Potenciadores (tratamientos específicos de las mutaciones de clase III y IV) para la fibrosis quística
Resumen
Antecedentes
La fibrosis quística (FQ) es la enfermedad hereditaria más frecuente que acorta la vida de los caucásicos y es causada por una mutación en el gen que codifica la proteína reguladora de transmembrana de la fibrosis quística (en inglés, CFTR), que funciona como un transportador de sal. Esta mutación afecta principalmente las vías respiratorias, donde la absorción excesiva de sales deshidrata el recubrimiento de las vías respiratorias y da lugar al deterioro en la depuración mucociliar. En consecuencia, el moco espeso y pegajoso se acumula, lo que provoca que la vía respiratoria sea propensa a infecciones crónicas y a inflamación progresiva, y a menudo provoca insuficiencia respiratoria. Otras complicaciones incluyen: desnutrición, diabetes y subfertilidad.
La mayor comprensión del trastorno ha permitido a las compañías farmacéuticas diseñar tratamientos específicos para las mutaciones, dirigidos al defecto molecular subyacente. Los potenciadores de CFTR se dirigen a las clases de mutación III y IV e intentan normalizar el líquido de la superficie de las vías respiratorias y la depuración mucociliar, lo que a la vez repercute en la infección crónica y la inflamación. Ésta es una actualización de una revisión publicada anteriormente.
Objetivos
Evaluar los efectos de los potenciadores de CFTR sobre los resultados clínicamente importantes en niños y adultos con FQ.
Métodos de búsqueda
Se realizaron búsquedas en el registro de ensayos del Grupo Cochrane de Fibrosis Quística y Enfermedades Genéticas (Cochrane Cystic Fibrosis and Genetic Disorders Group), compilado a partir de búsquedas en bases de datos electrónicas y búsquedas manuales en revistas y libros de resúmenes de congresos. También se hicieron búsquedas en las listas de referencias de los artículos relevantes, revisiones y registros de ensayos clínicos en línea. Última búsqueda: 21 de noviembre de 2018.
Criterios de selección
Ensayos controlados aleatorios (ECA) de diseño paralelo que compararon potenciadores de CFTR con placebo en pacientes con FQ. Otra revisión examina los ensayos que combinan potenciadores de CFTR con otros tratamientos específicos para las mutaciones.
Obtención y análisis de los datos
Los autores, de forma independiente, extrajeron los datos, evaluaron el riesgo de sesgo de los ensayos incluidos y utilizaron GRADE para evaluar la calidad de la evidencia. Se contactó con los autores de los ensayos para obtener datos adicionales.
Resultados principales
Se incluyeron cinco ECA (447 participantes con diferentes mutaciones) con una duración de 28 días a 48 semanas y que evaluaron el potenciador de CFTR ivacaftor. La certeza de la evidencia fue moderada a baja, debido principalmente al riesgo de sesgo (datos de resultado incompletos e informe selectivo) y la imprecisión de los resultados, en particular cuando pocos pacientes presentaron eventos adversos. Por lo general el diseño de los ensayos fue bien documentado. Todos los ensayos fueron patrocinados por la industria y apoyados por otros grupos de financiamiento no farmacéuticos.
F508del (clase II) (140 participantes)
Un ensayo de 16 semanas no informó muertes ni cambios en la calidad de vida (CdV) o la función pulmonar (cambio relativo o absoluto en el volumen espiratorio máximo en un segundo [VEF1]) (evidencia de calidad moderada). Las exacerbaciones pulmonares y la tos fueron los eventos adversos más informados en los grupos de ivacaftor y de placebo, pero no hubo diferencias entre los grupos (evidencia de baja calidad); no hubo diferencias entre los grupos en cuanto a los participantes que interrumpieron el tratamiento (evidencia de baja calidad). No se informó la cantidad de días hasta la primera exacerbación, pero no hubo diferencias entre los grupos en el número de exacerbaciones pulmonares. Tampoco hubo diferencias en el peso. La concentración de cloruro en el sudor disminuyó, diferencia de medias (DM) ‐2,90 mmol/l (intervalo de confianza [IC] del 95%: ‐5,60 a ‐0,20).
G551D (clase III) (238 participantes)
El ensayo de fase II de 28 días (19 participantes) y dos ensayos de fase III de 48 semanas (ensayo con pacientes adultos [167 adultos], ensayo pediátrico [52 niños]) no informaron muertes. Las puntuaciones de la CdV (dominio respiratorio) fueron mayores con ivacaftor en el ensayo con pacientes adultos a las 24 semanas, DM 8,10 (IC del 95%: 4,77 a 11,43) y a las 48 semanas, DM 8,60 (IC del 95%: 5,27 a 11,93 (evidencia de calidad moderada). El ensayo con pacientes adultos informó un cambio relativo mayor en el VEF1 con ivacaftor a las 24 semanas, DM 16,90% (IC del 95%: 13,60 a 20,20) y a las 48 semanas, DM 16,80% (IC del 95%: 13,50 a 20,10); el ensayo pediátrico informó estos datos a las 24 semanas, DM 17,4% (p < 0,0001]) (evidencia de calidad moderada). Estos ensayos demostraron mejorías absolutas en el VEF1 (% teórico) a las 24 semanas, DM 10,80% (IC del 95%: 8,91 a 12,69) y a las 48 semanas, DM 10,44% (IC del 95%: 8,56 a 12,32). Los ensayos de fase III informaron un aumento de la tos, odds ratio (OR) 0,57 (IC del 95%: 0,33 a 1,00) y episodios de disminución de la función pulmonar, OR 0,29 (IC del 95%: 0,10 a 0,82) en el grupo placebo; el ivacaftor dio lugar a un aumento en los mareos en los pacientes adultos, OR 10,55 (IC del 95%: 1,32 a 84,47). No hubo diferencias entre los grupos en cuanto a los participantes que interrumpieron el tratamiento (evidencia de baja calidad). Menos participantes que recibieron ivacaftor desarrollaron exacerbaciones pulmonares graves; los pacientes adultos que recibieron ivacaftor desarrollaron menos exacerbaciones (graves o no), OR 0,54 (IC del 95%: 0,29 a 1,01). Una proporción mayor de participantes no presentaron exacerbaciones a las 24 semanas con ivacaftor (evidencia de calidad moderada). El ivacaftor dio lugar a un mayor cambio absoluto desde el inicio en el VEF1 (% teórico) a las 24 semanas, DM 10,80% (IC del 95%: 8,91 a 12,69) y a las 48 semanas, DM 10,44% (IC del 95%: 8,56 a 12,32); el peso también aumentó a las 24 semanas, DM 2,37 kg (IC del 95%: 1,68 a 3,06) y a las 48 semanas, DM 2,75 kg (IC del 95%: 1,74 a 3,75). La concentración de cloruro en el sudor disminuyó a las 24 semanas, DM ‐48,98 mmol/l (IC del 95%: ‐52,07 a ‐45,89) y a las 48 semanas, DM ‐49,03 mmol/l (IC del 95%: ‐52,11 a ‐45,94).
R117H (clase IV) (69 participantes)
Un ensayo de 24 semanas no informó muertes. Las puntuaciones de la CdV (dominio respiratorio) fueron mayores con ivacaftor a las 24 semanas, DM 8,40 (IC del 95%: 2,17 a 14,63), pero no se informaron cambios relativos en la función pulmonar (evidencia de calidad moderada). Las exacerbaciones pulmonares y la tos fueron los eventos adversos más informados en ambos grupos, pero no hubo diferencias entre los grupos; no hubo diferencias entre los grupos en cuanto a los participantes que interrumpieron el tratamiento (evidencia de baja calidad). No se informó la cantidad de días hasta la primera exacerbación, pero no hubo diferencias entre los grupos en el número de exacerbaciones pulmonares. No se informaron cambios en el cambio absoluto en el VEF1 ni en el peso. La concentración de cloruro en el sudor disminuyó, DM ‐24,00 mmol/l (IC del 95%: ‐24,69 a ‐23,31).
Conclusiones de los autores
No existe evidencia que apoye la administración de ivacaftor en los pacientes con la mutación F508del. Los dos ensayos de fase III sobre la mutación G551D demostraron una repercusión clínicamente relevante del ivacaftor en los resultados a las 24 y 48 semanas en los pacientes adultos y en los niños (más de seis años de edad) con FQ. El ensayo de la mutación R117H demostró una mejoría en la puntuación de la CdV respiratoria, pero ninguna mejoría en la función respiratoria.
