulfilled the selection criteria and remained for inclusion (see Included studies). There were two studies with the same class of drug treatment (valproic acid) (Kissel 2014; Swoboda 2010), but one of these trials used L‐carnitine as add‐on medication (Swoboda 2010). Two studies only included people with SMA type II (Mercuri 2007; Mercuri 2018 (CHERISH)), one study only included ambulatory people with SMA type III (Kissel 2014), and one study included only non‐ambulatory children and adolescents with SMA types II and IIIa (Bertini 2017). Six studies did not make a distinction between the SMA subtypes for inclusion (Chen 2010; Kirschner 2014; Miller 2001; Swoboda 2010; Tzeng 2000; Wong 2007).
Oral creatine versus placebo
Wong 2007 was a double‐blind randomised placebo‐controlled trial that compared oral creatine with placebo in 55 participants divided into two age groups. Of the 22 participants aged two to five years, 10 received creatine 2 g once a day and 12 received placebo. Of the 33 participants aged five to 18 years, 17 received creatine 5 g once a day and 16 received placebo. Duration of treatment was six months with follow‐up at nine months.
Muscle strength for knee extension, knee flexion and elbow flexion were measured bilaterally with the Richmond Quantitative Measurement System. Hand grip strength was measured bilaterally with handheld dynamometry. The best scores were added to obtain a total, upper body and lower body quantitative muscle testing (QMT) score.
Treatment efficacy for each age group was evaluated by ITT analysis of continuous endpoints using analysis of covariance (ANCOVA), which included the qualifying screening measure as the baseline covariate, treatment group as between‐subject effect, time as within‐subject effect and a subject by time interaction.
The primary endpoint was the change in GMFM from baseline. Secondary endpoints were the changes in muscle strength and pulmonary function tests (e.g. FVC) from baseline in children five to 18 years of age, and change in quality of life (assessed by a neuromuscular module of the parent questionnaire for the Pediatric Quality of Life Inventory (PedsQL)) from baseline. Adverse events were routinely assessed at each visit.
Oral gabapentin versus placebo
Miller 2001 was a double‐blind, randomised, placebo‐controlled trial that compared oral gabapentin 1200 mg three times a day with placebo in 84 participants at least 21 years old. Duration of treatment was 12 months with follow‐up at quarterly intervals while on the treatment.
Muscle strength was measured bilaterally by maximum voluntary isometric contraction (MVIC) of elbow flexion and hand grip. Linear regression analysis was used to determine the change in muscle strength, FVC, SMAFRS and a combined measure of the functional capacity of the lower limbs and quality of life (mini‐Sickness Impact Profile: mini‐SIP) over time.
Treatment efficacy was determined by comparing the mean percentage change for the treatment and placebo groups in the ITT population (defined as participants with at least two study visits: 37 participants in the treatment group and 39 participants in the placebo group) using the Mann‐Whitney test.
The primary endpoint was mean percentage change in muscle strength from baseline. Secondary endpoints were the mean percentage change of FVC, SMAFRS and mini‐SIP from baseline, and the occurrence of adverse events. Adverse events were systematically assessed at each visit.
Oral hydroxyurea versus placebo
A phase II/III double‐blind randomised placebo‐controlled trial compared oral hydroxyurea with placebo in 57 participants with SMA types II and III aged above five years (Chen 2010). Participants received an escalated daily dose over four weeks to a final daily dose of 20 mg/kg/day hydroxyurea or placebo. For the first four weeks, participants received 10 mg/kg/day and for the second four weeks the dose was escalated to 15 mg/kg/day. Duration of treatment was 18 months. Follow‐up of post‐treatment effects was at six months.
The safety and tolerability of hydroxyurea were measured through serum level measurement. Muscle strength and motor function were measured with the MMT and the GMFM. The GMFM and MMT were performed in all 57 participants. The Modified Hammersmith Functional Motor Scale (MHFMS) was performed in 28 participants with SMA type II and 10 participants with SMA type III who were already non‐ambulatory at the beginning of the trial. Lung function was evaluated by FVC measurements. In all participants, quantitative full‐length SMN mRNA was measured. Adverse events and serious adverse events were monitored at each assessment by a full blood count, chemistry profiles of liver and renal function, and completion of a questionnaire.
Treatment efficacy was evaluated by ITT analysis with a LOCF approach. Changes in GMFM, MHFMS, MMT, FVC and serum full‐length SMN mRNA were analysed by ANCOVA. Measures at time points of the treatment period and the post‐treatment period for primary and secondary endpoints were compared by mixed models with adjusted covariates. A two‐tailed t‐test was used to compare the incidence of adverse events and serious adverse events during the treatment phase.
The primary endpoints were GMFM, MMT and serum full‐length SMN mRNA level. Secondary endpoints were the MHFMS and FVC. Adverse events were systematically assessed by a questionnaire at each visit.
Intrathecal nusinersen versus sham procedure
Mercuri 2018 (CHERISH) was a phase III double‐blind randomised, sham‐procedure controlled study that compared intrathecally injected nusinersen with a sham procedure in 126 participants with SMA type II, aged two to 12 years. Inclusion criteria included a minimal score of 10 and maximum score of 54 on the HMFSE. Participants were randomised 2:1 (nusinersen: sham‐procedure) to receive intrathecally injected nusinersen or the sham‐procedure. Participants received their treatment or sham‐procedure at days one, 29, 85 and 274.
Participants in the treatment group received nusinersen 12 mg intrathecally. The sham‐procedure consisted of a small needle prick on the lower back at the location where the lumbar puncture (LP) injection is normally made. The needle would break the skin but no LP injection or needle insertion occurred. The needle prick was covered with the same bandage that was used to cover the LP injection in the treatment group. Treatment period was planned to be 15 months, but was stopped after interim analysis showing beneficiary effects of nusinersen compared to the sham procedure.
Motor abilities were assessed by HFMSE and Upper Limb Module Test (ULMT). Motor milestone development was monitored, including standing and walking with or without support. Assessment of vital signs, weight changes and neurological examination were included. Adverse events and serious adverse events were monitored using laboratory parameters, urine analysis and electrocardiogram.
The interim analysis on treatment efficacy was done by ITT analysis with a LOCF approach and multiple‐imputation method to account for missing data. Interim analysis was performed when all the children had been enrolled for at least six months and at least 39 children had completed their 15‐month assessment. In the final analysis, the least squares mean changes in the total HFMSE score, the number of World Health Organization motor milestones achieved per child, and the Revised Upper Limb Module (RULM) score and least‐squares MDs in change between groups were based on an ANCOVA, with group assignment as a fixed effect and with adjustment for each child's age at screening and the value at baseline. The primary endpoint was change from baseline between treatment groups in the HFMSE. Secondary outcome measures were dichotomised analysis of the HFMSE scores (responder analysis of a 3‐point change in HFMSE), change from baseline in ULMT, milestone development and adverse events. Adverse events were systematically assessed at each visit.
Oral olesoxime versus placebo
Bertini and colleagues performed a double‐blind, randomised, placebo‐controlled trial compared oral olesoxime with placebo in 165 non‐ambulatory participants with SMA types II and IIIa aged three to 25 years (Bertini 2017). Participants were randomised 2:1 (olesoxime:placebo) to receive oral liquid suspension of olesoxime 10 mg/kg once daily or oral liquid suspension of placebo. Treatment period was 24 months.
Participants started with a screening and baseline visit. Follow‐up visits were scheduled four and 13 weeks after baseline, with follow‐up every 13 weeks during the treatment period of 24 months.
Motor abilities were assessed by MFM at weeks 26, 52, 78 and 104, and the HMFS at weeks 13, 39, 65, 91 and 104. Children younger aged younger than six years (n = 48) were assessed with the adapted version of the MFM‐32, the MFM‐20, where participants older than six years (n = 112) were tested with the MFM‐32. Electromyography, including compound muscle action potential (CMAP) and motor unit number estimation (MUNE) assessments of ulnar and hypothenar nerves, were performed at weeks 26, 52, 78 and 104. FVC was tested at weeks 13, 26, 39, 52, 78 and 104. The PedsQL was tested every visit. Clinical examination and electrocardiogram were performed every visit as well. Safety laboratory studies were performed at baseline and every consecutive visit. Serum levels of olesoxime were reviewed at weeks four, 13 and 52.
Data analysis was done with ITT analyses using mixed‐effects repeated measure model. An interim analysis was performed at 12 months with predefined criteria to assess whether the trial should be continued or terminated.
The primary endpoint was the change from baseline between treatment groups in MFM, parts D1+D2. Secondary outcome measures were responder analyses of change from baseline in total MFM scores and individual MFM domains and change from baseline in HFMS, CMAP amplitude, MUNE, Clinical Global Impression, FVC and PedsQL. Adverse events were systematically assessed at each visit.
Oral phenylbutyrate versus placebo
Mercuri 2007 was a phase II, double‐blind, randomised, placebo‐controlled trial that compared oral phenylbutyrate 500 mg/kg/day, divided into five doses and using an intermittent schedule (seven days on treatment, seven days off treatment), with placebo in 107 participants with SMA type II. Duration of treatment was 13 weeks with follow‐up at the end of the study period (also at 13 weeks).
Motor function was assessed in all participants. In addition, muscle strength and FVC were assessed in children older than five years. Muscle strength was measured by handheld dynamometry of elbow flexion, hand grip, 3‐point pinch, knee flexion and knee extension; the best scores were added to obtain an arm megascore and a leg megascore.
Treatment efficacy was evaluated by ITT analysis in 90 participants (45 in the treatment group and 45 in the placebo group) with continuous endpoints at five and 13 weeks' follow‐up using ANCOVA which included the baseline outcome values as covariates, treatment group and age as between‐patient factors, time as a within‐patient factor, and possible interaction between treatment group, time and age.
The primary endpoint was the change in HFMS from baseline. Secondary endpoints were the change in muscle strength and FVC from baseline and the occurrence of adverse events. Adverse events were systematically assessed at each visit by means of a questionnaire.
Subcutaneous somatotropin versus placebo
A double‐blind, randomised, placebo‐controlled, cross‐over pilot trial compared subcutaneous injections of somatropin with subcutaneous injections of placebo in 20 participants with SMA types II and III aged between six and 36 years old (Kirschner 2014). Participants were randomised to two cohorts, in which one started with treatment for 12 weeks and crossed over to placebo for 12 weeks after a washout period of eight weeks, while the other cohort started with placebo for 12 weeks and crossed over to treatment for 12 weeks after a washout period of eight weeks. During the 12‐week period, participants received either somatotropin 0.015 mg/kg/day subcutaneously in the first week which was increased after one week up to 0.03 mg/kg/day for weeks two to 12 or placebo at the same dose regimen. Duration of the trial was 40 weeks. Follow‐up after the last treatment was eight weeks.
Muscle strength was measured with MVIC using hand‐held myometry and MRC scale in elbow flexion, handgrip, knee flexion and knee extension at baseline and weeks four, 12, 20, 24 and 32. Motor function was evaluated with the HFMSE, 10‐metre walking time and Gowers' time at baseline and weeks four, 12, 20, 24 and 32. Pulmonary functioning test were assessed with FVC and peak cough flow at baseline and weeks 12, 20 and 32. Laboratory studies included IGF‐1 serum concentrations and endocrinological measurements at baseline and weeks four, 12, 20, 24, 32 and 40.
Data analysis was done with a modified ITT concept using t‐test and Wilcoxon test.
The primary endpoint was change in quantitative muscle strength of upper limb using hand‐held myometry in elbow flexion and handgrip. Secondary outcomes measures were change in quantitative muscle strength of lower limb, muscle strength with MMT in seven muscles, change in HFMSE, change in Gowers' time, change in qualitative Gowers' manoeuvre, change in FVC and peak cough flow, and adverse events. Adverse events were systematically assessed at each visit.
Intravenous thyrotropin‐releasing hormone versus placebo
Tzeng 2000 was a double‐blind, randomised, placebo‐controlled trial that compared intravenous TRH 0.1 mg/kg once a day with placebo. Six participants were treated with TRH and three received placebo. The duration of treatment was 29 days over a 34‐day period with follow‐up and conclusion of the study at five weeks.
Muscle strength was evaluated by dynamometry of the deltoids, biceps, triceps, wrist extensors, hand grip, hip flexors, quadriceps and hamstrings.
Comparisons of total mean muscle strength and electrodiagnostic measures at baseline and at the end of the five‐week study period were made using paired t‐tests.
The primary endpoint was the change in total mean muscle strength from baseline. Secondary endpoints were change in electrodiagnostic measures and the occurrence of adverse events related to the treatment. Adverse events were collected when spontaneous reported by the participants.
Oral valproic acid (valproate) plus acetyl‐L‐carnitine versus placebo
One double‐blind, placebo‐controlled trial compared combination therapy with oral valproic acid and acetyl‐L‐carnitine to placebo in 61 non‐ambulatory children aged between two and eight years (Swoboda 2010). Thirty‐one children received treatment with valproic acid 125 mg, given in divided doses two to three times a day and sufficient to maintain overnight trough levels of 100 mg/dL, and acetyl‐L‐carnitine doses at 50 mg/kg/day divided into two daily doses. Thirty children received a double placebo. The duration of treatment was 12 months in the active treatment arm and six months in the placebo. After six months the placebo group switched over to active treatment per protocol.
In all participants, the MHFMS and GMFM were used to measure functional motor ability at baseline, three, six and 12 months after the start of treatment. The degree of innervation by the ulnar nerve was estimated using maximum ulnar CMAP amplitude. Myometry measurements were performed in children aged five years and older (24 children) with no significant contractures: three times for right and left elbow flexion and for right and left knee extension. Also in the children aged five years and older, pulmonary function testing was performed, which included FVC, forced expiratory volume (FEV), and maximum inspiratory and expiratory pressures (MIP and MEP). Quality of life was assessed using the PedsQL, filled in by parents at each visit. Children aged five years or older completed the age‐appropriate PedsQL. Bone mineral density and bone mineral content were measured with dual‐energy X‐ray absorptiometry (DEXA).
All analyses were performed on an ITT population of 61 people that was defined as all participants randomised to receive study medication. The analysis of variance (ANOVA) test was used to compare treatment groups for change in MHFMS from the baseline data. Non‐normally distributed data were tested with the Wilcoxon rank sum test.
The primary endpoints were laboratory safety data, adverse event data and change in MHFMS from baseline after six months. Secondary endpoints included measurement from baseline at six and 12 months in MHFMS, estimates of CMAPs, DEXA, body composition and bone density, quantitative SMN mRNA and quality of life. Adverse events were systematically assessed at each visit.
Oral valproic acid (valproate) versus placebo
Kissel 2014, a double‐blind, placebo‐controlled, cross‐over trial, compared oral valproic acid with placebo in 33 ambulatory participants with SMA type III aged above 18 years old. Participants were divided over two cohorts. Cohort one (16 participants) was first treated with oral valproic acid 10 mg/kg/day to 20 mg/kg/day divided over two or three doses (doses depending on serum levels of valproic acid with preferred levels of 50 mg/dL) for six months, after this period this cohort switched to equal dosage of oral placebo for six months. Cohort two (17 participants) started with six months' treatment with placebo and afterwards crossed over to oral valproic acid 10 mg/kg/day to 20 mg/kg/day divided over two to three doses (doses depending on serum levels of valproic acid with preferred levels of 50 mg/dL) for six months. Total duration of the trial was 12 months.
Participants started with two baseline visits within a six‐week period to assure that the methodologies were reliable and to assure test–retest stability. Clinical assessments were done at three, six and 12 months. Motor abilities were assessed by maximum voluntary isometric contraction testing (MVICT) in bilateral elbow flexors, elbow extensors, knee flexors, knee extensors and grip. Functional motor abilities were tested with modified SMAFRS, the ability to climb four standard stairs and endurance during the six‐minute walk test. Muscle mass was measured by DEXA scanning. The degree of innervation by the ulnar nerve was estimated using maximum ulnar CMAP. Pulmonary function testing was performed, which included FVC, FEV and MIP. Quality of life was assessed using the mini‐SIP. Safety laboratory studies (chemistry profile, blood and platelet count, transaminases, carnitine profile, amylase, lipase, valproic acid levels) were performed at baseline, two to three weeks after initiation, at thee, six and 12 months and one additional time between six and 12 months. Serum levels of SMN protein and mRNA were performed.
The two baseline visits and the visit closest to the start of the treatment were used as baseline evaluation. Changes from baseline between treatment and placebo at six months were analysed with t‐tests and at 12 months with mixed‐effects models.
The primary endpoint was the change in MVICT at six months. Secondary outcomes included laboratory safety data, adverse event and change in muscle scores of upper and lower extremities, SMAFRS, CMAPs of the ulnar nerve, DEXA, muscle mass, pulmonary functioning tests, SMN protein levels and mRNA levels from baseline after six and 12 months. Adverse events were systematically assessed at each visit.
Funding
In three trials, pharmaceutical companies were involved in funding, analysis, reporting of results, or a combination of these (Bertini 2017; Kirschner 2014; Mercuri 2018 (CHERISH)). In six trials, pharmaceutical companies provided the study drug without cost and they had no involvement in study design, or analysis and reporting of results (Kissel 2014; Mercuri 2007; Miller 2001; Swoboda 2010; Tzeng 2000; Wong 2007). Authors of one trial were reported to have a patent on the study drug (Chen 2010).