A medida que surgen nuevos tratamientos para mutaciones específicas, es importante que los ensayos examinen los resultados relevantes para los pacientes con FQ y sus familias y que los eventos adversos se informen de manera consistente y sistemática. La vigilancia posterior a la comercialización es esencial y se necesitan evaluaciones económicas sanitarias continuas.
PICO
Resumen en términos sencillos
El ivacaftor (comercializado como Kalydeco®) es un nuevo tratamiento específico para la fibrosis quística
Pregunta de la revisión
¿Cómo afecta el ivacaftor los resultados clínicos (supervivencia, calidad de vida y función pulmonar) en los pacientes con fibrosis quística (FQ)?
Antecedentes
En los pacientes con FQ, las superficies de las vías respiratorias no tienen suficiente agua debido a una proteína anormal; este hecho dificulta la eliminación del moco espeso y pegajoso y provoca que estos pacientes desarrollen infecciones pulmonares. El ivacaftor actúa sobre la proteína anormal en los pacientes con algunas mutaciones para permitir que las vías respiratorias retengan más agua y depuren mejor el moco, de manera que se desarrollen menos infecciones pulmonares.
El ivacaftor se dirigió a los pacientes con mutaciones de clase III y IV y se ha estudiado en pacientes con mutaciones G551D (clase III), R117H (clase IV) y F508del (clase II).
Características de los ensayos
Se incluyeron cinco ensayos (447 participantes) que compararon ivacaftor con placebo (tratamiento simulado sin medicación activa) entre cuatro y 48 semanas. Tres ensayos incluyeron a un total de 238 pacientes con al menos una copia de la mutación G551D, un ensayo incluyó a 140 pacientes con dos copias de la mutación F508del y uno incluyó a 69 pacientes con al menos una copia de la mutación R117H. Esta evidencia está actualizada hasta el 21 de noviembre de 2018.
Resultados clave
Mutación F508del
El ensayo no informó muertes ni mostró mejorías en la función pulmonar, las puntuaciones de la calidad de vida o el peso. La tos y las exacerbaciones pulmonares (agudizaciones de la enfermedad pulmonar) fueron los eventos adversos más informados en los pacientes que recibieron ivacaftor y en los que recibieron placebo; hubo un número similar de exacerbaciones en ambos grupos. Las concentraciones de cloruro en el sudor se redujeron con ivacaftor.
Mutación G551D
No se informaron muertes. Los niños y los adultos que recibieron ivacaftor mostraron mejorías en la función pulmonar, pero sólo los pacientes adultos informaron puntuaciones más altas en la calidad de vida. Los pacientes a los que se les administró placebo informaron más tos y presentaron más episodios de reducción de la función pulmonar; más pacientes adultos que recibieron ivacaftor informaron de episodios de mareos. En números similares de pacientes que recibieron ivacaftor y placebo se retardó el ciclo de la medicación, o se retiraron del ensayo por completo, debido a los efectos secundarios (p.ej., problemas psicológicos, enfermedades hepáticas, problemas respiratorios graves). Hubo exacerbaciones pulmonares más graves cuando se administró placebo en comparación con ivacaftor. Los pacientes adultos que recibieron ivacaftor ingresaron al hospital con menos frecuencia y recibieron menos ciclos de antibióticos intravenosos debido a las exacerbaciones. En los niños y en los adultos hubo un aumento el peso con ivacaftor. Hubo una disminución en las concentraciones de cloruro en el sudor con ivacaftor.
Mutación R117H
No se produjeron muertes en este ensayo. Aunque las puntuaciones de la calidad de vida mejoraron con ivacaftor, la función pulmonar no lo hizo. La tos y las exacerbaciones pulmonares (agudizaciones de la enfermedad pulmonar) fueron los eventos adversos más informados en los pacientes que recibieron ivacaftor y en los que recibieron placebo; hubo un número similar de exacerbaciones en ambos grupos. No hubo diferencias en el peso; sin embargo, en cuanto a otras mutaciones hubo una reducción de la concentración de cloruro en el sudor con ivacaftor.
La evidencia indica que el ivacaftor es un tratamiento efectivo en los pacientes (mayores de seis años de edad) con fibrosis quística y la mutación G551D, pero no en los pacientes con la mutación F508del ni R117H.
Calidad de la evidencia
En la mayoría de los ensayos, los pacientes se asignaron al azar a diferentes grupos de tratamiento, con probabilidades similares de recibir placebo o ivacaftor; nadie pudo determinar qué tratamiento recibiría el próximo paciente para que los pacientes más sanos no recibieran ivacaftor e hicieran que los resultados parecieran mejores. No hubo seguridad en cuanto a si algún participante del ensayo sabía quién recibía qué tratamiento, y cómo este hecho podría afectar los resultados. Ningún ensayo presentó todos los resultados de manera clara; en ocasiones no se informaron de una manera que se pudiera utilizar en la revisión y a veces no informaron los datos en absoluto. Lo anterior afectó la certeza con respecto a los resultados generales. La información acerca de algunos efectos secundarios fue limitada debido a que pocos pacientes los presentaron, por lo que es difícil determinar si hubo diferencias entre los grupos de tratamiento
Se consideró que la evidencia en esta revisión es de moderada a baja calidad.
Fuentes de financiación de los ensayos
Todos los ensayos fueron patrocinados por Vertex Pharmaceuticals Incorporated. El National Institute of Health (NIH), la Cystic Fibrosis Foundation (CFF) y otros grupos de financiamiento no farmacéuticos también apoyaron los ensayos.
Authors' conclusions
Summary of findings
| Ivacaftor compared with placebo for cystic fibrosis with the F508del CFTR mutation | ||||||
| Patient or population: adults and children with cystic fibrosis and with the F508del CFTR mutation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Ivacaftor | |||||
| Survival Follow‐up: 16 weeks | No deaths reported. | No deaths reported. | NA | 140 (1 study) | NA | |
| QoL Total score Follow‐up: NA | Not reported. | NA | NA | NA | ||
| QoL (CFQ‐R) Respiratory domain Follow‐up: 16 weeks | See comment.1 | See comment.1 | NA | 140 | ⊕⊕⊕⊝ | There was no significant difference between groups at 16 weeks. |
| FEV1 % predicted Relative change from baseline Follow‐up:16 weeks | Not reported.2 | The mean FEV1 (% predicted) was 2.4% higher (0.95% lower to 5.75% higher) in the ivacaftor group. | NA | 140 | ⊕⊕⊕⊝ | There was no significant difference between groups at 16 weeks. |
| FEV1 % predicted Absolute change from baseline Follow‐up: 16 weeks | Not reported.2 | The mean FEV1 (% predicted) was 1.7% higher (0.65% lower to 4.05% higher) in the ivacaftor group. | NA | 140 | ⊕⊕⊕⊝ | There was no significant difference between groups at 16 weeks. |
| Adverse events Follow‐up:16 weeks | The most commonly reported adverse events in the placebo group were: pulmonary exacerbation, cough, oropharyngeal pain and fatigue. | The most commonly reported adverse events in the ivacaftor group were: cough, pulmonary exacerbation, upper respiratory tract infection and nasal congestion. | NA | 140 | ⊕⊕⊝⊝ | There was no significant difference between groups in terms of any other adverse events. |
| Time to first pulmonary exacerbation Follow‐up: 16 weeks | Not reported. | NA | NA | NA | ||
| *The basis for the assumed risk is the mean placebo group risk across studies, unless otherwise stated. The corresponding risk (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 | ||||||
| 1. Presentation of the data prevented including data in analysis therefore results are presented narratively. | ||||||
| Ivacaftor compared with placebo for cystic fibrosis with at least one G551D CFTR mutation | ||||||
| Patient or population: adults and children with cystic fibrosis and with at least one G551D CFTR mutation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Ivacaftor | |||||
| Survival Follow‐up: 2 ‐ 48 weeks | No deaths reported. | No deaths reported. | NA | 238 | NA | |
| QoL Total score Follow‐up: NA | Not reported. | NA | NA | NA | ||
| QoL (CFQ‐R) Respiratory domain Follow‐up: 2 ‐ 48 weeks | See comment.1 | See comment.1 | NA | 222 (3 studies) | ⊕⊕⊕⊝ | A small phase 2 trial (n = 19) showed no significant difference at 2 or 4 weeks. A phase 3 trial (n = 151) in adults showed significantly higher quality of life in the ivacaftor group compared to placebo at 48 weeks A phase 3 trial (n = 52) showed no significant difference at 24 or 48 weeks in the child version of the CFQ‐R. The same trial showed a significantly higher quality of life in the ivacaftor group compared to placebo at 48 weeks in the parent / caregiver version at 24 weeks but not at 48 weeks.5 |
| FEV1 % predicted Relative change from baseline Follow‐up: 2 ‐ 48 weeks | See comment.1 | See comment.1 | NA | 232 (3 studies) | ⊕⊕⊕⊝ | A small phase 2 trial (n = 19) showed no significant difference at 2 or 4 weeks. Two phase 3 trials (n = 213) showed a significant improvement in FEV1 at 24 weeks (MD ranged between 16.9% to 17.4%) One phase 3 trial (n = 161) showed a significant improvement in FEV1 at 48 weeks (MD 16.8%). 6 |
| FEV1 L and % predicted Absolute change from baseline Follow‐up: 2 to 48 weeks | See comment.1 | See comment.1 | NA | 232 (3 studies) | ⊕⊕⊝⊝ | A small phase 2 trial (n = 19) showed no significant difference at 2 or 4 weeks. Two phase 3 trials (n = 213) showed a significant improvement in FEV1 (L and % predicted) at 24 weeks and 48 weeks.7 |
| Adverse events Follow‐up: 2 ‐ 48 weeks | The most commonly reported adverse events in the placebo group were: pulmonary exacerbation, cough, oropharyngeal pain and headache. | The most commonly reported adverse events in the ivacaftor group were: cough, pulmonary exacerbation, upper respiratory tract infection and headache. | NA | 232 (3 studies) | ⊕⊕⊝⊝ | Pulmonary exacerbations were significantly more common in the placebo group. There was no significant difference between groups in terms of any other adverse events.8 |
| Time to first pulmonary exacerbation Follow‐up: 48 weeks | 41% of the placebo group were exacerbation free at 48 weeks. | 67% of the ivacaftor group were exacerbation free at 48 weeks. | HR 0.46 (95% CI 0.29 to 0.73) | 161 (1 study) | ⊕⊕⊕⊝ | There was also a statistically significant difference between groups at 24 weeks; 78% and 51% of the ivacaftor and placebo groups were exacerbation free respectively; HR 0.46 (95% CI 0.28 to 0.76). |
| *The basis for the assumed risk is the mean placebo group risk across studies, unless otherwise stated. The corresponding risk (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 | ||||||
| 1. Presentation of the data prevented pooling the data from all three studies therefore results are summarised narratively. | ||||||
| Ivacaftor compared with placebo for cystic fibrosis with at least one R117H CFTR mutation | ||||||
| Patient or population: adults and children with cystic fibrosis and with at least one R117H CFTR mutation Settings: outpatients Intervention: ivacaftor Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Ivacaftor | |||||
| Survival Follow‐up: 2 ‐ 24 weeks | No deaths reported. | No deaths reported. | NA | 69 (1 study) | NA | |
| QoL Total score Follow‐up: NA | Not reported. | NA | NA | NA | ||
| QoL (CFQ‐R) Respiratory domain Follow‐up: 2 ‐ 24 weeks | Not reported. | The mean adjusted CFQ‐R respiratory domain score was 8.40% higher (2.17% higher to 14.63% higher) in the ivacaftor group. | NA | 69 (1 study) | ⊕⊕⊕⊝ | There was a significant improvement in CFQ‐R respiratory domain scores at 24 weeks.3 |
| FEV1 % predicted Relative change from baseline Follow‐up: 2 ‐ 24 weeks | See comment.1 | The mean adjusted FEV1 (% predicted) was 5.00% higher (0.24% lower to 10.24% higher) in the ivacaftor group. | NA | 69 (1 study) | ⊕⊕⊕⊝ | There was no significant difference between groups at 24 weeks.3 |
| FEV1 L and % predicted Absolute change from baseline Follow‐up: 2 ‐ 24 weeks | See comment.1 | The mean adjusted FEV1 (% predicted) was 2.10% higher (1.13% lower to 5.33% higher) in the ivacaftor group. | NA | 69 (1 study) | ⊕⊕⊕⊝ | There was no significant difference between groups at 24 weeks.3 |
| Adverse events Follow‐up: 2 ‐ 24 weeks | The most commonly reported adverse events in the placebo group were: pulmonary exacerbation and cough. | The most commonly reported adverse events in the ivacaftor group were: pulmonary exacerbation, cough, headache, nasal congestion, oropharyngeal pain, diarrhoea and increased sputum. | NA | 69 (1 study) | ⊕⊕⊝⊝ | There was no significant difference between groups in terms of any other adverse events. |
| Time to first pulmonary exacerbation Follow‐up: 24 weeks | 63% of the placebo group were exacerbation free at 24 weeks. | 68% of the ivacaftor group were exacerbation free at 24 weeks. | HR 0.93 (95% CI 0.42 to 2.08) | 69 (1 study) | ⊕⊕⊕⊝ | There was no significant difference between groups at 24 weeks. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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 | ||||||
| 1. Presentation of the data prevented including data in analysis therefore results are presented narratively. | ||||||
Background
A glossary of terms specific to this review can be found in the appendices (Appendix 1); a more general glossary of terms used in Cochrane Reviews can be accessed at Cochrane Glossary.
Description of the condition
Cystic fibrosis (CF) is the most common inherited life‐shortening illness in white populations, with a prevalence of 1 in 2000 at birth in Europeans (Bobadilla 2002) and varying prevalence in North American populations depending on ethnic composition (Hamosh 1998). According to the data report from the UK CF Registry which was published in July 2014, there were 10,338 people with a confirmed diagnosis of CF in the UK (UK CF Registry Report 2013). The clinical features of CF arise from abnormalities in a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) (Riordan 1989; Southern 1997). Normally, CFTR protein is transported to the outer cell membrane, where it has a role in co‐ordinating the transport of the salt ions, sodium (Na+) and chloride (Cl‐), in and out of the cell. This salt transport role is particularly important in the airways, pancreas, sweat gland, and vas deferens.
In the lungs of people with CF, defective salt transport leads to a reduction in airway surface liquid volume. This, in turn, leads to compromised mucociliary clearance, which initiates a cycle of infection, inflammation and progressive lung damage, eventually causing respiratory failure and premature death. Other consequences of CFTR dysfunction, including those related to abnormalities in the inflammatory response, are probably important but not as well characterized. In addition, CFTR‐related ion transport abnormalities can lead to other systemic complications. These include malnutrition and diabetes (through pancreatic damage, salt depletion through excess loss in sweat) and subfertility (in men and women) caused by various factors.
Over 1900 mutations have been identified in the CFTR gene, which can be categorised according to the impact they have on CFTR synthesis, processing, or function (CFMD 2012). These categories have been described (Rowntree 2003; Southern 2007); and a summary is presented in the additional tables (Table 1). The most common mutation is the delta F508 (F508del) mutation (class II mutation) and is present on at least one allele in 7990 (90.8%) people with CF in the UK. The second most common mutation in the UK is the G551D mutation (class III mutation). This mutation exists in 514 (5.84%) people with CF in the UK. The R117H mutation (class IV mutation) is the third most common mutation, present in 398 (4.52%) people with CF in the UK (UK CF Registry Report 2013).
| Class | Example mutation | Impact on CFTR structure and function |
| I | G542X | Synthesis of CFTR is critically impaired, and no functional protein is produced. This is due to the presence of a premature stop codon in the nucleotide sequence. Individuals have minimal CFTR function. |
| II | ΔF508 | A full length of CFTR is produced, but this is structurally abnormal and destroyed by the cell before it reaches the cell membrane. This is called a defect in the intracellular trafficking pathway. Minimal amounts of CFTR can escape being destroyed and be transported to the cell membrane. However here, class II CFTR products display defective ion transport. Individuals have minimal CFTR function. |
| III | G551D | CFTR is produced and embedded in the cell membrane, but the chloride channel does not respond (‘switch on’) to normal stimulation from the cell. This means there is no significant ion transport across the protein. Individuals have some residual CFTR function. |
| IV | R347P | CFTR is transported to the outer cell membrane, and responds to normal stimulation, but functions at a low level because chloride ions do not cross the channel appropriately. Individuals have some residual CFTR function. |
| V | A455E | Normal CFTR is produced, but the amount of protein is reduced. Individuals have some residual CFTR function. |
CFTR: cystic fibrosis transmembrane conductance regulator
Description of the intervention
Understanding how the mutations, which are described in the additional tables (Table 1), affect the production, structure, and function of CFTR has led to the concept of mutation‐specific therapies. One strategy, relating mainly to mutations classes III to V but also to class II, is to improve the function of CFTR that has reached the cell membrane, but whose function is compromised (McKone 2004). Drugs that improve CFTR function in the cell membrane are called potentiators and have the potential to correct the abnormal salt transport that characterises CF. Potentiators can be administered orally, or as an inhaled preparation.