Excluded studies
We identified and assessed 59 studies (36 new) for possible inclusion in the review. We excluded 36 studies (see Characteristics of excluded studies table) because they were not randomised or were uncontrolled (Abbara 2011; Brahe 2005; Brichta 2006; Chang 2002; Chiriboga 2016; Darbar 2011; EMOTAS 2014; Folkers 1995; Giovannetti 2016; JEWELFISH 2017; JPRN‐JapicCTI‐163450 2016; Kato 2009; Khirani 2017; Kinali 2002; Kissel 2011; Liang 2008; NCT02876094; Mercuri 2004; Merlini 2003; Nascimento 2010; NCT01703988; NCT02052791; NCT03709784; NPTUNE01 2007; OLEOS; Pane 2008; Piepers 2011; Prufer de Queiroz Campos Araujo 2010; Saito 2014; SHINE 2015; SMART01; SMART03; Swoboda 2009; Tan 2011; Tsai 2007; Weihl 2006). We could exclude 13 unpublished studies because they were not randomised or were uncontrolled, with eight of these studies still being ongoing (EMOTAS 2014; JEWELFISH 2017; JPRN‐JapicCTI‐163450 2016; NCT02876094; NCT03709784; OLEOS; SHINE 2015; SMART03), and five studies being completed but not yet published at time of the search (NCT01703988; NCT02052791; NPTUNE01 2007; Prufer de Queiroz Campos Araujo 2010; SMART01).
Studies awaiting classification
Nine trials were completed but no data were available for analysis (ASIRI 2008; CHICTR‐TRC‐10001093; Merlini 2007; MOONFISH 2014; Morandi 2013; NCT00568802; NCT01645787; NCT02644668; SPACE) (see Characteristics of studies awaiting classification table). Results of two trials, the EUROsmart trial with acetyl‐L‐carnitine (Merlini 2007), and a trial with salbutamol (Morandi 2013), were only published in conference abstracts which did not include enough data for analysis (Merlini 2010; Morandi 2013). We also could not obtain the results of three completed randomised, placebo‐controlled trials with hydroxyurea (NCT00568802), with riluzole in SMA types II and III (ASIRI 2008), and with 4AP in adults with SMA type III (NCT01645787). One trial was terminated for safety reasons and results are not yet published (MOONFISH 2014). We tried to obtain data and preliminary results for all of these completed but unpublished trials, but data were not available upon request at time of writing.
We could not obtain information about the trial methods or results of the completed two‐armed trial on rat nerve growth factor and, therefore, this study is awaiting classification (CHICTR‐TRC‐10001093).
Ongoing studies
Four trials were ongoing at the time of this search (EMBRACE 2015; NCT01671384; SMART02; SUNFISH 2016) (see Characteristics of ongoing studies table).
Risk of bias in included studies
The 'Risk of bias' assessments for the 10 included trials are shown in the Characteristics of included studies table and summarised in Figure 2 and Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all 10 included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
The randomisation method was not clear in four trials (Chen 2010; Kissel 2014; Tzeng 2000; Wong 2007), but was at low risk of bias in the remaining six trials. Allocation concealment was not clear in four trials (Chen 2010; Kissel 2014; Miller 2001; Wong 2007), but adequately reported in five trials, which we judged at low risk of bias (Bertini 2017; Kirschner 2014; Mercuri 2007; Mercuri 2018 (CHERISH); Swoboda 2010). Allocation concealment was at high risk of bias in one trial (Tzeng 2000), which used a coin toss method. In one trial, there were baseline differences probably due to inadequate randomisation, since muscle strength in the cohort of children aged five to 18 years in the creatine treatment group was slightly weaker than in the placebo group (Wong 2007).
Blinding
Blinding of parents, participants and observers were adequate and at low risk of bias in all trials except Kissel 2014, for which the risk of bias related to blinding was unclear.
Incomplete outcome data
Four trials were at high risk of bias from attrition and three at unclear risk of bias. The method for modified ITT analysis was unknown in Kirschner 2014 and we assessed this trial at high risk of bias. In one trial, the risk of attrition bias was high because fewer than expected numbers of participants provided data for some outcome measures (Swoboda 2010). A difference in the number of children over five years of age providing data on myometry and FVC was unexplained, with data on adverse events limited in Mercuri 2007. This resulted in a high‐risk assessment. Follow‐up was below 80% in two trials (Miller 2001; Wong 2007). Miller 2001 performed an ITT analysis but participants withdrew for unknown reasons and the number analysed was not the number initially included. We judged the risk of bias in Miller 2001 to be high and in Wong 2007 to be unclear. Participants withdrew for unknown reasons in two other studies; however, ITT analysis possibly minimised the risk of bias, which we judged unclear (Bertini 2017: n = 17; Kissel 2014: n = 4).
Risk of attrition bias in the other trials was low (Chen 2010; Mercuri 2018 (CHERISH); Tzeng 2000).
Selective reporting
Primary outcome measures were adequately stated in all trials. Trial authors provided data to complete analysis of primary and secondary outcomes, including muscle strength (Kirschner 2014; Kissel 2014; Miller 2001; Wong 2007), disability scores (Kirschner 2014; Kissel 2014; Miller 2001; Wong 2007), pulmonary function (Kirschner 2014; Kissel 2014; Wong 2007), quality of life (Kissel 2014; Miller 2001; Wong 2007), and adverse events (Kissel 2014; Miller 2001; Wong 2007).
We assessed four trials at high risk of reporting bias. Two studies dichotomised data post hoc for analysis (Bertini 2017; Chen 2010). A third study measured quality of life but the reporting was incomplete (Kirschner 2014). We also judged Tzeng 2000 at high risk of reporting bias. Although all outcomes were reported, the statistical plan was limited and unclear. Miller 2001 was at unclear risk of bias, as adverse events were not reported. We judged the other five trials at low risk of selective reporting (Kissel 2014; Mercuri 2007; Mercuri 2018 (CHERISH); Swoboda 2010; Wong 2007),
Other potential sources of bias
Two studies were at high risk from other potential sources of bias (Bertini 2017; Kissel 2014) and four at unclear risk (Kirschner 2014; Mercuri 2018 (CHERISH); Swoboda 2010; Wong 2007).
The cross‐over design with potential carry‐over effects placed two studies at unclear risk of bias (Kirschner 2014; Swoboda 2010) and one study at high risk of bias (Kissel 2014).
In four trials, there were baseline differences, with other potential bias graded as unclear (Mercuri 2018 (CHERISH); Swoboda 2010; Wong 2007) or high (Bertini 2017). In Swoboda 2010, there were baseline differences in gender as the valproic acid plus acetyl‐L‐carnitine treatment group consisted of 36.6% females compared to 56% females in the placebo group, and there were differences in body mass index. In Mercuri 2018 (CHERISH), we judged the risk as unclear, since the baseline differences resulted in more severely affected children in the nusinersen‐treated group. However, there was a beneficial significant effect on motor function in the nusinersen group, the effects of nusinersen even being underestimated in more severely affected children. No definite conclusions on this subject could be drawn. In Bertini 2017, we judged the risk of bias as high because there were differences in mean and median ages between the olesoxime and placebo group, with a higher mean and median age in the placebo group, and the proportion of males and females was uneven between the two treatment groups.
Four trials were at low risk of other potential sources of bias (Chen 2010; Mercuri 2007; Miller 2001; Tzeng 2000).
Effects of interventions
See: Summary of findings for the main comparison Oral creatine compared to placebo for children with SMA types II and III; Summary of findings 2 Oral gabapentin compared to placebo for adults with SMA types II and III; Summary of findings 3 Oral hydroxyurea compared to placebo for children and adults with SMA types II and III; Summary of findings 4 Intrathecal injected nusinersen compared to sham procedure for children with SMA type II; Summary of findings 5 Oral olesoxime compared to placebo for non‐ambulatory children and adolescents with SMA types II and III; Summary of findings 6 Oral phenylbutyrate compared to placebo for children with SMA type II; Summary of findings 7 Subcutaneous somatotropin compared to placebo for children and adults with SMA types II and III; Summary of findings 8 Intravenous thyrotropin releasing hormone compared to placebo for children with SMA types II and III; Summary of findings 9 Oral valproic acid plus acetyl‐L‐carnitine compared to placebo for non‐ambulatory children with SMA types II and III; Summary of findings 10 Oral valproic acid compared to placebo for ambulatory adults with SMA type III
Meta‐analysis was not possible due to the extensive variation in the drug treatments, outcomes and outcome measures, analyses, follow‐ups, study designs and the reporting of results in the 10 studies included in the review. We present the detailed results of each trial in tables (Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9; Table 10; Table 11).
| Creatine | Placebo | Difference (95% CI) | P value | |
| All ages | ||||
| Number of participants randomised | 27 | 28 | — | — |
| Number (%) of participants evaluable for analysis disability | 18 (67%) | 22 (79%) | — | — |
| Median change in disability score (GMFM) | 0 | ‐1 | 1 (‐1 to 2) | 0.19 |
| Number (%) of participants evaluable for analysis QoL | 17 (63%) | 21 (75%) | — | — |
| Median change in quality of life (PedsQL, neuromuscular module) | ‐5 | 2 | ‐7 (‐11 to 3) | 0.31 |
| Age 2 to 5 years | ||||
| Number of participants randomised | 8 | 12 | — | — |
| Number (%) of participants evaluable for analysis disability | 7 (88%) | 10 (83%) | — | — |
| Median change in disability score (GMFM) | 1 | ‐2 | 1.5 (‐4 to 9) | 0.18 |
| Number (%) of participants evaluable for analysis QoL | 6 (75%) | 9 (75%) | — | — |
| Median change in QoL (PedsQL, neuromuscular module) | 4.5 | 3 | 2 (‐8 to 13) | 0.71 |
| Age 5 to 18 years | ||||
| Number of participants randomised | 19 | 16 | — | — |
| Number (%) of participants evaluable for analysis disability and QoL | 11 (58%) | 12 (75%) | — | — |
| Median change in disability score (GMFM) | ‐1 | ‐0.5 | 0 (‐2 to 2) | 0.77 |
| Number (%) of participants evaluable for analysis QoL | 11 (58%) | 12 (75%) | — | — |
| Median change in quality of life (PedsQL, neuromuscular module) | ‐6 | 0 | ‐6 (‐15 to 2) | 0.11 |
| Number (%) of participants evaluable for analysis of muscle strength | 11 (58%) | 11 (69%) | — | — |
| Mean (SD) change in arms muscle strength (QMT) | ‐0.34 (6.98) | 1.49 (8.50) | ‐1.83 (‐8.75 to 5.09) | 0.59 |
| Mean (SD) change in legs muscle strength (QMT) | 1.51 (4.21) | 0.93 (3.06) | 0.58 (‐2.70 to 3.85) | 0.72 |
| Mean (SD) change in total muscle strength (QMT) | 1.17 (9.67) | 2.42 (10.3) | ‐1.25 (‐10.1 to 7.6) | 0.77 |
| Number (%) of participants evaluable for analysis pulmonary function | 11 (58%) | 12 (75%) | — | — |
| Mean (SD) change in pulmonary function (FVC % of predicted value in litres) | ‐0.27 (14.5) | ‐0.83 (11.5) | 0.56 (‐10.75 to 11.87) | 0.92 |
| Creatine | Placebo | Risk ratio (95% CI) | P value | |
| All ages | ||||
| Number of adverse events | 55 | 43 | — | — |
| Number of participants with adverse events | 13/27 | 16/28 | 0.84 (0.51 to 1.40) | 0.59 |
| Number of severe adverse events | NA | NA | — | — |
| Number of participants with severe adverse events | NA | 1 (death by respiratory failure) | — | — |
CI: confidence interval; FVC: forced vital capacity; GMFM: Gross Motor Function Measure; NA: not available; PedsQL: Pediatric Quality of Life Inventory; QMT: quantitative muscle test; QoL: quality of life; SD: standard deviation.
| Gabapentin | Placebo | Difference (95% CI) | P value | |
| Follow‐up at 12 months | ||||
| Number (%) of participants evaluable for analysis disability | 32 (80%) | 34 (77%) | — | — |
| Median change in disability score (SMAFRS) | 0 | ‐2 | 1 (‐1 to 4) | 0.30 |
| Number (%) of participants evaluable for analysis quality of life | 33 (83%) | 34 (77%) | — | — |
| Mean change in quality of life (mini‐SIP) | 0.09 | ‐0.26 | 0.36 (‐0.29 to 1) | 0.28 |
| Number (%) of participants evaluable for analysis grip muscle strength | 30 (75%) | 31 (70%) | — | — |
| Mean change in grip muscle strength (MVC) in percentage from baseline | 0.08 | ‐4.5 | 4.6 (‐2.5 to 11.6) | 0.57 |
| Number (%) of participants evaluable for analysis arms muscle strength | 28 (70%) | 29 (66%) | — | — |
| Mean change in arms muscle strength (MVC) in percentage from baseline | 0.05 | ‐1.8 | 1.9 (‐2.5 to 6.2) | 0.39 |
| Number (%) of participants evaluable for analysis feet muscle strength | 28 (70%) | 29 (66%) | — | — |
| Mean change in feet muscle strength (MVC) in percentage from baseline | 0.36 | 0.70 | 0.29 (‐8.3 to 8.9) | 0.95 |
| Number (%) of participants evaluable for analysis total muscle strength | 25 (63%) | 25 (57%) | — | — |
| Mean change in total muscle strength (MVC) in percentage from baseline | 1.2 | ‐2.2 | 3.3 (‐6.9 to 14) | 0.52 |
| Number (%) of participants evaluable for analysis development of walking | 38 (95%) | 35 (80%) | — | — |
| Number of participants with development of walking | 0 | 0 | — | — |
| Number (%) of participants evaluable for analysis pulmonary function | 31 (78%) | 34 (77%) | — | — |
| Mean change in pulmonary function (FVC % of predicted value) | ‐4.0 | ‐2.9 | ‐1.1 (‐4.1 to 1.9) | 0.48 |
| Gabapentin | Placebo | Risk ratio (95% CI) | P value | |
| Number of adverse events | NA | NA | — | — |
| Number of participants with adverse events | NA | NA | — | — |
| Number of severe adverse events | 0 | 0 | — | — |
| Number of participants with severe adverse events | 0 | 0 | — | — |
CI: confidence interval; FVC: forced vital capacity; mini‐SIP: mini Sickness Impact Profile; MVC: maximum voluntary contraction; NA: not available; SMAFRS: Spinal Muscular Atrophy‐Functional Rating Scale.
| Hydroxyurea | Placebo | Difference (95% CI) | P value | |
| All ages | ||||
| Number of participants randomised | 37 | 20 | — | — |
| Number (%) of participants evaluable for analysis disability (GMFM) | 37 (100%) | 20 (100%) | — | — |
| Mean change (SE) in disability score (GMFM) | 0.14 (0.57) | 2.02 (0.88) | ‐1.88 (‐3.89 to 0.13) | 0.07 |
| Number (%) of participants evaluable for analysis muscle strength (MMT) | 37 (100%) | 20 (100%) | — | — |
| Mean change (SE) in muscle strength (MMT) | ‐0.58 (0.56) | ‐0.03 (0.98) | ‐0.55 (‐2.65 to 1.55) | 0.60 |
| Number (%) of participants evaluable for pulmonary function (FVC in litres) | 37 (100%) | 20 (100%) | — | — |
| Mean (SE) change in pulmonary function (FVC in litres) | ‐0.21 (0.06) | ‐0.22 (0.12) | ‐0.01 (‐0.25 to 0.26) | 0.93 |
| Number (%) of participants evaluable for analysis disability (MHFMS) | 26 (100%) | 12 (100%) | — | — |
| Mean change (SE) in disability score (MHFMS) | 0.02 (0.03) | 0.04 (0.04) | ‐0.02 (‐0.12 to 0.07) | 0.70 |
| Hydroxyurea | Placebo | Risk ratio (95% CI) | P value | |
| Number of adverse event episodes | 224 | 129 | — | 0.65 |
| Mean number (SD) of adverse event episodes per participant | 6.05 (3.43) | 6.45 (2.91) | ‐0.4 (‐2.21 to 1.41) | 0.66 |
| Number of severe adverse event episodes | 19 | 10 | — | 0.96 |
| Mean number (SD) of severe adverse event episodes per participant | 0.51 (1.04) | 0.50 (0.83) | 0.01 (‐0.77 to 0.79) | 0.96 |
| Number (%) of participants discontinued intervention | 2 (5%) | 0 (0%) | — | — |
FVC: forced vital capacity; GMFM: Gross Motor Function Measure; MHFMS: Modified Hammersmith Functional Motor Scale; MMT: manual muscle testing; SD: standard deviation; SE: standard error.