Two distinct approaches have resulted in the recognition of candidate drugs with this mode of action (Amaral 2007):
-
testing of compounds known to affect CFTR or other ion‐channels (either pharmaceutical drugs or chemicals which occur naturally in plants, herbs, fruits or food components);
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high throughput screening, which involves testing large numbers of diverse chemicals, on laboratory cell lines, to identify which of these may stimulate CFTR.
In addition to potentiators, other drugs which aim to correct defects of the CFTR are also under investigation in clinical trials. These include correctors (which increase the amount of CFTR in the cell membrane by preventing early degradation ‐ class II mutations) and 'stop‐codon therapies' which act to prevent structural abnormalities of CFTR that occur when premature stop codons terminate protein synthesis too early ‐ class I mutations). Cochrane Reviews of trials assessing correctors and one assessing stop codon therapies have been published (Aslam 2017; Southern 2018).
How the intervention might work
The CFTR potentiator ivacaftor was identified through high‐throughput screening by Vertex Pharmaceuticals Incorporated. In cell and animal models, it was able to restore CFTR function for class III mutations and correct the abnormal transmembrane salt transport (Van Goor 2009). However, the precise mechanism of action of ivacaftor is unclear, owing to the limited amount of data.
The correction of the basic defect in CF in the airways of the lung could lead to the normalization of airway surface liquid; the resulting re‐establishment of mucociliary clearance, would then have a beneficial impact on the chronic infection and inflammation that characterizes CF lung disease.
Why it is important to do this review
Since CFTR potentiators are novel therapies, it is important that randomised controlled trials (RCTs) testing these agents are critically appraised. This will enable examination of the evidence relating to the benefits and harms of CFTR potentiators. It is important that funding bodies have a clear evidence base on which to assess new therapies for CF that aim to correct the basic defect, particularly given the large prevalence of people with mutations that might be impacted by CFTR potentiators. It is likely that these therapies will represent a significant healthcare resource. In addition, critical appraisal of included trials will help inform future trial design.
This review aims to collate evidence from RCTs that have evaluated the benefits and harms of CFTR potentiators in people with CF. This is an update of a previously published version (Patel 2012; Patel 2015).
Objectives
To evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with CF.
Methods
Criteria for considering studies for this review
Types of studies
RCTs of parallel design (published or unpublished). Cross‐over trials were considered inappropriate given the potential longer‐term impact of this therapy on outcomes.
Types of participants
We have included trials involving children or adults with CF, as confirmed either by the presence of two disease‐causing mutations, or by a combination of a positive sweat test and recognised clinical features of CF. We included trials involving people with any level of disease severity and any relevant mutation class, where CFTR has been demonstrated to successfully embed within the cell membrane and display defective function.
Types of interventions
In a post hoc change we have only included trials comparing CFTR potentiators to placebo or another intervention. Trials where CFTR potentiators are used in combination with other CFTR function modulators were excluded. There are many ongoing trials that use a CFTR potentiator alongside a CFTR corrector and we believe it would be more appropriate to conduct a separate systematic review for these trials (Southern 2018).
Types of outcome measures
Primary outcomes
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Survival (in a post hoc change mortality data were also considered)
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Quality of life (QoL) (measured using validated quantitative scales or scores (e.g. Cystic Fibrosis Questionnaire‐Revised (CFQ‐R) (Quittner 2009))
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total QoL score
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different sub‐domains which may be reported
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Forced expiratory flow rate at one second (FEV1) (relative change from baseline)
Secondary outcomes
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Adverse effects
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graded by review authors as mild (therapy does not need to be discontinued)
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graded by review authors as moderate (therapy is discontinued, and the adverse effect ceases)
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graded by review authors as severe (life‐threatening or debilitating, or which persists even after treatment is discontinued)
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other adverse effects of therapy (of any severity) that are not classifiable according to these categories, including pulmonary exacerbation (protocol defined or physician defined) and time‐to‐exacerbation data
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Hospitalisation
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number of days
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number of episodes
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School or work attendance (i.e. number of days missed)
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Other physiological measures of lung function (litres or per cent (%) predicted for age, sex and height)
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FEV1 absolute values (rather than "relative change from baseline", which is specified as primary outcome)
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forced vital capacity (FVC) (absolute values and change from baseline)
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Extra courses of antibiotics (measured as time‐to the next course of antibiotics and the total number of courses of antibiotics)
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oral
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intravenous
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inhaled
-
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Radiological measures of lung disease (assessed using any scoring system)
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chest radiograph scores
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computerised tomogram (CT) score
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Acquisition of respiratory pathogens
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Pseudomonas aeruginosa
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Staphylococcus aureus
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Haemophilus influenzae
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other significant pathogen
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Eradication of respiratory pathogens (as defined by trial authors)
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P aeruginosa
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S aureus
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H influenzae
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other significant pathogen
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Nutrition and growth (measured as relative change from baseline) (including z scores or centiles)
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weight
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body mass index (BMI)
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height
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Sweat chloride (change from baseline) as a measure of CFTR function
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Cost of treatment
Search methods for identification of studies
There are no restrictions regarding language or publication status.
Electronic searches
We identified relevant trials from the Group's Cystic Fibrosis Trials Register using the term: 'drugs that augment function of abnormal CFTR protein in the cell membrane'. Relevant trials have been tagged with this term for indexing purposes in the Group's Cystic Fibrosis Trials Register.
This is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library), weekly searches of MEDLINE, a search of Embase to 1995 and the handsearching of two journals – Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work was identified by searching through the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Group's website.
Date of latest search of the Group's Cystic Fibrosis Trials Register: 21 November 2018.
We also searched online clinical trial registries (Appendix 1). Date of last search of clinical trial registries: 21 November 2018.
Searching other resources
We screened references of included trials to identify other potentially relevant trials. We also contacted authors of included trials, leaders in the field, and companies known to be developing and investigating CFTR potentiators, to identify any trials that may have been missed by these searches.
Data collection and analysis
Selection of studies
For the original review, two authors (SP and IS) independently assessed the suitability of each trial identified by the search. From the 2018 update onwards MS and IS independently assessed the suitability of each trial and if disagreement arose regarding suitability for inclusion, we attempted to reach a consensus by discussion, failing which a third author (KWS) arbitrated.
Data extraction and management
For the updated review, two authors (MS and IS) independently extracted relevant data from each included trial using a standardised data extraction form. If disagreement arose on data extraction, we attempted to reach a consensus by discussion, failing which a fourth author (KWS) arbitrated.
We intended to report on our primary outcome 'survival' as survival to time X (time‐to‐event data). However, these data were not available, so we considered mortality data (number of deaths) as an alternative outcome (post hoc change). For lung function, where possible we reported the relative change from baseline in FEV1, since this way of presenting FEV1 is very important in clinical practice. If this was not possible, we reported absolute change from baseline in FEV1 as a secondary outcome. We extracted QoL as the absolute change from baseline.
With regards to the secondary outcome 'Adverse effects', we extracted the total number of participants who experienced adverse effects or required trial drug interruption or termination. When extracting data on pulmonary exacerbations, we noted whether they were protocol‐defined or physician‐defined. We reported the number of participants who experienced episodes of pulmonary exacerbation or reported time‐to‐exacerbation data. We extracted the number of participants who required hospitalisations. With regards to 'Extra courses of antibiotics', we reported on the total number of courses of antibiotics.
For the secondary outcomes 'Change from baseline in weight' and 'Change from baseline in sweat chloride concentration', we extracted the absolute change from baseline results.
For continuous outcomes, where standard deviations (SDs) were not provided, we calculated the standard error of the mean (SEM) from the 95% confidence intervals (CIs) and inserted the results into a generic inverse variance (GIV) analysis.
If the trial author presented non‐parametric data, we reported results in the written text and not in the analysis.
We have reported data at 4 weeks, 16 weeks, 24 weeks and 48 weeks.
Assessment of risk of bias in included studies
Two authors (MS and IS) assessed the risk of bias for each trial using the Cochrane risk of bias tool (Higgins 2011a). This includes assessment of the following methodological aspects of the included trials:
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procedure for randomisation (selection bias);
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allocation concealment (selection bias);
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masking (blinding) of the intervention from participants, clinicians, and trial personnel evaluating outcomes (performance bias);
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missing outcome data (attrition bias);
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selective outcome reporting (reporting bias);
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other sources of bias.
We also assessed whether all participants were included in an intention‐to‐treat analysis, regardless of whether they completed the treatment schedule or not. If disagreement arose on the assessment of risk of bias of a trial, we attempted to reach a consensus by discussion, failing which a third author (KWS) arbitrated.
Measures of treatment effect
For binary outcomes, we calculated a pooled estimate of the treatment effect for each outcome using the pooled odds ratio (OR) and 95% CIs or 99% confidence intervals for analysis of separate adverse events. If calculating a pooled OR was not appropriate, we calculated an estimate of the treatment effect for each outcome using the OR and 95% CIs.
For continuous outcomes, we calculated the mean change from baseline for each group or the mean post‐intervention values and 95% CIs for each group. We produced a pooled estimate of treatment effect by calculating the mean difference (MD) and 95% CIs. For QoL, CFQ‐R was the most frequently used questionnaire and so we calculated the MD and 95% CIs. No other questionnaire was used.
For time‐to‐event outcomes, such as 'Time to first pulmonary exacerbation', we used measures of survival analysis, and calculated hazard ratios (HR) and 95% CIs between different arms of the trial.
In future updates of this review, if different trials present data for the same outcomes in different forms (e.g. absolute values of lung function measures, or change in these measures from a baseline), we will combine these in a meta‐analysis where appropriate.
Where the trials did not report change data, but instead presented absolute post‐treatment data without baseline data (so it was not possible to calculate change data), we planned to use absolute post‐treatment data instead of change from baseline. However, if the report presented baseline and post‐treatment data for any outcome, we calculated SDs for the change from baseline, for example if the CI was available. If there was not enough information available to calculate the SDs for the changes, we planned to impute them from other trials in the review, where data were available and trials were similar (i.e. when they used the same measurement scale, had the same degree of measurement error, had the same time periods between baseline and final value measurement and had conducted the randomisation process appropriately). If neither of these methods were possible, we planned to calculate a change‐from‐baseline SD, making use of an imputed correlation coefficient (methods described in chapter 16 in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011b)).
Unit of analysis issues
Within this review, we have only included results from RCTs of parallel design in which individual trial participants were randomised. We excluded cross‐over trials, because they are not appropriate for evaluating therapies that potentially correct the underlying defect (Higgins 2011b). We did not identify any cluster RCTs. Further updates of this review will include any eligible cluster RCTs identified and these will be included and analysed as described in the Cochrane Handbook for Systematic Reviews of Inteventions (Higgins 2011b).
Where trials with multiple intervention groups reported dichotomous data i.e. adverse effects, we pooled the data to form one intervention group and compared data to the placebo group as recommended in chapter 16 of the Cochrane Handbook for Systematic Reviews of Inteventions (Higgins 2011b).
Dealing with missing data
In order to allow an intention‐to‐treat analysis, we extracted data on the number of participants with each outcome event, by allocated treated group, irrespective of compliance and whether or not the participant was later thought to be ineligible or otherwise excluded from treatment or follow‐up. We calculated the number of participants with outcome data and checked if this was consistent with the number of originally randomised participants. We checked that this finding was consistent with findings on the online ongoing trials database (clinicaltrials.gov). If there were any discrepancies or any uncertainty, we contacted the primary investigators for clarification. For more detail about what we requested and what information we were provided with, see the risk of bias section below (Incomplete outcome data (attrition bias)).
Assessment of heterogeneity
We assessed heterogeneity through a visual examination of the forest plots, and by considering the I² statistic (Higgins 2003) together with the Chi² test (P < 0.1) (Deeks 2011). The I² statistic reflects the likelihood that the variation of results across trials is due to heterogeneity rather than chance, and we interpreted this statistic using the following classification:
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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.
If we had identified heterogeneity between trials, we would have conducted a sensitivity analysis including only homogenous trials to determine the effect of heterogeneity on the overall treatment effect of the intervention.
Assessment of reporting biases
In order to identify selective outcome reporting, where possible we compared outcomes described in the trial protocol with those reported in the publication(s). We requested protocols for specific trials from the primary investigators, corresponding author, or relevant pharmaceutical company when they were not available. We have recorded the proportion of protocols that were available to us. If the protocol was not available, we checked published information on the trial registry databases. We also compared outcomes listed in the 'Methods' section of the final paper with those presented in the 'Results' section. If the published papers partially reported negative findings (i.e. P > 0.05), we contacted the primary investigators for these data.
We planned to assess publication bias by constructing and assessing the symmetry of a funnel plot. This would have been possible if we had included more than 10 trials in the review.
Data synthesis
We used a fixed‐effect model to analyse data from trials which we did not consider to be heterogeneous (see classifications above). If substantial or considerable heterogeneity had been present (I² greater than 50%), we used a random‐effects model to analyse data.
Subgroup analysis and investigation of heterogeneity
We planned to investigate any heterogeneity that we identified using subgroup analyses of potential confounding factors. For this review, we planned that these confounding factors would be:
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age (children (defined as younger than 18 years of age) versus adults);
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gender;
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different mutation classes (Table 1).
As we did not seek individual patient data from trial investigators, we did not undertake a subgroup analysis on the basis of disease severity. Such an analysis may be incorporated in future updates of this review.
Sensitivity analysis
If we had been able to combine a sufficient number of trials (at least 10), we planned to examine the impact of risk of bias on the results examined by comparing meta‐analyses including and excluding trials with concerns of high risk of selection or reporting bias due to issues relating to randomisation, allocation concealment, or masking of interventions from participants or trial personnel.
Summary of findings and quality of the evidence (GRADE)
In a post hoc change from protocol, we have presented three summary of findings tables (summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3) under the comparison of 'Ivacaftor compared to placebo' according to mutation class (see Table 1).
The following outcomes were reported in all tables (chosen based on relevance to clinicians and consumers):
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survival;
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QoL (total score);
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QoL (respiratory domain);
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FEV1 (relative and absolute change);
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adverse events; and
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time to first pulmonary exacerbation.
For clarity in the tables, adverse events are not presented according to the subdomains in Effects of interventions; instead the authors have inserted a general statement about the summary of findings for these outcomes and the evidence is graded based on all of the subdomains combined.
We determined the quality of the evidence using the GRADE approach; and downgraded evidence in the presence of a high risk of bias in at least one trial, indirectness of the evidence, unexplained heterogeneity or inconsistency, imprecision of results, high probability of publication bias. We evidence by one level if they considered the limitation to be serious and by two levels if very serious.
Results
Description of studies
Results of the search
The search of the Group's Cystic Fibrosis Trials Register identified a total of 201 publications (abstracts and full papers) representing 67 trials. A further 91 trials were identified from ongoing trials databases. Five trials (67 references) were included and 62 trials (115 references) were excluded. The two trials (two references) awaiting classification have both been published as conference abstracts; further details below (Kazani 2016; Uttamsingh 2016). In a post hoc change (2018), references to corrector and potentiator combination therapy trials have not been listed in the review, meaning 79 trials (110 references) identified have not been listed in the reference section of this review. The results of the search are displayed in the PRISMA diagram below (Figure 1).
Study flow diagram.
No additional trials were identified by screening references of included trials or by contacting authors of included trials, leaders in the field, and companies known to be developing and investigating CFTR potentiators.
Included studies
We included five trials (67 references) with 447 participants in this review (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011). All trials were available as full texts.
Trial design
All five included trials were RCTs of parallel design. The responsible funding body in all included trials was Vertex Pharmaceuticals Incorporated. The National Institute of Health (NIH), the Cystic Fibrosis Foundation (CFF) and other non‐pharmaceutical funding bodies were also involved in supporting the trials (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011).
The F508del trial (n = 140) was a phase 2 trial that lasted 16 weeks (DISCOVER 2011). Participants who met pre‐defined eligibility criteria and completed Part A of the trial were continued onto an open‐label extension phase (Part B) lasting 96 weeks (n = 48); data from this extension were not eligible for inclusion in this review (DISCOVER 2011). There were three trials of people with the G551D mutation; the phase 2 trial had three arms and lasted 28 days (Accurso 2010); the two phase 3 trials lasted 48 weeks (ENVISION 2013; STRIVE 2011). Participants in these trials who completed 48 weeks of treatment (n = 194) were entered into an open‐label extension phase, which lasted up to 96 weeks; participants from this trial were not eligible for inclusion in this review because they were not re‐randomised to treatment or control (PERSIST 2014). The phase 3 R117H trial (n = 69) lasted for 24 weeks (KONDUCT 2015). Participants that completed 24 weeks of treatment were eligible to enrol into an open‐label extension phase which lasted up to 104 weeks with an interim analysis at 12 weeks (KONTINUE 2017). Data from KONTINUE were not eligible for inclusion as participants were not re‐randomised (KONTINUE 2017).