| Nusinersen | Placebo | Difference (95% CI) | P value | |
| Number of participants randomised | 84 | 42 | — | — |
| Interim analysisa | 84b | 42b | — | — |
| Mean change in HFMSE | 4.0 | ‐1.9 | 5.9 (3.7 to 8.1) | < 0.001 |
| Final analysis | 84c | 42c | — | — |
| Mean change in HFMSE | 3.9 | ‐1.0 | 4.9 (3.1 to 6.7) | — |
| Nusinersen | Placebo | Difference (95% CI) | P value | |
| Percentage of participants with 3‐point‐change on HFMSE (%) | 57 | 26 | 30.5 (12.7 to 48.3) | < 0.001 |
| Percentage (number) of children who achieved ≥ 1 new WHO motor milestone (% (number)) | 20 (13) | 6 (2) | 14 (‐7 to 34) | 0.08 |
| Nusinersen | Placebo | Risk ratio (95% CI) | P value | |
| Percentage (number) of children who achieved ability to stand alone | 2 (1) | 3 (1) | 0.5 (0.03 to 7.80) | — |
| Percentage (number) of children who achieved ability to walk with assistance | 2 (1) | 0 (0) | 1.5 (0.06 to 36.1) | — |
| Number of participants with adverse events | 78 | 42 | 0.9 (0.9 to 1.0) | 0.01 |
CI: confidence interval; HFMSE: Hammersmith Functional Motor Scale Expanded; WHO: World Health Organization.
a Conducted in children who completed at least six months of the trial. Data of children who had not yet completed the 15‐month period were imputed.
b Included 35 participants in the nusinersen group and 19 participants in the control group who completed the 15‐month assessment. Data for 49 participants in the nusinersen group and 23 participants in the control group were imputed.
c The number of children with observed data for the 15‐month assessment was 66 in the nusinersen group and 34 in the control group, and the number of children with imputed data was 18 in the nusinersen group and eight in the control group.
| Olesoxime | Placebo | Estimated difference (95% CI)a | P value | |
| Number of participants randomised | 108 | 57 | — | — |
| Number (%) of participants evaluable for analysis MFM‐32 D1+D2 | 103 (95%) | 57 (100%) | — | — |
| Meanab change (95% CI) in disability score (MFM D1+D2) at 24 months | ‐0.18 (‐1.30 to 1.66) | ‐1.82 (‐3.68 to 0.04) | 2.00 (‐0.25 to 4.25) | 0.07 |
| Number (%) of participants evaluable for analysis MFM total score | 103 (95%) | 57 (100%) | — | — |
| Meanab change (95% CI) in disability score (MFM total score) at 24 months | 0.59 (‐0.9 to 2.070 | ‐1.45 (‐3.31 to 0.41) | 2.04 (‐0.21 to 4.28) | 0.08 |
| Number (%) of participants evaluable for analysis HFMS | 103 (95%) | 57 (100%) | — | — |
| Meanb change (95% CI) in disability score (HFMS) at 24 months | ‐0.78 (‐1.60 to 0.04) | ‐1.72 (‐2.74 to ‐0.70) | 0.94 (‐0.28 to 2.17) | 0.13 |
| Number (%) of participants evaluable for analysis of nerve innervation value (CMAP) (in mV) | 70 (65%) | 34 (60%) | — | — |
| Meanb (95% CI) change in total amplitude CMAP from baseline to 24 months | ‐0.07 (‐0.49 to 0.36) | ‐0.16 (‐0.74 to 0.43) | NA | 0.79 |
| Number (%) of participants evaluable for analysis of MUNE | 58 (54%) | 30 (53%) | — | — |
| Meanb (95% CI) change in total MUNE from baseline to 24 months | ‐4.51 (‐12.21 to 3.18) | ‐6.69 (‐16.86 to 3.48) | NA | 0.71 |
| Number (%) of participants evaluable for FVC | 64 (59%) | 38 (67%) | — | — |
| Meanb (95% CI) change in FVC from baseline to 24 months | 4.28 (‐0.32 to 8.88) | 6.16 (1.00 to 11.33) | ‐1.88 (‐3.14 to 6.91) | 0.57 |
| Olesoxime | Placebo | Difference (95% CI) | P value | |
| Number (%) of participants evaluable for analysis of quality of life (PedsQL) from baseline to 24 months | 71 (66%) | 37 (65%) | — | — |
| Mean (SD) change in quality of life (PedsQL) from baseline to 24 months | NA | NA | 0.25 (‐4.58 to 5.08) | 0.92 |
| Olesoxime | Placebo | Risk ratio (95% CI) | P value | |
| Number (%) of participants evaluable for responder analysis MFM‐32 score D1+D2 (24 months) | 103 (95%) | 57 (100%) | — | — |
| Proportion of participants with good response according to MFM‐32 score D1+D2c | 56 (54) | 22 (39) | 1.43 (‐0.98 to 2.08) | 0.06 |
| Number of adverse events | 1104 (64) | 612 (36) | — | — |
| Number (%) of participants with adverse events | 103 (95%) | 57 (100%) | 0.95 (0.91 to 0.99) | 0.02 |
| Number (%) of participants with severe adverse events | 18 (17%) | 14 (25%) | 0.67 (0.37 to 1.26) | — |
| Number of deaths | 1 | 1 | — | — |
| Number (%) of participants discontinued intervention | 10 (9%) | 7 (12%) | — | — |
CI: confidence interval; CMAP: compound muscle action potential; FVC: forced vital capacity; HFMS: Hammersmith Functional Motor Scale; MFM: Motor Function Measure; MFM D1+D2: functional domains 1 and 2 of the Motor Function Measure; MUNE: motor unit number estimation; NA: not available; PedsQL: Pediatric Quality of Life Inventory; SD: standard deviation.
a Least squared mean of MFM, including MFM‐32 and MFM‐20 assessments.
b Calculated with available data.
c Participants with no change or improvement of scores were considered 'responders', participants with a decline in score were considered 'non‐responders'.
| Phenylbutyrate | Placebo | Difference (95% CI) | P value | |
| All ages | ||||
| Number of participants randomised | 54 | 53 | — | — |
| Number (%) of participants evaluable for analysis of HFMS | 45 (83%) | 45 (85%) | — | — |
| Mean (SD) HFMS | 12.1 (9.60) | 12.8 (9.86) | ‐0.7 (‐4.78 to 3.78) | 0.70 |
| Mean (SD) change in HFMSa | 0.60 (0.22) | 0.73 (0.29) | ‐0.13 (‐0.84 to 0.58) | 0.70 |
| Age > 5 years | ||||
| Mean (SD) change in muscle strength arm megascore (dynamometry)a | 1.56 (6.94) | ‐0.42 (8.61) | 1.98 (‐1.67 to 5.63) | 0.74 |
| Mean (SD) change muscle strength leg megascore (dynamometry)a | 4.26 (8.64) | 3.22 (6.26) | 1.04 (‐2.46 to 4.54) | 0.78 |
| Number (%) of participants evaluable for analysis of HFMS | 26 (48%) | 23 (43%) | — | — |
| Mean (SD) change in pulmonary function (FVC % of predicted value in litres)a | 0.03 (0.17) | ‐0.01 (0.27) | 0.04 (‐0.07 to 0.15) | 0.39 |
| Phenylbutyrate | Placebo | Risk ratio (95% CI) | P value | |
| All ages | ||||
| Number of participants with adverse events | 19 | 5 | 3.1 (1.25 to 7.84) | 0.01 |
| Number of withdrawals because of adverse events | 6 | 3 | 1.86 (0.49 to 7.11) | 0.9 |
| Number of severe adverse events | 1 | 2 | — | — |
| Number of participants with severe adverse events | 1 | 2 | 1.96 (0.18 to 21.0) | 1.0 |
CI: confidence interval; FVC: forced vital capacity; HFMS: Hammersmith Functional Motor Scale; SD: standard deviation;
aMean change from baseline.
| Total number of participants randomised (cross‐over setting) | 20 | — | — | |
| Somatropin | Placebo | Difference (95% CI) | P value | |
| Number of participants completing phase 1 of study protocol | 9/10 | 10/10 | — | — |
| Number of participants completing phase 2 of study protocol | 8/10 | 9/10 | — | — |
| Number (%) of participants evaluable for intention‐to‐treat analysis | 17 (90%) | 17 (80%) | — | — |
| Mean (SD) change in muscle strength of upper limb (hand‐held myometry in megascore of biceps and handgrip) (Newton) | ‐1.05 (6.42) | 0.30 (10.6) | ‐1.35 (‐7.12 to 4.42) | 0.97 |
| Number (%) of participants evaluable for analysis disability score (HFMSE) | 19 (95%) | 19 (95%) | — | — |
| Median (SD) change in disability score (HFMSE) | 0.05 (3.19) | ‐1.05 (5.28) | 0.25 (‐1 to 2.5) | 0.58 |
| Number (%) of participants evaluable for analysis arm megascore | 19 (95%) | 19 (95%) | — | — |
| Mean (SD; range) change in arm megascore (Newton) | ‐1.05 (6.42; | 0.30 (10.60; | 0.08 (‐3.79 to 3.95) | 0.97 |
| Number (%) of participants evaluable for analysis leg megascore | 19 (95%) | 19 (95%) | — | — |
| Mean (SD; range) change in leg megascore (Newton) | 2.96 (7.64; ‐10 to 24.5) | 0.95 (9.93; ‐18 to 22) | 2.23 (‐2.19 to 6.63) | 0.30 |
| Number (%) of participants evaluable for analysis muscle strength (MRC) | 19 (95%) | 19 (95%) | — | — |
| Mean (SD) change MRC (% of maximum score) | ‐2.31 (5.1) | 0.43 (7.0) | ‐2.74 (‐6.7 to 1.29) | 0.19 |
| Number (%) of participants evaluable for analysis pulmonary function (FVC) | 19 (95%) | 19 (95%) | — | — |
| Mean (SD; range) change in pulmonary function (FVC improvement in litres) | 0.12 (0.25; ‐0.4 to 0.5) | ‐0.11 (0.40; ‐1.4 to 0.36) | 0.23 (‐0.01 to 0.45) | 0.08 |
| Somatropin | Placebo | Risk Ratio (95% CI) | P value | |
| Number of adverse events | 14 | 9 | — | — |
| Number of participants with adverse events | 11 | 7 | 1.57 (0.78 to 3.17) | 0.34 |
| Number (%) of participants discontinued intervention | 3 (15%) | 0 (0%) | — | — |
CI: confidence interval; FVC: forced vital capacity; HFMSE: Hammersmith Functional Motor Scale Expanded; MRC: Medical Research Council; SD: standard deviation.
| TRH | Placebo | Difference (95% CI) | |
| Number of participants randomised | 6 | 3 | — |
| Number (%) of participants evaluable for analysis | 6 (100%) | 3 (100%) | — |
| Mean (SD) change in muscle strength (dynamometry in pounds) | 0.82 (0.59) | 0.48 (0.29) | 0.34 (‐0.54 to 1.22) |
| TRH | Placebo | Risk ratio (95% CI) | |
| Number of adverse events | 12 | 0 | — |
| Number of participants with adverse events | NA | NA | — |
| Number of severe adverse events | 0 | 0 | — |
| Number of participants with severe adverse events | 0 | 0 | — |
CI: confidence interval; NA: not available; SD: standard deviation; TRH: thyrotropin‐releasing hormone.
| Valproic acid + acetyl‐L‐carnitine | Placebo | Difference (95% CI) | P value | |
| All ages | ||||
| Number of participants randomised | 31 | 30 | — | — |
| Number (%) of participants evaluable for analysis disability (MHFMS) | 28 (90%) | 28 (93%) | — | — |
| Mean change (SD) in disability score (MHFSM) at 6 months | 0.82 (2.88) | 0.18 (3.98) | 0.64 (‐1.1 to 2.38) | 0.50 |
| Number (%) of participants evaluable for analysis of nerve innervation value (CMAP) | 19 (61%) | 19 (63%) | — | — |
| Mean (SD) change in total amplitude CMAP from baseline to 6 months | 0.02 (0.70) | ‐0.10 (0.66) | 0.12 (‐0.33 to 0.57) | 0.59 |
| Number (%) of participants evaluable for analysis of quality of life (PedsQL) from baseline to 12 months | 27 (87%) | 27 (90%) | — | — |
| Mean (SD) change in quality of life (PedsQL) from baseline to 12 months | ‐1.9 (13.6) | 0.3 (12.9) | ‐2.2 (‐9.27 to 4.87) | 0.54 |
| Age < 3 years old | ||||
| Number (%) of participants evaluable for analysis disability (MHFMS) | 12 (52%) | 11 (48%) | — | — |
| Mean change (SD) in disability score (MHFSM) from baseline to 6 months | 1.33 (2.27) | 1.09 (5.37) | 0.24 (‐3.28 to 3.76) | 0.89 |
| Aged 3–8 years | ||||
| Number (%) of participants evaluable for analysis disability (MHFSM) | 18 (47%) | 17 (45%) | — | — |
| Mean change (SD) in disability score (MHFSM) from baseline to 6 months | 0.44 (3.29) | ‐0.41 (2.79) | 0.85 (‐1.25 to 2.95) | 0.42 |
| Aged ≥ 5 years | ||||
| Number of participants evaluable for analysis muscle strength in arms (myometry) | 7 | 7 | — | — |
| Mean (SD) change in arm muscle strength (myometry) from baseline to 6 months (kg) | 0.64 (0.6) | 0.07 (1.04) | 0.57 (‐0.45 to 1.58) | 0.23a |
| Number of participants evaluable for analysis muscle strength in legs (myometry) | 6 | 4 | — | — |
| Mean (SD) change in leg muscle strength (myometry) from baseline to 6 months (kg) | 0.55 (0.83) | ‐0.85 (2.22) | 1.40 (‐1.98 to 4.79) | 0.19a |
| Number of participants evaluable for analysis muscle strength in both arms and legs (myometry) | 7 | 8 | — | — |
| Mean (SD) change in total muscle strength (myometry) from baseline to 6 months (kg) | 1.18 (0.91) | ‐0.25 (2.47) | 1.43 (0.69 to 3.56) | 0.21 |
| Number of participants evaluable for analysis pulmonary function (FVC in % of predicted) | NA | NA | NAa | NAa |
| Mean (SD) change in pulmonary function (FVC in % of predicted) from baseline to 6 months | NA | NA | — | — |
| Valproic acid + acetyl‐L‐carnitine | Placebo | Risk ratio (95% CI) | P value | |
| All ages | ||||
| Number (%) of participants with adverse events (6 months) | 23 (77%) | 18 (58%) | 1.32 (0.92 to 1.89) | — |
| Number (%) of participants with severe adverse events (6 months) | 6 (20%) | 2 (6%) | 3.1 (0.60 to 12.1) | — |
CI: confidence interval; CMAP: compound maximum action potential; FVC: forced vital capacity; MHFMS: Modified Hammersmith Functional Motor Scale; PedsQL: Pediatric Quality of Life Inventory; SD: standard deviation.
a Underpowered.
| Valproic acid | Placebo | Difference (95% CI)a | P value | |
| Number (%) of participants randomised first 6 months (cross‐over setting) | 16 (100%) | 17 (100%) | — | — |
| Number (%) of participants evaluable for analysis after 12 months | 30 (91%) | 30 (91%) | — | — |
| Analysis after 6 months before cross‐over | ||||
| Number (%) of participants evaluable for analysis SMAFRS | 14 (88%) | 17 (100%) | — | — |
| Mean (SD) change in SMAFRS | ‐0.29 (1.59) | ‐0.35 (2.32) | 0.06 (‐1.32 to 1.44) | 0.93 |
| Number (%) of participants evaluable for analysis upper extremity | 14 | 16 | — | — |
| Mean (SD) change in MVICT upper extremity (Newton) | ‐0.24 (1.17) | ‐0.01 (1.05) | ‐0.23 (‐1.03 to 0.57) | 0.54 |
| Number (%) of participants evaluable for analysis lower extremity | 13 | 16 | — | — |
| Mean (SD) change in lower extremity MVICT (Newton) | ‐0.02 (0.65) | 0.35 (1.30) | ‐0.37 (‐1.09 to 0.35) | 0.36 |
| Number (%) of participants evaluable for analysis pulmonary function (FVC) | 14 (88%) | 17 (100%) | — | — |
| Mean (SD; range) change in pulmonary function (FVC improvement in litres) | ‐0.04 (0.35) | 0.30 (1.20) | ‐0.34 (‐0.94 to 0.26) | 0.31 |
| Number of participants evaluable for QoL analysis | 14 | 17 | — | — |
| Mean (SD) change in mini‐SIP for QoL | ‐0.19 (2.80) | 0.91 (4.78) | ‐1.1 (‐3.8 to 1.6) | 0.53 |
| Valproic acid | Placebo | Risk ratio (95% CI)a | P value | |
| Number of adverse events | 30 | 66 | — | — |
| Number of participants with adverse events | 12 | 15 | 0.8 (0.44 to 1.44) | |
| Number of severe adverse events | 2 | 3 | — | — |
| Number of participants with severe adverse events | 2 | 2 | 1.0 (0.15 to 6.69) | — |
| Number (%) of participants discontinued intervention | NA | NA | — | — |
CI: confidence interval; FVC: forced vital capacity; mini‐SIP: mini‐Sickness Illness Profile; MVICT: maximum voluntary isometric contraction; NA: not available; QoL: quality of life; SD: standard deviation; SMAFRS: Spinal Muscular Atrophy Functional Rating Scale.
aCalculated with available data.
We re‐analysed the data from four trials according to our predefined primary and secondary outcome measures (Kissel 2014; Miller 2001; Tzeng 2000; Wong 2007). To enable this analysis, we obtained the raw study data from the principal investigators of two studies (Miller 2001; Wong 2007). We performed additional analysis on the available data of one study to retrieve MDs and CIs of data (Kissel 2014). We obtained additional data for one study to complete information on effect sizes and CIs (Kirschner 2014). The results of this re‐analysis are shown separately for each included trial in Table 2, Table 3, Table 8, Table 9, and Table 11.