All trials were conducted at multiple centres (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011). The F508del trial was run across 34 sites in North America (DISCOVER 2011). Although this trial recruited participants with a class II mutation, we included it in the initial version of the review on the basis that the trial evaluated ivacaftor and its effect of the minimal amount of CFTR reaching the cell surface in this mutation. The phase 2 G551D trial recruited participants from 13 sites in North America and Europe (Accurso 2010). The paediatric G551D trial (65 sites) and the adult G551D trial (29 sites) were conducted in North America, Europe and Australia (ENVISION 2013; STRIVE 2011). The phase 3 R117H trial was conducted at 31 sites across Europe and North America (KONDUCT 2015).
Outcome data were reported at time frames ranging from 2 to 48 weeks (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011).
Participants
All 447 participants in the included trials had a confirmed diagnosis of CF. The F508del trial examined the effect of ivacaftor on people homozygous for the F508del mutation (class II mutation) (DISCOVER 2011). In the three G551D trials (class III mutation), participants were required to possess at least one G551D‐CFTR allele (Accurso 2010; ENVISION 2013; STRIVE 2011). The R117H trial required participants to have at least one R117H‐CFTR allele (KONDUCT 2015).
Two trials recruited recruited participants aged 12 years and older (DISCOVER 2011; STRIVE 2011); participants in the F508del trial had a mean age of 25.5 years (DISCOVER 2011) and participants in the adult G551D trial had a mean age of 23.2 years (STRIVE 2011). The phase 2 G551D trial recruited participants aged 18 years and over and participants had a median 21 age of years (Accurso 2010). The paediatric phase 3 G551D trial enrolled participants aged 6 to 11 years of age and participants had a mean age of 8.9 years (ENVISION 2013). The R117H trial recruited those over 6 years of age and participants had a mean age of 31 years (KONDUCT 2015).
In the F508del trial 140 participants were allocated in a 4:1 ratio to either intervention or placebo (DISCOVER 2011). Sample sizes in the G551D trials ranged between 19 participants (Accurso 2010) and 167 participants (STRIVE 2011). The phase 2 G551D trial allocated 19 participants in a 2:2:1 ratio to either one of two intervention groups or a placebo group respectively (Accurso 2010). In the phase 3 G551D trials, 52 children and 167 adults were allocated in a 1:1 ratio to either intervention or placebo (ENVISION 2013; STRIVE 2011). During randomisation, the adults were stratified according to age (less than 18 years versus 18 years and over) and pulmonary function (less than 70% versus 70% and over of the predicted FEV1) (STRIVE 2011). Similarly, a 1:1 ratio was used to allocate participants to intervention or placebo groups in the R117H trial; participants were stratified by age (6 to 11 years, 12 to 17 years, and 18 years and over) and % predicted FEV1 (< 70%, ≥ 70% to ≤ 90% and > 90%) during randomisation (KONDUCT 2015).
All participants had a baseline FEV1 reading of 40% or over for age, sex and height and where baseline information was available, similar characteristics were seen (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011).
Interventions
Ivacaftor was the intervention drug in all included trials (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011). Four trials compared 150 mg of ivacaftor every 12 hours to placebo (ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011). The phase 2 G551D trial compared 150 mg and 250 mg of ivacaftor every 12 hours to placebo (Accurso 2010).
To determine the doses to be used, two G551D trials (the phase 2 trial and the paediatric phase 3 trial) conducted earlier investigations (Accurso 2010; ENVISION 2013). Ivacaftor dose levels used in the phase 2 G551D trial were determined based on pharmacokinetic modelling of data from a previous cross‐over trial (Accurso 2010). Pre‐trial single‐dose pharmacokinetic analysis and phase 2a data were used to determine doses in the paediatric phase 3 G551D trial (ENVISION 2013).
Participants in four of the five included trials continued on prescribed medications, that were approved for CF, during the trial period (Accurso 2010; ENVISION 2013; DISCOVER 2011; STRIVE 2011). No information was provided for the R117H trial regarding how drug dosage was determined or whether participants continued taking prescribed medications (KONDUCT 2015).
Outcomes
The primary end points in the trials were safety (Accurso 2010) or absolute change in FEV1 (ENVISION 2013; KONDUCT 2015; STRIVE 2011) or both (DISCOVER 2011).
All trials employed the CFQ‐R respiratory domain to measure QoL (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011). One trial reported data for all domains (Accurso 2010). In the adult phase 3 G551D trial, data for other CFQ‐R domains were reported where improvements were seen in the ivacaftor group (STRIVE 2011). Relative change from baseline in FEV1 was reported in the full text by four trials (Accurso 2010; DISCOVER 2011; KONDUCT 2015; STRIVE 2011) and in a conference abstract by the fifth trial (24‐week interim data only) (ENVISION 2013).
All trials reported on the safety profile of ivacaftor and the total number of participants who developed pulmonary exacerbations (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011). The adult G551D trial and R117H trial also reported data for hospitalisation and number of days of hospitalisation (KONDUCT 2015; STRIVE 2011). Three trials reported on the number of participants who required extra courses of antibiotics (DISCOVER 2011; KONDUCT 2015; STRIVE 2011).
All trials examined the effect of ivacaftor on absolute change in FEV1 (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011). Two trials reported on absolute change from baseline in FEV1 for subgroups, according to pulmonary function, geographic region and gender (ENVISION 2013; STRIVE 2011).
Three trials reported on weight (change from baseline), BMI and BMI as z score for age (ENVISION 2013; DISCOVER 2011; STRIVE 2011) and one trial reported change in BMI from baseline (KONDUCT 2015). Two trials reported on height z scores (ENVISION 2013; STRIVE 2011).
All included trials reported on change from baseline in sweat chloride concentration (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011).
Nasal potential difference, a primary outcome in the Accurso trial, was not included in this review, as it is not yet a validated outcome measure (Accurso 2010).
Excluded studies
A total of 62 trials (115 references) were listed as excluded. We excluded 12 trials which were of cross‐over design (Altes 2011; Berkers 2017; Edgeworth 2017; Davies 2012; KONNECTION 2013; EudraCT Number: 2016‐001619‐19; McGarry 2015; NCT01685801; NCT01784419; NCT02709109; NCT02742519; NCT03068312) and one trial which carried out secondary analysis on trials of cross‐over design (Accurso 2013). Eleven trials were excluded as they used treatments to correct the molecular defect and were not potentiators (ALBATROSS 2017; Chadwick 1998; Clancy 2012; FLAMINGO 2017; Horsley 2018; McCarty 2002; NCT03474042; NCT02323100; Rubenstein 1998; Rubenstein 2006; Zeitlin 2002). Six trials were excluded as they examined stop codon therapies for class I mutations (Kerem 2014; Pradal 2002; Romano 2000; Sermet‐Gaudelus 2010; Wilschanski 2003; Wilschanski 2008). We excluded 12 trials due to an observational study design (EudraCT Number: 2016‐001440‐18; Hubert 2018; NCT01549314; NCT01863238; NCT02039986; NCT02141464; NCT02311140; NCT02445053; NCT02722057; NCT03390985; NCT03652090; Seliger 2015) and a further 12 trials were excluded as they had a single interventional arm with no comparator (ARRIVAL 2018; Davies 2016; EudraCT Number: 2014‐000817‐30; NCT01946412; NCT02310789; NCT02690519; NCT02707562; NCT02934698; NCT03256799; NCT03256968; NCT03277196; PERSIST 2014). Three trials used treatments to amplify or modify the molecular defect rather than potentiate it (NCT02718495; NCT02724527; NCT03258424). Four trials did not use mutation‐specific treatments e.g. antibiotic therapy (EUudraCT Number: 2016‐001785‐29; NCT02443688; NCT02759562; RIO‐CF 2017). One trial excluded people with CF (TOPIC 2018).
We excluded 79 trials (110 references) comparing potentiator and corrector combination therapy to placebo, but these have not been referenced within the list of excluded studies as a separate systematic review has been conducted which focuses on combination therapy (Southern 2018).
Studies awaiting classification
Two trials are listed as awaiting classification (Kazani 2016; Uttamsingh 2016), one of which has been terminated according to the record on clinicaltrials.gov (Kazani 2016).
Trial design
Both trials are double‐blind RCTs of parallel design, but one is a phase 1 trial (Uttamsingh 2016) and the second is a phase 2 trial (Kazani 2016). The phase 1 trial lasted for seven days with no additional follow‐up (Uttamsingh 2016). The phase 2 trial had a duration of 14 days with a follow‐up to 42 days (Kazani 2016).
Participants
In the phase 1 trial, investigators enrolled 40 participants with a confirmed diagnosis of CF, but no details of participants' baseline characteristics are available (Uttamsingh 2016).
In the three‐arm phase 2 trial, only the third phase of the trial was eligible which randomised 49 adults with CF heterozygous with one allele represented as any CFTR mutation and the other allele must represent a class III, IV, V, VI CFTR mutation (Kazani 2016). In the phase 2 trial the mean age of participants was 31.7 years. With regards to gender split the trial randomised more males (n = 30) than females (n = 19).
Intervention
Investigators enrolled 40 participants and allocated them in a 4:1 ratio to either intervention or placebo (Uttamsingh 2016). CTP‐656 (a deuterated analogue of ivacaftor) was used as the intervention drug. Participants received either 75mg, 150mg, or 225mg of CTP‐656. Dose escalation was initiated only after safety and tolerability were found to support proceeding to the higher dose. All participants were dosed under fed conditions; a high‐fat breakfast was provided on Day 1 through Day 7 approximately 30 minutes prior to dosing (Uttamsingh 2016). (Since this trial was undertaken CTP‐656 has been sold by its developers (Concert Pharmaceuticals Inc.) to Vertex and has been renamed VX‐561.)
The phase 2 trial compared QBW251 (a membrane‐associated wild‐type CFTR potentiator) at two doses ‐ 150 mg twice daily and 450 mg twice daily ‐ to placebo. The 450 mg daily dose group was split into participants with a number of different mutations (n = 12) and a second group who were homozygous for F508del (n = 19) (Kazani 2016).
Outcomes
The phase 1 trial's main outcome was the pharmacokinetic (PK) profile and PK blood samples were collected at several time points post‐dose on Day 1 and Day 7, and at 12 and 24 hours post‐dose on Day 2 through Day 6. The plasma concentrations of CTP‐656 and its metabolites, (D‐M1 and D‐M6) were analysed by a combination of liquid chromatography with mass spectrometry for all three dose cohorts (Uttamsingh 2016).
In the phase 2 trial, the primary outcomes were the change in LCI and adverse events; secondary outcomes included the change in FEV1, the change in CFQR reported outcomes and the change in sweat chloride. Some limited results have been published on clinicaltrials.gov (Kazani 2016).
Risk of bias in included studies
A summary of the risk of bias judgements can be found in the figures (Figure 2; Figure 3).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. This Figure demonstrates the high proportion of trials that were judged to have a high risk of attrition bias (incomplete outcome data addressed) and selective reporting bias.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Sequence generation
Four trials reported on random sequence generation; all four employed an unblinded statistician (not otherwise associated with the trial) to produce the final randomisation list using a code produced by the trial sponsor and we judged these to have a low risk of bias for sequence generation (Accurso 2010; DISCOVER 2011; KONDUCT 2015; STRIVE 2011). One phase 3 G551D trial did not report on how the children were randomised and we judged this to have an unclear risk of bias (ENVISION 2013).
Allocation concealment
Four trials reported on allocation concealment (Accurso 2010; DISCOVER 2011; KONDUCT 2015; STRIVE 2011). Participants were allocated to groups using an interactive voice response system (IVRS) according to the concealed randomisation list and we judged these to have a low risk of bias with regards to allocation concealment (Accurso 2010; DISCOVER 2011; KONDUCT 2015; STRIVE 2011). The paediatric phase 3 G551D trial did not report on allocation concealment and we judged this to have an unclear risk of bias (ENVISION 2013).
Blinding
Three trials reported on the blinding of trial personnel (Accurso 2010; DISCOVER 2011; STRIVE 2011). All trial personnel were blinded to participant treatment assignments. Tasks requiring unblinded personnel were conducted by people not otherwise involved in the trials; hence we judged these three trials to have a low risk of bias for blinding of personnel (Accurso 2010; DISCOVER 2011; STRIVE 2011). Two trials stated that they were 'double‐blinded' but did not provide sufficient information to allow a clear judgement giving an unclear risk of bias (ENVISION 2013; KONDUCT 2015).
With regards to the blinding of participants, none of the included trials reported details of the oral tablets such as colour, size, consistency or taste; therefore we judge them all to have an unclear risk of bias with regards to the blinding of participants (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
Incomplete outcome data
There was low attrition (less than 15%) in all included trials (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
In the phase 2 G551D trial, one participant withdrew consent prior to dosing, but all 19 remaining participants completed the trial and were included in the analysis of reported outcomes; therefore, we judged this trial to have a low risk of attrition bias (Accurso 2010). In the R117H trial, two participants from the ivacaftor group withdrew after dosing due to one participant becoming pregnant and one for non‐compliance. All 69 participants who received at least one dose of the trial drug were included in the analysis. We judged this trial to also have a low risk of attrition bias (KONDUCT 2015).
In the remaining three trials, some participant data were excluded from the analysis and these trials were judged to have a high risk of attrition bias (DISCOVER 2011; ENVISION 2013; STRIVE 2011).
A total of 10 participants (7.1%) withdrew from the F508del trial (DISCOVER 2011); eight out of 112 (7.1%) participants withdrew from the ivacaftor group (three due to adverse events, two for non‐compliance, one refused medication, one was lost to follow up; and one due to "early termination per sponsor decision") and two participants out of 28 (7.1%) withdrew from the placebo group due to adverse events (DISCOVER 2011). Participant data were excluded from the analysis of the change from baseline in sweat chloride concentration (one participant excluded from the ivacaftor group) and the absolute change from baseline in FEV1 (one participant excluded from the ivacaftor group). The author was approached for information on these missing data (DISCOVER 2011).
In the paediatric phase 3 G551D trial, 4 out of 52 children (7.7%) withdrew from the placebo group, one for each of the following reasons: adverse events; refusal of medication; withdrawal of consent; and wrong genotype. Participant data were excluded from the analysis for absolute change from baseline in % predicted FEV1 (one child excluded from placebo group), change from baseline in sweat chloride concentration (three children excluded from ivacaftor group and three children excluded from the placebo group) and CFQ‐R respiratory domain paediatric version (one child excluded from placebo group). The author was approached for information on these missing data and revealed that a modified intention‐to‐treat analysis (not per protocol) was employed, where data were excluded from the analysis (ENVISION 2013).
In the adult phase 3 G551D trial, 10 out of 167 participants (6.0%) withdrew from the placebo group; four due to adverse events, one on the physician's decision, two required prohibited medication; one withdrew consent; one was the wrong genotype; and one had "Increased Lab Draws/Difficult Lab Stick". Six out of 167 participants (3.6%) withdrew from the ivacaftor group; one due to adverse events; two for non‐compliance; one became pregnant; one refused medication; and one withdrew consent. After these 16 randomised participants (9.6%) withdrew, a total of 161 participants (78 in the placebo group and 83 in the ivacaftor group) were included in the analysis. However, in the analysis of change from baseline in CFQ‐R respiratory domain scores, data from 10 participants (seven participants from the placebo group and three participants from the ivacaftor group) were excluded; and data from nine participants (four participants from the placebo group and five participants from the ivacaftor group) were excluded from the analysis of the change from baseline in sweat chloride concentration. The author was approached for information on these missing data (STRIVE 2011).
Selective reporting
Trial protocols were available for the phase 2 G551D and the adult phase 3 G551D trials (Accurso 2010; STRIVE 2011). In the phase 2 trial, weight was measured at days 1, 3, 14, 21 and 28, but not reported. In such a trial, the change in weight of participants from baseline is a key outcome and by not reporting this outcome, the trial is at high risk of selective reporting bias (Accurso 2010). In the adult trial, the following tertiary outcomes were not reported in the full text: change from baseline in oxygen saturation; change from baseline in EuroQol Questionnaire (EQ‐5D); and outpatient sick visits to the clinic or hospital for CF–related complications. Also CFQ‐R domain scores were reported for domains where improvements were seen in the ivacaftor group only. Hence, this trial was also judged to have a high risk of selective reporting bias (STRIVE 2011).