Oral creatine versus placebo
Wong 2007 compared creatine versus placebo and reported outcomes at nine months. See Table 2 for numerical results and summary of findings Table for the main comparison.
Primary outcome
Change in disability score
Change in disability, assessed by the GMFM was a primary outcome in Wong 2007. Trial authors supplied additional data on GMFM for re‐analysis. The change in disability scores showed little or no difference between the treatment and placebo groups (n = 40; moderate‐certainty evidence, downgraded one level for imprecision owing to a small sample size).
Secondary outcomes
Change in muscle strength
The study measured muscle strength via quantitative myometry, but (re‐)analysis of data showed no evidence of a difference for change in hand, arm, feet, leg or total muscle strength between the treatment and placebo groups (n = 22; low‐certainty evidence, downgraded one level for imprecision owing to a small sample size and one level for inconsistency due to unknown cohort representation).
Acquiring the ability to stand within one year after the onset of treatment
The study did not measure ability to stand.
Acquiring the ability to walk or improvement of walking within one year after the onset of treatment
The study did not measure ability to walk.
Change in quality of life
The study measured quality of life using the mini‐SIP and PedsQL. There was no evidence of a difference in quality of life measures between the treatment and placebo groups (n = 38; low‐certainty evidence, downgraded one level for imprecision owing to a small sample size and one level for inconsistency).
Change in pulmonary function
The study measured change in FVC in participants more than five years old. There was no evidence of a difference in pulmonary function between the treatment and placebo groups (n = 23; low‐certainty evidence, downgraded one level for imprecision owing to a small sample size and one level for inconsistency due to unknown cohort representation).
Time from beginning of treatment until death or full‐time ventilation
One participant in Wong 2007 died. The death was reported not to be related to the study treatment and occurred in the placebo group. None of the participants reached the state of more than 16 hours' ventilation a day (n = 40; moderate‐certainty evidence, downgraded one level for imprecision owing to a small sample size).
Adverse events, separated into severe and others
In Wong 2007, adverse events rates were similar in the creatine and placebo groups: 13/27 participants who received creatine and 16/28 participants who received placebo had an adverse event (n = 40; low‐certainty evidence, downgraded two levels for study limitations (risk of bias) and because it is unlikely the trial captured uncommon adverse events (risk of imprecision). The report did not include information on type of adverse events. Data on the number of adverse events were available for analysis, but the trial authors were unable to provide other data on (severe) adverse events on request.
Oral gabapentin versus placebo
Miller 2001 compared gabapentin versus placebo and reported outcomes at 12 months. See Table 3 for numerical results and summary of findings Table 2.
Primary outcome
Change in disability score
Change in disability, measured with the SMAFRS, was a primary outcome in Miller 2001.
There was no evidence of a difference for change in disability scores between the treatment and placebo groups (n = 66; low‐certainty evidence, downgraded two levels for study limitations (risk of bias and imprecision)).
Secondary outcomes
Change in muscle strength
The trial measured muscle strength using quantitative myometry. There was no evidence of a difference for change in hand, arm, feet, leg or total muscle strength between the treatment and placebo groups.
In Miller 2001, some participants were unable to perform all of the muscle strength tests and, therefore, these were not included in the analyses. Moreover, the raw data from this trial showed several extreme values of muscle strength in one particular participating centre. Therefore, we re‐analysed the data with and without these outliers, but this did not result in a different statistical outcome. For a limited number of participants in this trial, data were available at 12 months' follow‐up. Re‐analysis of these limited data also showed no clinically or statistically significant difference for change in muscle strength between the treatment and placebo groups (for total muscle strength, n = 50; low‐certainty evidence, downgraded one level for study limitations (risk of bias) and one level for imprecision; Table 3).
Acquiring the ability to stand within one year after the onset of treatment
The study did not measure ability to stand.
Acquiring the ability to walk or improvement of walking within one year after the onset of treatment
In Miller 2001, none of the participants who were unable to walk before treatment acquired this ability after treatment, and none of the participants who could walk lost this ability in either the treatment or placebo group (n = 73; low‐certainty evidence, downgraded one level for study limitations (risk of bias) and one level for imprecision).
Change in quality of life
Quality of life was measured with the use of mini‐SIP. There was no evidence of a difference in quality of life between the treatment and placebo groups (n = 73; low‐certainty evidence, downgraded one level for study limitations (risk of bias) and one level for imprecision).
Change in pulmonary function
Miller 2001 included only adults and measured the change in FVC. There was no evidence of a difference in pulmonary function between the treatment and placebo groups (n = 65; low‐certainty evidence, downgraded one level for study limitations (risk of bias) and one level for imprecision).
Time from beginning of treatment until death or full‐time ventilation
No deaths were reported and none of the participants reached the state of more than 16 hours' ventilation a day (n = 84; moderate‐certainty evidence, downgraded one level for imprecision).
Adverse events, separated into severe and others
Miller 2001 did not provide specific information on adverse events (n = 65; low‐certainty evidence, downgraded one level for risk of bias and one level for imprecision).
Oral hydroxyurea versus placebo
Chen 2010 compared oral hydroxyurea versus placebo, with a follow‐up of 18 months. See Table 4 for numerical results. and summary of findings Table 3.
Primary outcome
Change in disability score
Chen 2010 measured change in disability as a primary outcome using the GMFM. There was no evidence of a difference in change from baseline between the treatment and placebo groups (n = 57; low‐certainty evidence, downgraded two levels for imprecision (wide CIs and small sample size)). The trial also measured the MHFMS in non‐ambulatory participants as a secondary outcome. There were no clinically or statistically significant difference between the hydroxyurea and placebo groups (n = 38; moderate‐certainty evidence, downgraded one level for imprecision).
Secondary outcomes
Change in muscle strength
Muscle strength was measured via quantitative myometry. There was no evidence of a difference for change in hand, arm, feet, leg or total muscle strength between the treatment and placebo groups (n = 57; moderate‐certainty evidence, downgraded one level for imprecision).
Acquiring the ability to stand within one year after the onset of treatment
The study did not measure ability to stand.
Acquiring the ability to walk or improvement of walking within one year after the onset of treatment
The study did not measure ability to walk.
Change in quality of life
The study did not measure quality of life.
Change in pulmonary function
Chen 2010 measured change in FVC in participants more than five years old. There was no evidence of a difference in pulmonary function between the treatment and placebo groups (n = 57; low‐certainty evidence, downgraded one level for indirectness and one level for imprecision).
Time from beginning of treatment until death or full‐time ventilation
One participant in the treatment group died. The death was reported not to be related to the study treatment. No other deaths were reported and none of the participants reached the state of more than 16 hours' ventilation a day (n = 57; moderate‐certainty evidence, downgraded one level for imprecision).
Adverse events, separated into severe and others
In Chen 2010, all participants had at least one adverse event (n = 57; moderate‐certainty evidence, downgraded one level for imprecision) and 19/61 participants had a severe adverse event.
Intrathecal nusinersen versus sham procedure
Mercuri 2018 (CHERISH) compared intrathecal nusinersen versus placebo. Results were reported after 15 months of treatment. See Table 5 for numerical results and summary of findings Table 4.
Primary outcome
Change in disability score
Change in disability measured using the HFMSE was a primary outcome in Mercuri 2018 (CHERISH). There were significant differences in HFMSE score in favour of the nusinersen‐treated participants compared to the sham procedure‐treated participants (n = 126; moderate‐certainty evidence, downgraded one level for imprecision). More participants in the nusinersen‐treated group than the sham procedure‐treated group had a 3‐point change in disability score (n = 126; moderate‐certainty evidence, downgraded one level for imprecision).
Secondary outcomes
Change in muscle strength
Mercuri 2018 (CHERISH) did not report change in muscle strength.
Acquiring the ability to stand within one year after the onset of treatment
One child treated with nusinersen and one child treated with the sham procedure acquired the ability to stand alone (n = 126; low‐certainty evidence, downgraded two levels for imprecision).
Acquiring the ability to walk or improvement of walking within one year after the onset of treatment
One child treated with nusinersen acquired the ability to walk with assistance compared to no children in the sham‐controlled group (n = 126; low‐certainty evidence, downgraded two levels for imprecision).
Change in quality of life
The study did not measure quality of life.
Change in pulmonary function
The study did not measure pulmonary function.
Time from beginning of treatment until death or full‐time ventilation
No deaths were reported and none of the participants reached the state of more than 16 hours' ventilation a day (n = 126; moderate‐certainty evidence).
Adverse events, separated into severe and others
In Mercuri 2018 (CHERISH), 78/84 (93%) participants treated with nusinersen experienced an adverse event, while 42/42 (100%) participants treated with the sham procedure had any adverse event (n = 126; moderate‐certainty evidence, downgraded one level for imprecision). Serious adverse events were reported in 14/84 (17%) participants in the nusinersen group and in 12/42 (29%) participants in the sham procedure group.
Oral olesoxime versus placebo
Bertini 2017 compared oral olesoxime versus placebo and reported outcomes at 24 months. See Table 6 for numerical results and summary of findings Table 5.
Primary outcome
Change in disability score
Change in disability, measured using the MFM was a primary outcome in Bertini 2017. There was no evidence of a difference in change in disability scores between the treatment and placebo groups (n = 160; very low‐certainty evidence, downgraded one level for study limitations (risk of bias), one level for imprecision and one level for indirectness). The trial also measured motor function using the HFMS, with little or no difference in the change from baseline between the treatment and placebo groups (n = 160; low‐certainty evidence, downgraded one level for study limitations (risk of bias) and one level for imprecision).
Secondary outcomes
Change in muscle strength
The study did not measure muscle strength.
Acquiring the ability to stand within one year after the onset of treatment
The study did not measure ability to stand.
Acquiring the ability to walk or improvement of walking within one year after the onset of treatment
The study did not measure ability to walk.
Change in quality of life
Bertini 2017 measured quality of life using the PedsQL Neuromuscular Module. There was no evidence of a difference in quality of life between the olesoxime‐treated group and the placebo group (n = 108; low‐certainty evidence, downgraded one level for study limitations and one level for imprecision).
Change in pulmonary function
Bertini 2017 measured the change in FVC in participants more than five years old. There was no evidence of a difference in pulmonary function between the treatment and placebo groups (n = 102; low‐certainty evidence, downgraded one level for study limitations and one level for imprecision).
Time from beginning of treatment until death or full‐time ventilation
Two participants died, one in the olesoxime group and one in the placebo group. Deaths were reported not to be related to the study treatment. There were no other deaths and none of the participants reached the state of more than 16 hours' ventilation a day (n = 160; moderate‐certainty evidence, downgraded one level for imprecision).
Adverse events, separated into severe and others
Bertini 2017 reported that 103 (95%) participants receiving olesoxime and 57 (100%) participants receiving placebo had at least one adverse event, with a total of 1104 adverse events in the olesoxime and 612 in the placebo group (n = 165; moderate‐certainty evidence, downgraded one level for imprecision). Severe adverse events occurred in 18 (17%) participants in the olesoxime group and 14 (25%) participants in the placebo group (Bertini 2017).
Oral phenylbutyrate versus placebo
Mercuri 2007 compared oral phenylbutyrate versus placebo. See Table 7 for numerical results and summary of findings Table 6.
Primary outcome
Change in disability score
Change in disability, measured on the HFMSE was a primary outcome in Mercuri 2007. There was no evidence of a difference for change in disability scores between the treatment and placebo groups (n = 90; low‐certainty evidence, downgraded one level because of risk of bias and one level for imprecision).
Secondary outcomes
Change in muscle strength
Muscle strength was measured via quantitative myometry. There was no evidence of a difference for change in arm or leg megascore between the treatment and placebo groups (both measurements n = 70; low‐certainty evidence, downgraded one level for study limitations and one level for imprecision).
Acquiring the ability to stand within one year after the onset of treatment
The study did not measure ability to stand.
Acquiring the ability to walk or improvement of walking within one year after the onset of treatment
The study did not measure ability to walk.
Change in quality of life
The study did not measure quality of life.
Change in pulmonary function
Mercuri 2007 measured the change in FVC in participants aged more than five years. There was no evidence of a difference in pulmonary function between the treatment and placebo groups (n = 67; low‐certainty evidence, downgraded one level for study limitations and one level for imprecision).
Time from beginning of treatment until death or full‐time ventilation
No deaths were reported (n = 107; low‐certainty evidence, downgraded one level for imprecision and one level for risk of bias).
Adverse events, separated into severe and others
In Mercuri 2007, 2/54 participants treated with phenylbutyrate, compared with 1/53 participants treated with placebo had adverse events. Only one person in each group had a severe adverse event (n = 107; moderate‐certainty evidence, downgraded one level for imprecision).
Subcutaneous somatotropin versus placebo
Kirschner 2014, which was a cross‐over study, compared subcutaneous somatotropin with placebo. See Table 8 for numerical results and summary of findings Table 7.
Primary outcome
Change in disability score
Kirschner 2014 measured disability as a secondary outcome using the HFMSE. Trial authors supplied additional data on the HFMSE for re‐analysis.
There was no evidence of a difference between the treatment and placebo periods in the change in disability scores (n = 19; very low‐certainty evidence, downgraded two levels for risk of bias and one level for imprecision).
Secondary outcomes
Change in muscle strength
Muscle strength was measured via quantitative myometry (MMT). Trial authors supplied additional data upon request. There was no evidence of a difference between the treatment and placebo periods for change in muscle strength in the upper limbs (n = 19; low‐certainty evidence) or in the lower limbs (n = 19; low‐certainty evidence, downgraded one level for risk of bias and one level for imprecision).
Acquiring the ability to stand within one year after the onset of treatment
The study did not measure ability to stand.
Acquiring the ability to walk or improvement of walking within one year after the onset of treatment
The study did not measure ability to walk.
Change in quality of life
The trial report states that significant differences were not detected between somatotropin and placebo in quality of life measures, but the report does not specify the measures used or provide numerical data.
Change in pulmonary function
Kirschner 2014 measured the change in FVC in participants aged more than five years. Trial authors supplied additional data on pulmonary function for re‐analysis. There was no evidence of a difference in pulmonary function between the treatment and placebo periods (n = 19; low‐certainty evidence, downgraded one level for risk of bias and one level for imprecision).
Time from beginning of treatment until death or full‐time ventilation
No deaths were reported and none of the participants reached more than 16 hours' ventilation a day (n = 19; low‐certainty evidence, downgraded one level for risk of bias and one level for imprecision).
Adverse events, separated into severe and others
In Kirschner 2014, 11 participants (55%) experienced 14 adverse events attributed to treatment while receiving somatotropin. Five events were classified as 'moderate' and two as 'severe', which resulted in termination of trial participation. In the placebo phase, a slightly smaller proportion of participants experienced adverse events, with seven participants reporting nine adverse events (n = 19; low‐certainty evidence, downgraded one level for risk of bias and one level for imprecision).
Intravenous thyrotropin‐releasing hormone versus placebo
Tzeng 2000 compared intravenous TRH versus placebo. See Table 9 for numerical results and summary of findings Table 8.
Primary outcome
Change in disability score
The study did not measure change in disability score.
Secondary outcomes
Change in muscle strength
Tzeng 2000 measured muscle strength via quantitative myometry. There was no evidence of a difference for change in hand, arm, feet, leg or total muscle strength except in one participant treated with TRH (n = 9; very low‐certainty evidence, downgraded one level for imprecision and two levels for study limitations).
No comparison was made by the study investigators between the treatment and placebo groups because the study size was considered too small.
Acquiring the ability to stand within one year after the onset of treatment
The study did not measure ability to stand.
Acquiring the ability to walk or improvement of walking within one year after the onset of treatment
The study did not measure ability to walk.
Change in quality of life
The study did not measure quality of life.
Change in pulmonary function
The study did not measure pulmonary function.
Time from beginning of treatment until death or full‐time ventilation
No deaths were reported and none of the participants reached the state of more than 16 hours' ventilation a day (n = 9; low‐certainty evidence, downgraded one level for imprecision and one level for study limitations).
Adverse events, separated into severe and others
In Tzeng 2000, the six participants treated with TRH had 12 adverse events, compared to no adverse events in the three participants in the placebo group (n = 9; very low‐certainty evidence, downgraded two levels for imprecision and one level for study limitations and indirectness).
Oral valproic acid (valproate) plus acetyl‐L‐carnitine versus placebo
Swoboda 2010 compared oral valproate plus ACL versus placebo. See Table 10 for numerical results and summary of findings Table 9.
Primary outcome
Change in disability score
Change in disability was a primary outcome in Swoboda 2010. The scale used was the GMFM. There was no evidence of a difference for change in disability scores between the treatment and placebo groups (n = 61; moderate‐certainty evidence, downgraded one level for imprecision).
Secondary outcomes
Change in muscle strength
Swoboda 2010 measured change in muscle strength via quantitative myometry. There was no evidence of a difference for change in hand, arm, feet, leg or total muscle strength between the treatment and placebo groups (n = 16; low‐certainty evidence, downgraded two levels for imprecision because of very small sample size).
Acquiring the ability to stand within one year after the onset of treatment
The study did not measure ability to stand.
Acquiring the ability to walk or improvement of walking within one year after the onset of treatment
The study did not measure ability to walk.
Change in quality of life
Quality of life was measured in Swoboda 2010 with the Profile Pediatric Quality of Life Inventory. There was no evidence of a difference in quality of life between the treatment and placebo groups (n = 16; very low‐certainty evidence, downgraded one level for risk of bias, one level for indirectness and one level for imprecision).
In Swoboda 2010 there was no statistically significant association between quality of life and change in MHFMS, but there was a non‐significant trend towards deterioration of quality of life as MHFMS declined.
Change in pulmonary function
Swoboda 2010 measured the change in FVC in participants aged more than five years. There was no evidence of a difference in pulmonary function between the treatment and placebo groups. The trial was noted to have insufficient power to observe a statistically significant association (n = 24; low‐certainty evidence, downgraded one level for risk of bias and one level for imprecision).
Time from beginning of treatment until death or full‐time ventilation
No deaths were reported and none of the participants reached the state of more than 16 hours' ventilation a day (n = 61; moderate‐certainty evidence, downgraded one level for imprecision).
Adverse events, separated into severe and others
In Swoboda 2010, 23/30 (77%) participants receiving treatment with valproic acid plus ALC had one or more adverse event compared to 18/31 (58%) participants in the placebo group. Severe adverse events occurred in 20% of the participants treated with valproic acid plus ALC and in 6% of the placebo group (n = 61; moderate‐certainty evidence, downgraded one level for imprecision).
Oral valproic acid (valproate) versus placebo
Kissel 2014 compared oral valproic acid (valproate) versus placebo. See Table 11 for numerical results and summary of findings Table 10.
Primary outcome
Change in disability score
Change in disability was a secondary outcome in Kissel 2014. The scale used was the SMAFRS. The trial authors made additional data available. There was no evidence of a difference for change in disability scores between treatment and placebo periods (n = 31; low‐certainty evidence, downgraded one level for study limitations and one level for imprecision).
Secondary outcomes
Change in muscle strength
Muscle strength was measured via quantitative myometry. There was no evidence of a difference for change in hand, arm, feet, leg or total muscle strength between treatment and placebo periods(n = 30; low‐certainty evidence, downgraded one level for study limitations and one level for imprecision).
Acquiring the ability to stand within one year after the onset of treatment
The study did not measure ability to stand.
Acquiring the ability to walk or improvement of walking within one year after the onset of treatment
The study did not measure ability to walk.
Change in quality of life
Change in quality of life was assessed with the mini‐SIP. Additional data were made available by the trial authors for re‐analysis. There was no evidence of a difference between treatment and placebo periods (n = 28; moderate‐certainty evidence, downgraded one level for study limitations).
Change in pulmonary function
Kissel 2014 included only adults and measured the change in FVC. Additional data were made available by the trial authors for re‐analysis. There was no evidence of a difference in pulmonary function between treatment and placebo periods (n = 24; low‐certainty evidence, downgraded one level for study limitations and one level for imprecision).
Time from beginning of treatment until death or full‐time ventilation
No deaths were reported and none of the participants reached the state of more than 16 hours' ventilation a day (n = 33; low‐certainty evidence, downgraded one level for imprecision and one level for study limitations)
Adverse events, separated into severe and others
The trial reported 96 adverse events. Trial authors supplied additional information on the types and number of adverse events. Thirty of the adverse events occurred in the valproic acid treatment period and 60 occurred in the placebo treatment period. Two of the events led to early termination of trial participation. Additionally, there were five serious adverse events; two in the valproic acid treatment period and three in the placebo treatment period, but all five were classified as unrelated to treatment (Kissel 2014) (n = 33; low‐certainty evidence, downgraded one level for imprecision and one level for study limitations).
Discussion
Summary of main results
We found 10 randomised controlled trials (including 717 participants) with data available to evaluate the efficacy of drug treatment in people with SMA types II and III (Bertini 2017; Chen 2010; Mercuri 2007; Mercuri 2018 (CHERISH); Miller 2001; Kirschner 2014; Kissel 2014; Swoboda 2010; Tzeng 2000; Wong 2007). Two of these trials included only people with SMA type II (Mercuri 2007; Mercuri 2018 (CHERISH)), and one trial only included ambulatory participants with SMA type III (Kissel 2014). Two RCTs included solely non‐ambulatory participants with SMA types II and III (Swoboda 2010), and types II and IIIa (Bertini 2017). The treatments investigated were oral creatine, oral gabapentin, oral hydroxyurea, intrathecally injected nusinersen, oral olesoxime, oral phenylbutyrate, subcutaneous injections of somatropin, intravenous TRH, and oral therapy with valproic acid with or without oral acetyl‐L‐carnitine.
Intrathecally injected nusinersen was an effective treatment for the improvement of motor function in SMA type II (Mercuri 2018 (CHERISH)), with moderate‐certainty evidence of improvement on the primary outcome (HFMSE) in the treatment group compared to a mean decline of motor scores in the sham‐procedure group.
Although open and uncontrolled trials with other drugs had seemed promising, none of the other included nine trials showed any efficacy on any of the primary outcome measures (Bertini 2017; Chen 2010; Mercuri 2007; Miller 2001; Kirschner 2014; Kissel 2014; Swoboda 2010; Tzeng 2000; Wong 2007).
One RCT did not demonstrate efficacy of oral gabapentin in adults aged 21 years and older with SMA types II and III (Miller 2001). Efficacy of oral hydroxyurea was not established in one trial in 57 participants (Chen 2010).
One RCT of olesoxime in 165 participants with SMA types II and III suggested beneficial effects from olesoxime compared to placebo with stabilisation or slight improvement of motor function in post hoc responder analysis (dichotomous analysis), but there was no effect on the original primary or secondary outcomes (Bertini 2017). The RCT in 107 participants with SMA type II showed no efficacy after three months of treatment with phenylbutyrate (Mercuri 2007). The cross‐over RCT of subcutaneous somatotropin in 20 participants with SMA types II and III showed no effect on muscle strength, motor function or pulmonary function (Kirschner 2014). Two trials investigated the effects of valproic acid in SMA, but both the trial of the combined therapy of valproic acid plus ALC in non‐ambulatory and the trial of monotherapy with valproic acid showed no significant improvement of motor function and muscle strength compared to placebo treatment (Kissel 2014; Swoboda 2010).
Our confidence in these findings of little or no effect was very low for TRH; low to very low for olesoxime and somatotropin; low for valproic acid, phenylbutyrate, gabapentin and hydroxyurea; and moderate for nusinersen, creatine and valproic acid plus ALC.
Nine additional RCTs investigating 4‐aminopyridine, ALC, CK‐2121707 hydroxyurea, pyridostigmine, riluzole, RO6885247/RG7800, salbutamol and valproic acid were completed but no data for analysis were available at the time of writing and they could not be included in the final assessment (ASIRI 2008; CHICTR‐TRC‐10001093; Merlini 2007; MOONFISH 2014; Morandi 2013; NCT00568802; NCT01645787; NCT02644668; SPACE). We consider it unlikely that the results of Merlini 2007 (last update received 2007), NCT00568802 (last update received 2008) and ASIRI 2008 (last update received 2011) will be published in the future, because publication of the results has already been delayed many years.
Evidence from other studies in spinal muscular atrophy
We discuss the results of treatment with each of these drugs from unreported and non‐randomised trials in SMA types II and III. Result of treatment in SMA type I is the topic of another Cochrane Review (Wadman 2019).
Carnitine
One RCT of treatment with ALC in 110 people with SMA types II and III is completed, but results are not available (Merlini 2007).
Celecoxib
One open‐label trial in children and adults with SMA types II and III is planned to investigate the effect of different dosages of celecoxib on SMN protein levels in peripheral leukocytes (NCT02876094).
CK‐2127107
One phase II RCT in 72 participants with SMA types II, III and IV to investigate safety and efficacy of CK‐2127107 150 mg or 450 mg daily compared to placebo is completed, but results are not yet available (see Characteristics of studies awaiting classification; NCT02644668).
Creatine
There are no known trials or studies on creatine in SMA, apart from the trial included in this review (Wong 2007).
Gabapentin
In one large randomised, unblinded and uncontrolled trial with gabapentin in 120 participants with SMA types II and III, there was a trend for improvement in the strength in favour of gabapentin treatment observed after 12 months, with no effect on FVC or other functional tests (Merlini 2003).
Hydroxyurea
In one uncontrolled pilot trial in two people with SMA type I, five people with SMA type II and two people with SMA type III, hydroxyurea showed an improvement in muscle strength without adverse effects (Chang 2002). One larger randomised uncontrolled trial from the same investigators, included 33 people with SMA types II and III and treated them with three different doses of hydroxyurea for eight weeks (Liang 2008). This trial showed increased SMN gene expression and a trend towards improvement in clinical outcome measures.
Lamotrigine
One case series of two people with SMA types II (aged 28 years) and III (aged 37 years) described the use of lamotrigine 50 mg/day for 10 years and reported no deterioration in motor function over five years of treatment (Nascimento 2010).
Neuromuscular junction interactors
Two out of four participants with SMA type II and III reported improved endurance in daily activities after taking pyridostigmine 4 mg/day divided over multiple daily doses (Wadman 2012a). One placebo‐controlled, cross‐over trial in people with SMA types II to IV on the effect of the acetylcholine esterase inhibitor pyridostigmine versus placebo is completed, but results are not yet available (SPACE). One double‐blind RCT in 12 participants with SMA type III aged 18 to 50 years has investigated the effect of 4‐aminopyridine 10 mg twice daily versus placebo. This trial is completed and results are pending (NCT01645787).
Nusinersen
Two phase I/II studies (one open‐label phase I study and its long‐term extension) in 28 participants with SMA types II or III aged two to 14 years showed no safety or tolerability concerns with intrathecal nusinersen treatment (Chiriboga 2016; Darras 2013; Haché 2016). One RCT investigating one dose of nusinersen compared to a sham‐procedure is ongoing and includes participants with atypical SMA type I, while excluding infants with a typical type I presentation (age at onset less than six months and having two SMN2 copies) (EMBRACE 2015). One trial is including genetically confirmed, presymptomatic infants with probable SMA type I (NURTURE 2015). One trial in 34 children with SMA types II and III, aged two to 14 years that investigated the effects of three doses of nusinersen at four different doses has been completed, and results are pending (NCT01703988). One open‐label trial in 52 children with SMA types II and III testing one dose of nusinersen is completed, but results are pending (NCT02052791). One open‐label extension study (SHINE 2015) evaluated the effects of continuous treatment in patients previously participating in Mercuri 2018 (CHERISH) and Finkel 2017 (ENDEAR). The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved the use of nusinersen for SMA types I to IV.
Olesoxime
One open‐label extension study with olesoxime was started (see OLEOS) to analyse long‐term effects in non‐ambulatory participants with SMA types II and III who participated in the previous study (Bertini 2017), but the pharmaceutical company announced that the trial and further development of olesoxime would be cancelled due to unsatisfactory results (Roche 2018).
Phenylbutyrate
One pilot study with phenylbutyrate 500 mg/kg/day using an intermittent schedule (seven days on and seven days off) in participants with SMA type II suggested positive effects on motor function after nine weeks of treatment with oral phenylbutyrate (Mercuri 2004). One multicentre phase I/II open‐label trial intentionally evaluating multiple dosage levels of sodium phenylbutyrate to determine the maximum tolerated dose or the highest dose that can be safely given to children with SMA types II or III was terminated after the inclusion of nine participants due to poor compliance to the study drug administration of 500 mg/kg/day (NPTUNE01 2007). Analysis of data is pending but is probably underpowered. One phase I/II open‐label study on sodium phenylbutyrate 450 mg/kg/day to 600 mg/kg/day in 14 presymptomatic infants genetically confirmed to have SMA with suspected SMA type I or II according to family history and SMN2 copy number, has been completed, but results are pending (see STOPSMA 2007).
Riluzole
One study on pharmacokinetics of oral riluzole in 14 participants aged six to 20 years with SMA types II and III indicated that a dose of 50 mg/day of riluzole showed the same daily exposure of riluzole as in the indicated levels in previous trials with people with amyotrophic lateral sclerosis (Abbara 2011). One RCT with riluzole in 141 participants with SMA types II and III is completed, but has not been published and data were not available (ASIRI 2008).
Salbutamol
One case series of nine people with SMA type II treated with salbutamol showed positive effects on pulmonary function and patient perception of motor function (Pasanisi 2014; Tan 2011). In one pilot trial with 13 participants with SMA types II and III, there was a significant increase in muscle strength and pulmonary function after six months of salbutamol treatment (Kinali 2002). The next open‐label trial involving 23 participants with SMA type II presented a significant improvement in functional scores after six and 12 months of treatment with salbutamol without any major adverse effects (Pane 2008). One open‐label trial with 28 participants with SMA types I to III, aged one to 20 years, showed an increase in motor function (HFMS) and pulmonary function in 25% of participants and stability of functional scores in the rest of participants. The results of this study have not been published and are only available through conference reports (Prufer de Queiroz Campos Araujo 2010). One pilot study in 10 participants with SMA types II to IV reported an improvement on perceived motor function, disability and fatigue after salbutamol treatment (Giovannetti 2016). Pulmonary function, including maximal static inspiratory pressure, sniff nasal inspiratory pressure and slow vital capacity, showed effects of one‐year treatment with daily oral salbutamol in seven children with SMA type II and III compared to a natural history cohort of children with SMA type II (Khirani 2017). Only one RCT with salbutamol is completed and suggested that salbutamol induced improvement of motor performance in the majority of the 45 adults with SMA type III. However, this trial has not been published and limited information is only available through conference abstracts (Morandi 2013).
Small molecules
RO6885247/RG7800
One phase I randomised, double‐blind, placebo‐controlled, multiple‐dose study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of RO6885247/RG7800 in people with SMA types I, II and III was started in November 2014, but later terminated due to potential safety reasons in December 2016 (for details see Studies awaiting classification; MOONFISH 2014).
RO7034067 or RG7916 (risdiplam)
One open‐label trial including children and adults aged 12 to 60 years with SMA types II and III, previously treated with an SMN2 anti‐sense oligonucleotide, is recruiting participants (JEWELFISH 2017). One RCT with RO7034067/RG7916 has started recruiting children and adults with SMA types II and III (SUNFISH 2016). One trial will include genetically confirmed, presymptomatic infants with SMA (RAINBOWFISH), but has not started at time of writing this review.
Somatropin
There are no known trials or studies on somatotropin in SMA, apart from the trial included in this review (Kirschner 2014).
Thyrotropin‐releasing hormone
A positive effect of TRH in SMA was considered since one uncontrolled study found improvement in motor function and electromyographic findings in participants with SMA types II and III after TRH therapy (Takeuchi 1994).
Valproic acid
Two case series and four open‐label studies showed an increase of SMN transcripts levels in almost all participants with oral valproic acid, but only possibly a beneficial effect on pulmonary function and variable results on motor abilities and muscle strength (Darbar 2011; Kissel 2011; Saito 2014; Swoboda 2009; Tsai 2007; Weihl 2006). One retrospective uncontrolled case series reported improvement of motor function in seven adults with SMA types III and IV during treatment with valproic acid (Weihl 2006). In another retrospective case series, global muscle strength improved in two children and one adolescent with SMA types II and III, but there was no effect in three other participants (Tsai 2007). One prospective case series of seven people with SMA types II and III showed increased SMN transcripts, overall improvement of pulmonary function and improved motor function (Saito 2014). One open‐label trial with 12‐month treatment of valproic acid and L‐carnitine in 33 children with SMA type III found no effects on motor function (Kissel 2011). One open‐label trial with valproic acid in 42 children and adults with SMA types I, II and III showed only slight improvement in gross motor function in younger non‐ambulatory type II children, variable responses of SMN transcripts in blood and carnitine depletion during treatment (Swoboda 2009). Results from the open‐label study in 13 participants aged one to seven years with SMA types I to III are pending (SMART01).
There are four ongoing studies with valproic acid in SMA, including one RCT investigating monotherapy with valproic acid in children with SMA types I and II aged one to seven years (SMART02), one RCT investigating combined therapy of valproic acid plus L‐carnitine in children aged two to 15 years with SMA types II and III (NCT01671384), and two open‐label trials including people with SMA types I, II and III (JPRN‐JapicCTI‐163450 2016; SMART03).
Overall completeness and applicability of evidence
All trials included in this review investigated the effects of drug treatment in children or adults (or both) with SMA types II and III, in terms of disability, muscle strength, ability to stand or walk, quality of life, time to death or full‐time ventilation and adverse events. The trials investigated 10 different treatments, additionally the inclusion criteria and outcome measures varied between trials, which makes it impossible to perform meta‐analyses.
A major issue in SMA, irrespective of the investigated therapy, is the timing of the treatment in relation to its potential effect. Previous experimental studies suggested that there is a limited window of opportunity to rescue or stabilise motor neuron function in the early or presymptomatic stages of the disease. None of the 10 trials identified for inclusion in this review primarily included people who had just been diagnosed. One phase I/II study with phenylbutyrate in presymptomatic infants genetically confirmed to have SMA, and suspected to have SMA type I or II according to family history and SMN2 copy number, has been completed and results are pending (STOPSMA 2007). One trial was started with nusinersen treatment in presymptomatic infants with genetically confirmed SMA (NURTURE 2015).
The practice of supportive care, e.g. pulmonary, nutritional and orthopaedic supportive therapy, in children and adults with SMA types II and III probably differs between centres and countries (Bladen 2014). Practice guidelines for the clinical care of children and adults with SMA are given in the consensus statement for standard care in SMA (Finkel 2018; Mercuri 2018). For future trials it is important that the level of supportive care is explicitly mentioned to avoid baseline differences in the treatment arms and between participating centres.
Certainty of the evidence
None of the included trials were completely free of bias according to the Cochrane 'Risk of bias' tool (Higgins 2011).
The randomisation method was not clear in four trials (Chen 2010; Kissel 2014; Tzeng 2000; Wong 2007). Allocation concealment was not clear in four trials (Chen 2010; Kissel 2014; Miller 2001; Wong 2007) and at high risk of bias in Tzeng 2000. Blinding of parents, participants and observers were adequate in all trials except Kissel 2014, for which the risk of bias related to blinding of participants and personnel and outcome assessors was unclear. We graded the risk of attrition bias high in four trials (Kirschner 2014; Mercuri 2007; Miller 2001; Swoboda 2010), and unclear in three trials (Bertini 2017; Kissel 2014; Wong 2007). Reporting bias was suspected in four trials (Bertini 2017; Chen 2010; Kirschner 2014; Tzeng 2000), and unclear in one trial (Miller 2001).
The cross‐over design with potential carry‐over effects in three studies placed two studies at unclear risk of bias (Kirschner 2014; Swoboda 2010), and one study at high risk of bias (Kissel 2014). Baseline differences resulted in potential bias in four trials, which we graded at either an unclear risk of bias (Mercuri 2018 (CHERISH); Swoboda 2010), or a high risk of bias (Bertini 2017; Wong 2007).
Grading unexplained heterogeneity or inconsistency of results was not possible, since we could not pool data in a meta‐analysis for any drug treatment. We downgraded the evidence one level for imprecision when studies were small or included an insufficient number of participants according to the power analysis of the study.
One issue that is noteworthy and unique for SMA is that the phenotype of patients varies significantly among and within SMA types II and III. Additionally, SMN2 copy number correlates with disease severity. Therefore, studies should consider SMA type and SMN2 copy number as a stratification criterion. None of the included studies incorporated SMN2 copy number in the inclusion criteria or subgroup analyses, which might have influenced results.
Motor assessments were all done with methods validated in SMA or other neuromuscular disorders. However, the disability scores and techniques to measure muscle strength currently used are possibly not sensitive enough to detect subtle changes in muscle strength and motor function, and may therefore underestimate or fail to detect a potential beneficial effect of treatment (type II error).
We are confident that we have minimised the risk of publication bias by evaluating all trial registries and screening trials and studies awaiting publication.
Potential biases in the review process
There may be some potential for bias in this review process as there were changes to the protocol. These included additions and deletions to the outcomes and alterations to the reporting of adverse events, as reported in Differences between protocol and review. None of these changes were made as a result of the findings of the included studies but rather to improve the structure of the review.
All the included trials were relatively small and had a short‐term follow‐up period. We did not extensively report on adverse events. We could not exclude the possibility of missing uncommon adverse events in our review.
We are confident that we have identified all clinically relevant trials, as we conducted a comprehensive search of all published literature and clinical trial registries, and three of the review authors regularly attend international conferences on SMA.
The results of our review might be biased since, at the time of writing, the results had not been published from nine completed trials, investigating 4‐AP (NCT01645787), ALC (Merlini 2007), CK‐2127107 (NCT02644668), hydroxyurea (NCT00568802), pyridostigmine (SPACE), riluzole (ASIRI 2008), rat nerve growth factor (CHICTR‐TRC‐10001093), RO06885247/RG7800 (MOONFISH 2014), and salbutamol (Morandi 2013).
The review authors are investigators in trials of different drug treatments in SMA. The search and selection of trials were not, however, biased by the review authors' involvement in these trials. Data analysis of the creatine trial (Wong 2007, with Dr Iannaccone as investigator and author) was performed by Drs Wadman and Vrancken. Data analysis for the olesoxime trial was checked by Dr Iannaccone, as Drs Wadman, van der Pol and Vrancken were site investigators (Bertini 2017).
Agreements and disagreements with other studies or reviews
To the best of our knowledge, there are no other systematic reviews considering the whole spectrum of drug treatments in SMA. Several reviews have also identified and discussed various drug treatments in SMA (Anderton 2015; Arnold 2013; Darras 2007; Lewelt 2012; Nurputra 2013; Stavarachi 2010; Swoboda 2007; Tisdale 2015), with some focusing specifically on preclinical studies (Seo 2013), genetic therapies (Donnelly 2012; Zanetta 2014), solely histone deacetylase inhibitor therapies (Mohseni 2013), SMN‐inducing therapies (Kaczmarek 2015), or small molecule and molecular therapies (Zanetta 2014). Our conclusions are in line with these reviews.
Although we have tried to give an overview of the efficacy of drug treatment with gabapentin, creatine, nusinersen, valproic acid with and without acetylcarnitine, somatotropin, TRH, phenylbutyrate, olesoxime and hydroxyurea in preclinical studies, studies with animal models of SMA or studies in participants with SMA (Discussion), the overview on non‐randomised and preclinical trials and studies was not based on a systematic review and potential studies might have been missed.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all 10 included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
| Oral creatine compared to placebo for children with SMA types II and III | ||||||
| Patient or population: children with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with oral creatine | |||||
| Change in disability score | The median change in disability score was –1 | Median change 1 higher | — | 40 | ⊕⊕⊕⊝ | — |
| Change in total muscle strength (total muscle strength) | The mean change in total muscle strength was 2.42 pounds | MD 1.25 pounds lower | — | 22 | ⊕⊕⊝⊝ | Only participants aged ≥ 5 years. |
| Acquiring the ability to stand or walk | Not measured | |||||
| Change in quality of life | The median change in quality of life was 2 | Median change 7 lower | — | 38 | ⊕⊕⊝⊝ | Higher scores on the PedsQL indicate better quality of life. |
| Change in pulmonary function | The mean change in pulmonary function was –0.83 % predicted | MD 0.56 % predicted higher | — | 23 | ⊕⊕⊝⊝ | Only participants aged ≥ 5 years. |
| Time from beginning of treatment until death or full‐time ventilation | 1 death occurred in the placebo group in 28 participants (36 per 1000) | 0 deaths occurred in the treatment group among 27 participants (0 per 1000) | — | 40 | ⊕⊕⊕⊝ | — |
| Adverse events related to treatment | 571 per 1000 | 480 per 1000 (291 to 800) | 0.84 (0.51 to 1.4) | 40 | ⊕⊕⊝⊝ | There were 43 events in 16/28 participants in placebo group and 55 events in 13/27 participants treated with creatine. Adverse events were systematically, prospectively collected at every study visit. Adverse events included mainly respiratory infections. |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; GMFM: Gross Motor Function Measure; MD: mean difference; MHFMS: Modified Hammersmith Functional Motor Scale; MMT: Manual Muscle Testing; PedsQL: Pediatric Quality of Life Inventory; RCT: randomised controlled trial; RR: risk ratio; SMA: spinal muscular atrophy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level for imprecision because of the small sample size. | ||||||
| Oral gabapentin compared to placebo for adults with SMA types II and III | ||||||
| Patient or population: adults with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with oral gabapentin | |||||
| Change in disability score | The median change in the SMAFRS score was 0 in the gabapentin group (37 participants) and –2 in the placebo group (34 participants) | — | 66 | ⊕⊕⊝⊝ | Higher scores on the SMAFRS indicate better function. | |
| Change in muscle strength | The mean change in muscle strength was –2.2% | MD 3.3% higher | — | 50 | ⊕⊕⊝⊝ | — |
| Acquiring ability to walk | 0/35 participants in the placebo group developed the ability to walk at 9 or 12 months' follow‐up | 0/38 participants treated with oral gabapentin developed the ability to walk at 9 or 12 months' follow‐up | — | 73 | ⊕⊕⊝⊝ | — |
| Change in quality of life | The mean change in quality of life was –0.26% | MD 0.36% higher | — | 67 | ⊕⊕⊝⊝ | Higher scores on the mini‐SIP indicate poorer health status. |
| Change in pulmonary function | The mean change in pulmonary function was –2.9 % predicted | MD 1.1 % predicted lower | — | 65 | ⊕⊕⊝⊝ | Data from analysis of participants who completed ≥ 2 visits. |
| Time from beginning of treatment to death or full‐time ventilation | 0 reported deaths and 0 participants required full‐time ventilation | — | 84 | ⊕⊕⊕⊝ | — | |
| Adverse events related to treatment | Adverse events were reported to be infrequent and not statistically different between treatment groups. Numerical data on adverse events were not available. | — | 65 | ⊕⊕⊝⊝ | Adverse events were systematically, prospectively collected at every study visit. | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; MD: mean difference; mini‐SIP: mini‐Sickness Impact Profile; PedsQL: Pediatric Quality of Life Inventory; RCT: randomised controlled trial; RR: risk ratio; SMA: spinal muscular atrophy; SMAFRS: Spinal Muscular Atrophy Functional Rating Scale. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level for imprecision because the small sample size. | ||||||
| Oral hydroxyurea compared to placebo for children and adults with SMA types II and III | ||||||
| Patient or population: children and adults with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with oral hydroxyurea | |||||
| Change in disability score | The mean change in disability score was 2.02 | MD 1.88 lower | — | 57 | ⊕⊕⊝⊝ | Higher scores on the GMFM indicate better function. |
| Change in disability score | The mean change in disability score was 0.04 | MD 0.02 lower | — | 38 | ⊕⊕⊕⊝ | Only performed in non‐ambulatory participants. |
| Change in muscle strength | The mean change in muscle strength was –0.03 | MD 0.55 lower | — | 57 | ⊕⊕⊕⊝ | — |
| Acquiring the ability to stand or walk | Not measured | |||||
| Change in quality of life | Not measured | |||||
| Change in pulmonary function | The mean change in pulmonary function was –0.22 L | MD 0.01 L higher | — | 57 | ⊕⊕⊝⊝ | — |
| Time from beginning of treatment until death or full‐time ventilation | 1 participant died in the treatment group after 5 visits (after 8 months of treatment), due to respiratory complications. | — | 57 | ⊕⊕⊕⊝ | Also reported as the 1 serious adverse event. | |
| Adverse events related to treatment | All participants experienced adverse events. 129 events occurred in the 20 participants in the placebo group. 224 events occurred in the 37 participants in the hydroxyurea group. | — | 57 | ⊕⊕⊕⊝ | Adverse events were systematically, prospectively collected using a questionnaire at every study visit. Adverse events: laboratory disturbances (e.g. neutropenia, thrombocytopenia, high transaminases), respiratory complaint, gastrointestinal complaints, rash, neurological symptoms, unspecified. 1 participant died in the treatment group due to respiratory complications.d | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level for imprecision. CIs were very wide. | ||||||
| Intrathecal injected nusinersen compared to sham procedure for children with SMA type II | |||||||
| Patient or population: children with SMA type II | |||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | ||
| Risk with sham procedure | Risk with intrathecal injected nusinersen | ||||||
| Change in disability score | The mean change in HFMSE in the control group was –1.9 points | The mean change in HFMSE in the nusinersen‐treated group was 5.9 points higher than in the sham procedure group (3.7 higher to 8.1 higher) | MD 5.9 (3.7 to 8.1) | 126 | ⊕⊕⊕⊝ | ||
| Change in disability score (3 point‐change) | 262 per 1000 | 471 per 1000 (259 to 812) | RR 1.8 (0.99 to 3.1) | 126 | ⊕⊕⊕⊝ | 11/42 participants in the sham‐controlled group showed a 3‐point change on the HFMSE. 48/84 participants in the nusinersen group showed a 3‐point change on the HFMSE. | |
| Change in muscle strength | Not measured | ||||||
| Acquiring the ability to stand or walk | Acquiring the ability to stand | 1/42 children in the sham‐controlled group acquired the ability to stand alone. | 1/84 children treated with nusinersen acquired the ability to stand alone. | RR 0.5 (0.03 to 7.80) | 126 | ⊕⊕⊝⊝ | |
| Acquiring the ability to walk | 0/42 children in the sham‐controlled group acquired the ability to walk with assistance. | 1/84 children treated with nusinersen acquired the ability to walk with assistance. | RR 1.5 (0.06 to 36.1) | 126 | ⊕⊕⊝⊝ | ||
| Change in quality of life | Not measured | ||||||
| Change in pulmonary function | Not measured | ||||||
| Time from beginning of treatment until death or full‐time ventilation | Not measured | ||||||
| Adverse events related to treatment | 1000 per 1000 | 900 per 1000 | RR 0.9 (0.9 to 1.0) | 126 | ⊕⊕⊕⊝ | 78/84 (93%) participants treated with nusinersen experienced an adverse event, while 42/42 (100%) participants treated in the sham‐controlled group had any adverse event. Adverse events were systematically, prospectively collected at every study visit. Adverse events included proteinuria, hyponatraemia, transient low platelet counts, vasculitis, pyrexia, headache, vomiting, back pain and epistaxis. | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HFMSE: Hammersmith Functional Motor Measure Expanded; MD: mean difference; MHFMS: Modified Hammersmith Functional Motor Scale; MMT: manual muscle testing; RCT: randomised controlled trial; RR: risk ratio; SMA: spinal muscular atrophy; WHO: World Health Organization. | |||||||
| GRADE Working Group grades of evidence | |||||||
| a Downgraded one level for imprecision because of the small sample size. | |||||||
| Oral olesoxime compared to placebo for non‐ambulatory children and adolescents with SMA types II and III | ||||||
| Patient or population: non‐ambulatory children and adolescents with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with oral olesoxime | |||||
| Change in disability score | The mean change in disability score was –1.82 | MD 2 higher | — | 160 | ⊕⊝⊝⊝ | Higher scores on the MFM indicate better function. Combined analysis of participants assessed with MFM‐32 or MFM‐20. |
| Change in disability score | The mean change in disability score was –1.45 | MD 2.04 higher | — | 160 | ⊕⊝⊝⊝ | Higher scores on the MFM indicate better function. Combined analysis of participants assessed with MFM‐32 or MFM‐20. |
| Change in disability score | Study population | RR 1.43 | 160 | ⊕⊝⊝⊝ | Higher scores on the MFM indicate better function. Participants were classified as 'responders' in case MFM‐32 or MFM‐20 showed no change or better scores compared to baseline, and 'non‐responders'. | |
| 39 per 100 | 55 per 100 | |||||
| Change in disability score | The mean change in disability score was –1.72 | MD 0.94 higher | — | 160 | ⊕⊕⊝⊝ | Higher scores on the HFMS indicate better function.a |
| Change in muscle strength | Not measured | |||||
| Acquiring the ability to stand or walk | Not measured | |||||
| Change in quality of life | — | MD 0.25 | — | 108 | ⊕⊕⊝⊝ | Higher scores on the PedsQL indicate a better quality of life. Scores on participants aged > 5 years. |
| Change in pulmonary function | The mean change in pulmonary function was +6.16 % predicted | MD 1.88 % predicted lower | — | 102 | ⊕⊕⊝⊝ | — |
| Time from beginning of treatment until death or full‐time ventilation | 2 participants died; 1 with cardiac arrest (olesoxime group) and 1 with increased bronchial secretions (placebo group). Deaths were not deemed to be related to treatment. | — | 160 | ⊕⊕⊕⊝ | — | |
| Adverse events related to treatment | 1000 per 1000 | 950 per 1000 | RR 0.95 (0.91 to 0.99) | 165 | ⊕⊕⊕⊝ | 612 events occurred in 57 participants in the placebo group. 1104 events occurred in 108 participants in the olesoxime group. Adverse events were systematically, prospectively collected at every study visit. Adverse events: (upper) respiratory tract infection, gastroenteritis, influenza, vomiting, abdominal pain, diarrhoea, cough, pyrexia, pain in extremity, scoliosis, arthralgia, fall, headache. |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; HFMS: Hammersmith Functional Motor Score; MD: mean difference; MFM: Motor Function Measure; MMT: manual muscle testing; PedsQL: Pediatric Quality of Life Inventory; RCT: randomised controlled trial; RR: risk ratio; SMA: spinal muscular atrophy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level for indirectness because trial authors combined two different outcome measures (MFM‐32 and MFM20) to assess the primary outcome with no correction in analysis. | ||||||
| Oral phenylbutyrate compared to placebo for children with SMA type II | |||||||
| Patient or population: children with SMA type II | |||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | ||
| Risk with placebo | Risk with oral phenylbutyrate | ||||||
| Change in disability score | The mean change in disability score was 0.73 | MD 0.13 lower | ‐ | 90 | ⊕⊕⊝⊝ | Higher scores on the HFMS indicate better function. | |
| Change in muscle strength | Leg megascore | The mean change in muscle strength (leg megascore) was 3.22 N | MD 1.04 N higher | — | 70 | ⊕⊕⊝⊝ | Children aged > 5 years had additional assessment of muscle strength by myometry. |
| Arm megascore | The mean change in muscle strength (arm megascore) was –0.42 N | MD 1.98 N higher | — | 72 | ⊕⊕⊝⊝ | Children aged > 5 years had additional assessment of muscle strength by myometry. | |
| Acquiring the ability to stand or walk | Not measured | ||||||
| Change in quality of life | Not measured | ||||||
| Change in pulmonary function | The mean change in pulmonary function was –0.01 % predicted | MD 0.04 % predicted higher | — | 67 | ⊕⊕⊝⊝ | Children aged > 5 years had additional assessment of FVC. | |
| Time from beginning of treatment until death or full‐time ventilation | No deaths were reported. No data available on ventilation. | — | 107 | ⊕⊕⊝⊝ | — | ||
| Adverse events related to treatment | 994 per 1000 | 292 per 1000 (118 to 740) | RR 3.1 (1.25 to 7.84) | 107 | ⊕⊕⊕⊝ | 5/53 participants had ≥ 1 adverse events in the phenylbutyrate and placebo group. 19/54 participants had ≥ 1 adverse events in the phenylbutyrate group. Adverse events were systematically and prospectively collected at every study visit. Adverse events included rash, drowsiness with hallucinations, nausea and constipation. No full report on types of adverse events was available. 3 participants discontinued the trial because of severe drowsiness, rash or constipation.b | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||||
| GRADE Working Group grades of evidence | |||||||
| a Downgraded one level because of risk of bias. | |||||||
| Subcutaneous somatotropin compared to placebo for children and adults with SMA types II and III | |||||||
| Patient or population: children and adults with SMA types II and III | |||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | ||
| Risk with placebo | Risk with subcutaneous somatotropin | ||||||
| Change in disability score | The median change in disability score was –1.05 | Median change 0.25 higher | — | 19 | ⊕⊝⊝⊝ | Higher scores on the HFMSE indicate better function. | |
| Change in muscle strength | Upper limbs | The mean change in muscle strength (upper limbs) was 0.30 N | MD 0.08 N lower | — | 19 | ⊕⊕⊝⊝ | — |
| Lower limbs | The mean change in muscle strength (lower limbs) was 0.95 N | MD 2.23 N higher | — | 19 | ⊕⊕⊝⊝ | — | |
| Acquiring the ability to stand or walk | Not measured | ||||||
| Change in quality of life Follow‐up: 40 weeks | The trial report states that the trial found no significant differences in quality of life between the somatotropin‐treated group and the placebo group. | — | 19 | ⊕⊝⊝⊝ | |||
| Change in pulmonary function | The mean change in pulmonary function was –0.11 L | MD 0.22 L higher | — | 19 | ⊕⊕⊝⊝ | — | |
| Time from beginning of treatment until death or full‐time ventilation | No participant died or required full‐time ventilation in either group | — | 19 | ⊕⊕⊝⊝ | — | ||
| Adverse events related to treatment | 368 per 1000 | 578 per 1000 (278 to 1000) | RR 1.57 | 19 | ⊕⊕⊝⊝ | 23 adverse events occurred, 14 during somatotropin treatment and 9 during placebo treatment. Adverse events were systematically, prospectively collected at every study visit. Adverse events included headache, arthralgia, myalgia, oedema, elevated serum thyroid‐stimulating hormone and myalgia. | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||||
| GRADE Working Group grades of evidence | |||||||
| a Downgraded two levels due to risk of bias. HFMSE ranges were not available and because of the potential carry‐over effect due to the cross‐over design. | |||||||
| Intravenous thyrotropin releasing hormone compared to placebo for children with SMA types II and III | ||||||
| Patient or population: children with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with intravenous TRH | |||||
| Change in disability score | Not measured | |||||
| Change in muscle strength | The mean change in muscle strength was 0.48 pounds | MD 0.34 pounds higher | — | 9 | ⊕⊝⊝⊝ | — |
| Acquiring the ability to stand or walk | Not measured | |||||
| Change in quality of life | Not measured | |||||
| Change in pulmonary function | Not measured | |||||
| Time to death or full‐time ventilation | Not measured but no deaths reported | — | 9 | ⊕⊕⊝⊝ Lowa,b | — | |
| Adverse events related to treatment | No events in 3 participants treated with placebo | 12 events in 6 participants treated with TRH | — | 9 | ⊕⊝⊝⊝ | Adverse events included abdominal discomfort, flushing, nausea and vomiting. |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; SMA: spinal muscular atrophy; TRH: thyrotropin‐releasing hormone. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level for sample size. | ||||||
| Oral valproic acid + acetyl‐L‐carnitine compared to placebo for non‐ambulatory children with SMA types II and III | ||||||
| Patient or population: non‐ambulatory children with SMA types II and III | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with oral valproic acid + acetyl‐L‐carnitine | |||||
| Change in disability score | The mean change in disability score was 0.18 | MD 0.64 higher | — | 61 | ⊕⊕⊕⊝ | Higher scores on the MHFMS indicate better function. |
| Change in muscle strength | The mean change in muscle strength was –0.25 kg | MD 1.43 kg higher | — | 16 | ⊕⊕⊝⊝ | Only performed in participants aged > 5 years. |
| Acquiring the ability to stand or walk | Not measured | |||||
| Change in quality of life | The mean change in quality of life was 0.3 | MD 2.2 lower | — | 54 | ⊕⊝⊝⊝ | Higher scores on the PedsQL indicate better quality of life. Only 54 participants completed PedsQL at follow‐up. Characteristics of this subset are unknown. |
| Change in pulmonary function | No numerical data available for analysis | — | 24 | ⊕⊕⊝⊝ | Only performed in participants aged > 5 years. | |
| Time from beginning of treatment until death or full‐time ventilation | 0 deaths or no need for full‐time ventilation | — | 61 | ⊕⊕⊕⊝ | — | |
| Adverse events related to treatment | 581 per 1000 | 755 per 1000 (534 to 1000) | RR 1.32 (0.92 to 1.89) | 61 | ⊕⊕⊕⊝ | 18/31 participants in the placebo group had ≥ 1 adverse events. 23/30 participants in the valproic acid + acetyl‐L‐carnitine group had ≥ 1 adverse events. Adverse events were systematically, prospectively collected at every study visit. |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; MD: mean difference; MHFMS: Modified Hammersmith Functional Motor Scale; PedsQL: Pediatric Quality of Life Inventory; RCT: randomised controlled trial; SMA: spinal muscular atrophy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded for imprecision because the small sample size. | ||||||
| Oral valproic acid compared to placebo for ambulatory adults with SMA type III | |||||||
| Patient or population: ambulatory adults with SMA type III | |||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | ||
| Risk with placebo | Risk with oral valproic acid | ||||||
| Change in disability score | The mean change in disability score was –0.35 | MD 0.06 higher | — | 31 | ⊕⊕⊝⊝ | Higher scores on the SMAFRS indicate better function. | |
| Change in muscle strength | Arms | The mean change in muscle strength of arms was –0.01 N | MD 0.23 N lower | — | 30 | ⊕⊕⊝⊝ | — |
| Legs | The mean change in muscle strength of legs was 0.35 N | MD 0.37 N lower | — | 30 | ⊕⊕⊝⊝ | — | |
| Acquiring the ability to stand or walk | Not measured | ||||||
| Change in quality of life | The mean change in quality of life was 0.91 | MD 1.1 lower | — | 28 | ⊕⊕⊝⊝ | Higher score on the mini‐SIP indicates a poorer health status. | |
| Change in pulmonary function | The mean change in pulmonary function was 0.53% predicted | MD 1.24% predicted lower | — | 24 | ⊕⊕⊕⊝ | — | |
| Time from beginning of treatment until death or full‐time ventilation | No deaths or full‐time ventilation | — | 33 | ⊕⊕⊕⊝ | — | ||
| Adverse events related to treatment | 455 per 1000 | 364 per 1000 (200 to 655) | RR 0.80 (0.44 to 1.44) | 33 | ⊕⊕⊝⊝ | 96 adverse events occurred, 66 in the placebo group and 30 in the valproic acid group. Adverse events were systematically, prospectively collected at every study visit and included upper airway tract infection or symptoms, dizziness, headache, peripheral neuropathy, tremor, fatigue, pain, abdominal pain, nausea, vomiting, decreased platelet count, weight gain and alopecia.a,b | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; MD: mean difference; mini‐SIP: mini‐Sickness Impact Profile; MVICT: maximum voluntary isometric contraction testing; RCT: randomised controlled trial; SMA: spinal muscular atrophy; SMAFRS: Spinal Muscular Atrophy Rating Scale; TRH: thyrotropin‐releasing hormone. | |||||||
| GRADE Working Group grades of evidence | |||||||
| a Downgraded one level because of potential carry‐over effect due to the cross‐over design. | |||||||
| Primary criteria |
| SMA type II: age of onset between 6 and 18 months and have been able to sit independently, but never been able to walk without assistance. SMA type III: age of onset after 18 months and has/had the ability to walk without assistance. |
| Genetic analysis to confirm the diagnosis, with deletion or mutation of the SMN1 gene (5q11.2‐13.3) |
| Supporting criteria |
| Symmetrical muscle weakness of limb and trunk. |
| Proximal muscles more affected than distal muscles and lower limbs more than upper limbs. |
| No abnormality of sensory function. |
| Serum creatine kinase activity ≤ 5 times the upper limit of normal |
| Denervation on electrophysiological examination, and no nerve conduction velocities < 70% of the lower limit of normal. No abnormal sensory nerve action potentials. |
| Muscle biopsy showing atrophic fibres of both types, hypertrophic fibres of one type (usually type I), and in chronic cases type grouping. |
| No involvement of the central neurological systems, such as hearing or vision. |
| Creatine | Placebo | Difference (95% CI) | P value | |
| All ages | ||||
| Number of participants randomised | 27 | 28 | — | — |
| Number (%) of participants evaluable for analysis disability | 18 (67%) | 22 (79%) | — | — |
| Median change in disability score (GMFM) | 0 | ‐1 | 1 (‐1 to 2) | 0.19 |
| Number (%) of participants evaluable for analysis QoL | 17 (63%) | 21 (75%) | — | — |
| Median change in quality of life (PedsQL, neuromuscular module) | ‐5 | 2 | ‐7 (‐11 to 3) | 0.31 |
| Age 2 to 5 years | ||||
| Number of participants randomised | 8 | 12 | — | — |
| Number (%) of participants evaluable for analysis disability | 7 (88%) | 10 (83%) | — | — |
| Median change in disability score (GMFM) | 1 | ‐2 | 1.5 (‐4 to 9) | 0.18 |
| Number (%) of participants evaluable for analysis QoL | 6 (75%) | 9 (75%) | — | — |
| Median change in QoL (PedsQL, neuromuscular module) | 4.5 | 3 | 2 (‐8 to 13) | 0.71 |
| Age 5 to 18 years | ||||
| Number of participants randomised | 19 | 16 | — | — |
| Number (%) of participants evaluable for analysis disability and QoL | 11 (58%) | 12 (75%) | — | — |
| Median change in disability score (GMFM) | ‐1 | ‐0.5 | 0 (‐2 to 2) | 0.77 |
| Number (%) of participants evaluable for analysis QoL | 11 (58%) | 12 (75%) | — | — |
| Median change in quality of life (PedsQL, neuromuscular module) | ‐6 | 0 | ‐6 (‐15 to 2) | 0.11 |
| Number (%) of participants evaluable for analysis of muscle strength | 11 (58%) | 11 (69%) | — | — |
| Mean (SD) change in arms muscle strength (QMT) | ‐0.34 (6.98) | 1.49 (8.50) | ‐1.83 (‐8.75 to 5.09) | 0.59 |
| Mean (SD) change in legs muscle strength (QMT) | 1.51 (4.21) | 0.93 (3.06) | 0.58 (‐2.70 to 3.85) | 0.72 |
| Mean (SD) change in total muscle strength (QMT) | 1.17 (9.67) | 2.42 (10.3) | ‐1.25 (‐10.1 to 7.6) | 0.77 |
| Number (%) of participants evaluable for analysis pulmonary function | 11 (58%) | 12 (75%) | — | — |
| Mean (SD) change in pulmonary function (FVC % of predicted value in litres) | ‐0.27 (14.5) | ‐0.83 (11.5) | 0.56 (‐10.75 to 11.87) | 0.92 |
| Creatine | Placebo | Risk ratio (95% CI) | P value | |
| All ages | ||||
| Number of adverse events | 55 | 43 | — | — |
| Number of participants with adverse events | 13/27 | 16/28 | 0.84 (0.51 to 1.40) | 0.59 |
| Number of severe adverse events | NA | NA | — | — |
| Number of participants with severe adverse events | NA | 1 (death by respiratory failure) | — | — |
| CI: confidence interval; FVC: forced vital capacity; GMFM: Gross Motor Function Measure; NA: not available; PedsQL: Pediatric Quality of Life Inventory; QMT: quantitative muscle test; QoL: quality of life; SD: standard deviation. | ||||
| Gabapentin | Placebo | Difference (95% CI) | P value | |
| Follow‐up at 12 months | ||||
| Number (%) of participants evaluable for analysis disability | 32 (80%) | 34 (77%) | — | — |
| Median change in disability score (SMAFRS) | 0 | ‐2 | 1 (‐1 to 4) | 0.30 |
| Number (%) of participants evaluable for analysis quality of life | 33 (83%) | 34 (77%) | — | — |
| Mean change in quality of life (mini‐SIP) | 0.09 | ‐0.26 | 0.36 (‐0.29 to 1) | 0.28 |
| Number (%) of participants evaluable for analysis grip muscle strength | 30 (75%) | 31 (70%) | — | — |
| Mean change in grip muscle strength (MVC) in percentage from baseline | 0.08 | ‐4.5 | 4.6 (‐2.5 to 11.6) | 0.57 |
| Number (%) of participants evaluable for analysis arms muscle strength | 28 (70%) | 29 (66%) | — | — |
| Mean change in arms muscle strength (MVC) in percentage from baseline | 0.05 | ‐1.8 | 1.9 (‐2.5 to 6.2) | 0.39 |
| Number (%) of participants evaluable for analysis feet muscle strength | 28 (70%) | 29 (66%) | — | — |
| Mean change in feet muscle strength (MVC) in percentage from baseline | 0.36 | 0.70 | 0.29 (‐8.3 to 8.9) | 0.95 |
| Number (%) of participants evaluable for analysis total muscle strength | 25 (63%) | 25 (57%) | — | — |
| Mean change in total muscle strength (MVC) in percentage from baseline | 1.2 | ‐2.2 | 3.3 (‐6.9 to 14) | 0.52 |
| Number (%) of participants evaluable for analysis development of walking | 38 (95%) | 35 (80%) | — | — |
| Number of participants with development of walking | 0 | 0 | — | — |
| Number (%) of participants evaluable for analysis pulmonary function | 31 (78%) | 34 (77%) | — | — |
| Mean change in pulmonary function (FVC % of predicted value) | ‐4.0 | ‐2.9 | ‐1.1 (‐4.1 to 1.9) | 0.48 |
| Gabapentin | Placebo | Risk ratio (95% CI) | P value | |
| Number of adverse events | NA | NA | — | — |
| Number of participants with adverse events | NA | NA | — | — |
| Number of severe adverse events | 0 | 0 | — | — |
| Number of participants with severe adverse events | 0 | 0 | — | — |
| CI: confidence interval; FVC: forced vital capacity; mini‐SIP: mini Sickness Impact Profile; MVC: maximum voluntary contraction; NA: not available; SMAFRS: Spinal Muscular Atrophy‐Functional Rating Scale. | ||||
| Hydroxyurea | Placebo | Difference (95% CI) | P value | |
| All ages | ||||
| Number of participants randomised | 37 | 20 | — | — |
| Number (%) of participants evaluable for analysis disability (GMFM) | 37 (100%) | 20 (100%) | — | — |
| Mean change (SE) in disability score (GMFM) | 0.14 (0.57) | 2.02 (0.88) | ‐1.88 (‐3.89 to 0.13) | 0.07 |
| Number (%) of participants evaluable for analysis muscle strength (MMT) | 37 (100%) | 20 (100%) | — | — |
| Mean change (SE) in muscle strength (MMT) | ‐0.58 (0.56) | ‐0.03 (0.98) | ‐0.55 (‐2.65 to 1.55) | 0.60 |
| Number (%) of participants evaluable for pulmonary function (FVC in litres) | 37 (100%) | 20 (100%) | — | — |
| Mean (SE) change in pulmonary function (FVC in litres) | ‐0.21 (0.06) | ‐0.22 (0.12) | ‐0.01 (‐0.25 to 0.26) | 0.93 |
| Number (%) of participants evaluable for analysis disability (MHFMS) | 26 (100%) | 12 (100%) | — | — |
| Mean change (SE) in disability score (MHFMS) | 0.02 (0.03) | 0.04 (0.04) | ‐0.02 (‐0.12 to 0.07) | 0.70 |
| Hydroxyurea | Placebo | Risk ratio (95% CI) | P value | |
| Number of adverse event episodes | 224 | 129 | — | 0.65 |
| Mean number (SD) of adverse event episodes per participant | 6.05 (3.43) | 6.45 (2.91) | ‐0.4 (‐2.21 to 1.41) | 0.66 |
| Number of severe adverse event episodes | 19 | 10 | — | 0.96 |
| Mean number (SD) of severe adverse event episodes per participant | 0.51 (1.04) | 0.50 (0.83) | 0.01 (‐0.77 to 0.79) | 0.96 |
| Number (%) of participants discontinued intervention | 2 (5%) | 0 (0%) | — | — |
| FVC: forced vital capacity; GMFM: Gross Motor Function Measure; MHFMS: Modified Hammersmith Functional Motor Scale; MMT: manual muscle testing; SD: standard deviation; SE: standard error. | ||||
| Nusinersen | Placebo | Difference (95% CI) | P value | |
| Number of participants randomised | 84 | 42 | — | — |
| Interim analysisa | 84b | 42b | — | — |
| Mean change in HFMSE | 4.0 | ‐1.9 | 5.9 (3.7 to 8.1) | < 0.001 |
| Final analysis | 84c | 42c | — | — |
| Mean change in HFMSE | 3.9 | ‐1.0 | 4.9 (3.1 to 6.7) | — |
| Nusinersen | Placebo | Difference (95% CI) | P value | |
| Percentage of participants with 3‐point‐change on HFMSE (%) | 57 | 26 | 30.5 (12.7 to 48.3) | < 0.001 |
| Percentage (number) of children who achieved ≥ 1 new WHO motor milestone (% (number)) | 20 (13) | 6 (2) | 14 (‐7 to 34) | 0.08 |
| Nusinersen | Placebo | Risk ratio (95% CI) | P value | |
| Percentage (number) of children who achieved ability to stand alone | 2 (1) | 3 (1) | 0.5 (0.03 to 7.80) | — |
| Percentage (number) of children who achieved ability to walk with assistance | 2 (1) | 0 (0) | 1.5 (0.06 to 36.1) | — |
| Number of participants with adverse events | 78 | 42 | 0.9 (0.9 to 1.0) | 0.01 |
| CI: confidence interval; HFMSE: Hammersmith Functional Motor Scale Expanded; WHO: World Health Organization. a Conducted in children who completed at least six months of the trial. Data of children who had not yet completed the 15‐month period were imputed. | ||||
| Olesoxime | Placebo | Estimated difference (95% CI)a | P value | |
| Number of participants randomised | 108 | 57 | — | — |
| Number (%) of participants evaluable for analysis MFM‐32 D1+D2 | 103 (95%) | 57 (100%) | — | — |
| Meanab change (95% CI) in disability score (MFM D1+D2) at 24 months | ‐0.18 (‐1.30 to 1.66) | ‐1.82 (‐3.68 to 0.04) | 2.00 (‐0.25 to 4.25) | 0.07 |
| Number (%) of participants evaluable for analysis MFM total score | 103 (95%) | 57 (100%) | — | — |
| Meanab change (95% CI) in disability score (MFM total score) at 24 months | 0.59 (‐0.9 to 2.070 | ‐1.45 (‐3.31 to 0.41) | 2.04 (‐0.21 to 4.28) | 0.08 |
| Number (%) of participants evaluable for analysis HFMS | 103 (95%) | 57 (100%) | — | — |
| Meanb change (95% CI) in disability score (HFMS) at 24 months | ‐0.78 (‐1.60 to 0.04) | ‐1.72 (‐2.74 to ‐0.70) | 0.94 (‐0.28 to 2.17) | 0.13 |
| Number (%) of participants evaluable for analysis of nerve innervation value (CMAP) (in mV) | 70 (65%) | 34 (60%) | — | — |
| Meanb (95% CI) change in total amplitude CMAP from baseline to 24 months | ‐0.07 (‐0.49 to 0.36) | ‐0.16 (‐0.74 to 0.43) | NA | 0.79 |
| Number (%) of participants evaluable for analysis of MUNE | 58 (54%) | 30 (53%) | — | — |
| Meanb (95% CI) change in total MUNE from baseline to 24 months | ‐4.51 (‐12.21 to 3.18) | ‐6.69 (‐16.86 to 3.48) | NA | 0.71 |
| Number (%) of participants evaluable for FVC | 64 (59%) | 38 (67%) | — | — |
| Meanb (95% CI) change in FVC from baseline to 24 months | 4.28 (‐0.32 to 8.88) | 6.16 (1.00 to 11.33) | ‐1.88 (‐3.14 to 6.91) | 0.57 |
| Olesoxime | Placebo | Difference (95% CI) | P value | |
| Number (%) of participants evaluable for analysis of quality of life (PedsQL) from baseline to 24 months | 71 (66%) | 37 (65%) | — | — |
| Mean (SD) change in quality of life (PedsQL) from baseline to 24 months | NA | NA | 0.25 (‐4.58 to 5.08) | 0.92 |
| Olesoxime | Placebo | Risk ratio (95% CI) | P value | |
| Number (%) of participants evaluable for responder analysis MFM‐32 score D1+D2 (24 months) | 103 (95%) | 57 (100%) | — | — |
| Proportion of participants with good response according to MFM‐32 score D1+D2c | 56 (54) | 22 (39) | 1.43 (‐0.98 to 2.08) | 0.06 |
| Number of adverse events | 1104 (64) | 612 (36) | — | — |
| Number (%) of participants with adverse events | 103 (95%) | 57 (100%) | 0.95 (0.91 to 0.99) | 0.02 |
| Number (%) of participants with severe adverse events | 18 (17%) | 14 (25%) | 0.67 (0.37 to 1.26) | — |
| Number of deaths | 1 | 1 | — | — |
| Number (%) of participants discontinued intervention | 10 (9%) | 7 (12%) | — | — |
| CI: confidence interval; CMAP: compound muscle action potential; FVC: forced vital capacity; HFMS: Hammersmith Functional Motor Scale; MFM: Motor Function Measure; MFM D1+D2: functional domains 1 and 2 of the Motor Function Measure; MUNE: motor unit number estimation; NA: not available; PedsQL: Pediatric Quality of Life Inventory; SD: standard deviation. a Least squared mean of MFM, including MFM‐32 and MFM‐20 assessments. | ||||
| Phenylbutyrate | Placebo | Difference (95% CI) | P value | |
| All ages | ||||
| Number of participants randomised | 54 | 53 | — | — |
| Number (%) of participants evaluable for analysis of HFMS | 45 (83%) | 45 (85%) | — | — |
| Mean (SD) HFMS | 12.1 (9.60) | 12.8 (9.86) | ‐0.7 (‐4.78 to 3.78) | 0.70 |
| Mean (SD) change in HFMSa | 0.60 (0.22) | 0.73 (0.29) | ‐0.13 (‐0.84 to 0.58) | 0.70 |
| Age > 5 years | ||||
| Mean (SD) change in muscle strength arm megascore (dynamometry)a | 1.56 (6.94) | ‐0.42 (8.61) | 1.98 (‐1.67 to 5.63) | 0.74 |
| Mean (SD) change muscle strength leg megascore (dynamometry)a | 4.26 (8.64) | 3.22 (6.26) | 1.04 (‐2.46 to 4.54) | 0.78 |
| Number (%) of participants evaluable for analysis of HFMS | 26 (48%) | 23 (43%) | — | — |
| Mean (SD) change in pulmonary function (FVC % of predicted value in litres)a | 0.03 (0.17) | ‐0.01 (0.27) | 0.04 (‐0.07 to 0.15) | 0.39 |
| Phenylbutyrate | Placebo | Risk ratio (95% CI) | P value | |
| All ages | ||||
| Number of participants with adverse events | 19 | 5 | 3.1 (1.25 to 7.84) | 0.01 |
| Number of withdrawals because of adverse events | 6 | 3 | 1.86 (0.49 to 7.11) | 0.9 |
| Number of severe adverse events | 1 | 2 | — | — |
| Number of participants with severe adverse events | 1 | 2 | 1.96 (0.18 to 21.0) | 1.0 |
| CI: confidence interval; FVC: forced vital capacity; HFMS: Hammersmith Functional Motor Scale; SD: standard deviation; aMean change from baseline. | ||||
| Total number of participants randomised (cross‐over setting) | 20 | — | — | |
| Somatropin | Placebo | Difference (95% CI) | P value | |
| Number of participants completing phase 1 of study protocol | 9/10 | 10/10 | — | — |
| Number of participants completing phase 2 of study protocol | 8/10 | 9/10 | — | — |
| Number (%) of participants evaluable for intention‐to‐treat analysis | 17 (90%) | 17 (80%) | — | — |
| Mean (SD) change in muscle strength of upper limb (hand‐held myometry in megascore of biceps and handgrip) (Newton) | ‐1.05 (6.42) | 0.30 (10.6) | ‐1.35 (‐7.12 to 4.42) | 0.97 |
| Number (%) of participants evaluable for analysis disability score (HFMSE) | 19 (95%) | 19 (95%) | — | — |
| Median (SD) change in disability score (HFMSE) | 0.05 (3.19) | ‐1.05 (5.28) | 0.25 (‐1 to 2.5) | 0.58 |
| Number (%) of participants evaluable for analysis arm megascore | 19 (95%) | 19 (95%) | — | — |
| Mean (SD; range) change in arm megascore (Newton) | ‐1.05 (6.42; | 0.30 (10.60; | 0.08 (‐3.79 to 3.95) | 0.97 |
| Number (%) of participants evaluable for analysis leg megascore | 19 (95%) | 19 (95%) | — | — |
| Mean (SD; range) change in leg megascore (Newton) | 2.96 (7.64; ‐10 to 24.5) | 0.95 (9.93; ‐18 to 22) | 2.23 (‐2.19 to 6.63) | 0.30 |
| Number (%) of participants evaluable for analysis muscle strength (MRC) | 19 (95%) | 19 (95%) | — | — |
| Mean (SD) change MRC (% of maximum score) | ‐2.31 (5.1) | 0.43 (7.0) | ‐2.74 (‐6.7 to 1.29) | 0.19 |
| Number (%) of participants evaluable for analysis pulmonary function (FVC) | 19 (95%) | 19 (95%) | — | — |
| Mean (SD; range) change in pulmonary function (FVC improvement in litres) | 0.12 (0.25; ‐0.4 to 0.5) | ‐0.11 (0.40; ‐1.4 to 0.36) | 0.23 (‐0.01 to 0.45) | 0.08 |
| Somatropin | Placebo | Risk Ratio (95% CI) | P value | |
| Number of adverse events | 14 | 9 | — | — |
| Number of participants with adverse events | 11 | 7 | 1.57 (0.78 to 3.17) | 0.34 |
| Number (%) of participants discontinued intervention | 3 (15%) | 0 (0%) | — | — |
| CI: confidence interval; FVC: forced vital capacity; HFMSE: Hammersmith Functional Motor Scale Expanded; MRC: Medical Research Council; SD: standard deviation. | ||||
| TRH | Placebo | Difference (95% CI) | |
| Number of participants randomised | 6 | 3 | — |
| Number (%) of participants evaluable for analysis | 6 (100%) | 3 (100%) | — |
| Mean (SD) change in muscle strength (dynamometry in pounds) | 0.82 (0.59) | 0.48 (0.29) | 0.34 (‐0.54 to 1.22) |
| TRH | Placebo | Risk ratio (95% CI) | |
| Number of adverse events | 12 | 0 | — |
| Number of participants with adverse events | NA | NA | — |
| Number of severe adverse events | 0 | 0 | — |
| Number of participants with severe adverse events | 0 | 0 | — |
| CI: confidence interval; NA: not available; SD: standard deviation; TRH: thyrotropin‐releasing hormone. | |||
| Valproic acid + acetyl‐L‐carnitine | Placebo | Difference (95% CI) | P value | |
| All ages | ||||
| Number of participants randomised | 31 | 30 | — | — |
| Number (%) of participants evaluable for analysis disability (MHFMS) | 28 (90%) | 28 (93%) | — | — |
| Mean change (SD) in disability score (MHFSM) at 6 months | 0.82 (2.88) | 0.18 (3.98) | 0.64 (‐1.1 to 2.38) | 0.50 |
| Number (%) of participants evaluable for analysis of nerve innervation value (CMAP) | 19 (61%) | 19 (63%) | — | — |
| Mean (SD) change in total amplitude CMAP from baseline to 6 months | 0.02 (0.70) | ‐0.10 (0.66) | 0.12 (‐0.33 to 0.57) | 0.59 |
| Number (%) of participants evaluable for analysis of quality of life (PedsQL) from baseline to 12 months | 27 (87%) | 27 (90%) | — | — |
| Mean (SD) change in quality of life (PedsQL) from baseline to 12 months | ‐1.9 (13.6) | 0.3 (12.9) | ‐2.2 (‐9.27 to 4.87) | 0.54 |
| Age < 3 years old | ||||
| Number (%) of participants evaluable for analysis disability (MHFMS) | 12 (52%) | 11 (48%) | — | — |
| Mean change (SD) in disability score (MHFSM) from baseline to 6 months | 1.33 (2.27) | 1.09 (5.37) | 0.24 (‐3.28 to 3.76) | 0.89 |
| Aged 3–8 years | ||||
| Number (%) of participants evaluable for analysis disability (MHFSM) | 18 (47%) | 17 (45%) | — | — |
| Mean change (SD) in disability score (MHFSM) from baseline to 6 months | 0.44 (3.29) | ‐0.41 (2.79) | 0.85 (‐1.25 to 2.95) | 0.42 |
| Aged ≥ 5 years | ||||
| Number of participants evaluable for analysis muscle strength in arms (myometry) | 7 | 7 | — | — |
| Mean (SD) change in arm muscle strength (myometry) from baseline to 6 months (kg) | 0.64 (0.6) | 0.07 (1.04) | 0.57 (‐0.45 to 1.58) | 0.23a |
| Number of participants evaluable for analysis muscle strength in legs (myometry) | 6 | 4 | — | — |
| Mean (SD) change in leg muscle strength (myometry) from baseline to 6 months (kg) | 0.55 (0.83) | ‐0.85 (2.22) | 1.40 (‐1.98 to 4.79) | 0.19a |
| Number of participants evaluable for analysis muscle strength in both arms and legs (myometry) | 7 | 8 | — | — |
| Mean (SD) change in total muscle strength (myometry) from baseline to 6 months (kg) | 1.18 (0.91) | ‐0.25 (2.47) | 1.43 (0.69 to 3.56) | 0.21 |
| Number of participants evaluable for analysis pulmonary function (FVC in % of predicted) | NA | NA | NAa | NAa |
| Mean (SD) change in pulmonary function (FVC in % of predicted) from baseline to 6 months | NA | NA | — | — |
| Valproic acid + acetyl‐L‐carnitine | Placebo | Risk ratio (95% CI) | P value | |
| All ages | ||||
| Number (%) of participants with adverse events (6 months) | 23 (77%) | 18 (58%) | 1.32 (0.92 to 1.89) | — |
| Number (%) of participants with severe adverse events (6 months) | 6 (20%) | 2 (6%) | 3.1 (0.60 to 12.1) | — |
| CI: confidence interval; CMAP: compound maximum action potential; FVC: forced vital capacity; MHFMS: Modified Hammersmith Functional Motor Scale; PedsQL: Pediatric Quality of Life Inventory; SD: standard deviation. a Underpowered. | ||||
| Valproic acid | Placebo | Difference (95% CI)a | P value | |
| Number (%) of participants randomised first 6 months (cross‐over setting) | 16 (100%) | 17 (100%) | — | — |
| Number (%) of participants evaluable for analysis after 12 months | 30 (91%) | 30 (91%) | — | — |
| Analysis after 6 months before cross‐over | ||||
| Number (%) of participants evaluable for analysis SMAFRS | 14 (88%) | 17 (100%) | — | — |
| Mean (SD) change in SMAFRS | ‐0.29 (1.59) | ‐0.35 (2.32) | 0.06 (‐1.32 to 1.44) | 0.93 |
| Number (%) of participants evaluable for analysis upper extremity | 14 | 16 | — | — |
| Mean (SD) change in MVICT upper extremity (Newton) | ‐0.24 (1.17) | ‐0.01 (1.05) | ‐0.23 (‐1.03 to 0.57) | 0.54 |
| Number (%) of participants evaluable for analysis lower extremity | 13 | 16 | — | — |
| Mean (SD) change in lower extremity MVICT (Newton) | ‐0.02 (0.65) | 0.35 (1.30) | ‐0.37 (‐1.09 to 0.35) | 0.36 |
| Number (%) of participants evaluable for analysis pulmonary function (FVC) | 14 (88%) | 17 (100%) | — | — |
| Mean (SD; range) change in pulmonary function (FVC improvement in litres) | ‐0.04 (0.35) | 0.30 (1.20) | ‐0.34 (‐0.94 to 0.26) | 0.31 |
| Number of participants evaluable for QoL analysis | 14 | 17 | — | — |
| Mean (SD) change in mini‐SIP for QoL | ‐0.19 (2.80) | 0.91 (4.78) | ‐1.1 (‐3.8 to 1.6) | 0.53 |
| Valproic acid | Placebo | Risk ratio (95% CI)a | P value | |
| Number of adverse events | 30 | 66 | — | — |
| Number of participants with adverse events | 12 | 15 | 0.8 (0.44 to 1.44) | |
| Number of severe adverse events | 2 | 3 | — | — |
| Number of participants with severe adverse events | 2 | 2 | 1.0 (0.15 to 6.69) | — |
| Number (%) of participants discontinued intervention | NA | NA | — | — |
| CI: confidence interval; FVC: forced vital capacity; mini‐SIP: mini‐Sickness Illness Profile; MVICT: maximum voluntary isometric contraction; NA: not available; QoL: quality of life; SD: standard deviation; SMAFRS: Spinal Muscular Atrophy Functional Rating Scale. aCalculated with available data. | ||||