Full protocols were not available, either online or upon request, for the remaining three trials (DISCOVER 2011; ENVISION 2013; KONDUCT 2015). In the paediatric phase 3 G551D trial, FVC was measured at days 1 and 15, then at weeks 8, 16, 24, 32, 40 and 48; but results were not reported in the full text; also, relative change in FEV1 from baseline was reported at 24 weeks, but not at any other time point (ENVISION 2013). In such trials, the change from baseline in FVC and relative change from baseline in FEV1 are key outcomes and by not reporting these outcomes, the trial is at high risk of selective reporting (ENVISION 2013). In the F508del trial, there were missing data for change from baseline in FEV1 score (at day 15 and week 8) and in change from baseline in FVC or mid‐forced expiratory flow (FEF25‐75%) measured throughout the trial. Also, one withdrawal from the ivacaftor group was due to "early termination per sponsor decision" and attempts to illicit further information about this were unsuccessful; we therefore found the risk of selective reporting in this trial to be high (DISCOVER 2011). In the R117H trial, a protocol synopsis was made available by the trial sponsor which reported a number of tertiary outcomes; however, no results were made available for these outcomes. We therefore judged the trial to be at high risk of selective reporting bias (KONDUCT 2015).
Other potential sources of bias
The baseline characteristics of participants were similar in all included trials (Accurso 2010; ENVISION 2013; DISCOVER 2011; KONDUCT 2015; STRIVE 2011).
In the phase 2 G551D trial, drug dosing was monitored by clinical staff via returned dosage units and dosing diaries; an adherence rate of 100% (range 92.6 to 100) was achieved (Accurso 2010). In the paediatric phase 3 G551D trial, reviewing dosing with participants and caregivers ensured correct doses were taken; mean rates of compliance of 94.4% in the ivacaftor group and of 95.7% in the placebo group were reported (ENVISION 2013). Two trials ensured adherence by drug accountability (DISCOVER 2011; STRIVE 2011). No information was provided regarding drug adherence for the R117H trial (KONDUCT 2015).
In the R117H trial additional age subgroup analyses were performed for participants aged 6 to 11 years and ≥ 18 years, however, there were only two participants between 12 to 17 years of age so no statistical analysis was performed for this group (KONDUCT 2015). No reason was provided for the low numbers in 12 to 17 age group (KONDUCT 2015).
All trials were funded by a single company, Vertex Pharmaceuticals Incorporated (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
Effects of interventions
See: Summary of findings for the main comparison Summary of findings ‐ ivacaftor compared with placebo for cystic fibrosis with the F508del CFTR mutation; Summary of findings 2 Summary of findings ‐ ivacaftor compared with placebo for cystic fibrosis with at least one G551D CFTR mutation; Summary of findings 3 Summary of findings ‐ ivacaftor compared with placebo for cystic fibrosis with at least one R117H CFTR mutation
In the summary of findings tables, the quality of the evidence has been graded for pre‐defined outcomes (see above) and definitions of these gradings provided.
Ivacaftor versus placebo
Primary outcomes
1. Survival
No survival data or deaths were reported by any of the included trials (n = 447) (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
2. QoL
a. total QoL score
None of the trials reported on total QoL scores (n = 447) (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
b. different sub‐domains
All five trials reported the CFQ‐R respiratory domain scores (n = 447) (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011). The phase 2 G551D trial also reported scores for all other CFQ‐R domains (Accurso 2010) and the adult phase 3 G551D trial reported scores for CFQ‐R domains where improvements were reported in the ivacaftor group (STRIVE 2011).
In the F508del trial, investigators reported lower scores on the CFQ‐R respiratory domain score in the ivacaftor group (MD ‐1.3) at 16 weeks, but this difference was not significant (DISCOVER 2011) (moderate‐quality evidence). Insufficient data for this outcome were reported for inclusion in the analysis.
Data from both phase 3 G551D trials have not been combined as the paediatric trial reported individual change from baseline respiratory domain scores, for both children and parents or caregivers (ENVISION 2013), but the adult trial pooled the CFQ‐R respiratory domain scores from adult and child questionnaires (STRIVE 2011). In the paediatric trial, at 24 weeks children in the ivacaftor group reported higher CFQ‐R respiratory domain scores, MD 6.10 (95% CI ‐1.35 to 13.55), but the difference between groups was not significant (ENVISION 2013) (Analysis 2.1) (moderate‐quality evidence). In the same trial at 24 weeks, the parents or caregivers of children in the ivacaftor group reported significantly higher CFQ‐R respiratory domain scores, MD 5.90 (95% CI 0.41 to 11.39) (Analysis 2.2) (moderate‐quality evidence). In the adult trial, at 24 weeks participants reported significantly higher CFQ‐R respiratory domain scores in the ivacaftor group, MD 8.10 (95% CI 4.77 to 11.43) (STRIVE 2011) (Analysis 2.3) (moderate‐quality evidence).
At 48 weeks, both children and and parents or caregivers reported higher CFQ‐R respiratory domain scores in the ivacaftor group, MD 5.10 (95% CI ‐1.56 to 11.76) and MD 4.90 (95% CI ‐0.39 to 10.19) respectively (Analysis 2.1; Analysis 2.2) (moderate‐quality evidence); in neither case were treatment differences significant (ENVISION 2013). In the adult trial at 48 weeks, investigators reported significantly higher CFQ‐R respiratory domain scores in the ivacaftor group, MD 8.60 (95% CI 5.27 to 11.93) (STRIVE 2011) (Analysis 2.3) (moderate‐quality evidence). At the same time‐point, significantly higher CRQ‐R scores in the physical functioning scale (P < 0.001), social functioning scale (P = 0.0026), eating disturbances scale (P = 0.0021) and treatment burden scale (P = 0.0419) were observed (STRIVE 2011). Higher scores for the body, emotion and digestive scales were also seen but the treatment differences between groups for these domains were not significant (STRIVE 2011).
Accurso reported on improvement in the respiratory domain score at two weeks and four weeks using medians and ranges, precluding the analysis of these data in RevMan (Accurso 2010). At two weeks, a median (range) increase of 5.6 (0.0 to 16.7) points was achieved in the 150 mg ivacaftor group and 5.6 (‐11.1 to 11.1) in the 250 mg ivacaftor group. The median (range) change of 2.8 (‐5.6 to 11.1) in the placebo group meant the difference between the two treatment and the placebo groups was not significant. At four weeks, there were no significant differences between treatment groups and the placebo group; the 150 mg group reported a median (range) improvement of 8.3 (0.0 to 16.7) points, the 250 mg group reported a median (range) improvement of 11.1 (‐5.6 to 33.3) points and the placebo group reported a median (range) improvement of 2.8 (‐5.6 to 11.1) points (Accurso 2010). Accurso also presented median (range) scores for all other CFQ‐R domains which are shown in the additional tables (Table 2). None of the improvements were significant (Accurso 2010) (moderate‐quality evidence).
| Domain | Day 14 | Day 28 | ||||
| Placebo (n = 4) | VX‐770 150 mg (n = 8) | VX‐770 250 mg (n = 7) | Placebo (n = 4) | VX‐770 150 mg (n = 8) | VX‐770 250 mg (n = 7) | |
| Body image | 0 (‐11.1 to 22.2) | 0 | 0 | ‐5.6 | 0 (‐22.2 to 11.1) | 0 |
| Digestive symptoms | ‐5.6 | 0 | 0 | 0 | 5.6 (0 to 22.2) | 0 |
| Eating disturbances | 0 | 0 | 0 | ‐5.6 | 0 (0 to 0) | 0 |
| Emotional functioning | 13.3 | 0 | 0 | 3.3 | 0 | 6.7 |
| Health perceptions | 5.6 | 0 | 0 | 0 | 0 (‐22.2 to 22.2) | 0 |
| Physical functioning | 0 | 2.1 | 4.2 | 2.1 (0 to 4.2) | 4.2 (‐8.3 to 25.0) | 0 (0 to 12.5) |
| Respiratory symptoms | 2.8 | 5.6 | 5.6 | 2.8 | 8.3 | 11.1 |
| Role | 0 | 0 | 0 | 0 | 0 (‐8.3 to 8.3) | 0 |
| Social | 2.8 | 0 | ‐5.6 | 2.8 | 0 (‐11.1 to 5.6) | 0 |
| Treatment burden | 0 | ‐5.6 | 0 | 0 | ‐5.6 | 0 |
| Vitality | 4.2 | 4.2 | 0 | ‐8.3 | 0 (‐16.7 to 25.0) | 0 |
| Weight | 0 | 0 | 0 | 0 (0 to 33.3) | 0 (0 to 33.3) | 0 (‐33.3 to 33.3) |
CFQ‐R: Cystic Fibrosis Questionnaire‐Revised
In the R117H trial, investigators reported a significant improvement in the CFQ‐R respiratory domain scores in the ivacaftor group, MD 8.40 (95% CI 2.17 to 14.63) (KONDUCT 2015) (Analysis 3.1) (moderate‐quality evidence). The treatment effect was adjusted for continuous baseline values of age and % predicted FEV1 (KONDUCT 2015). The R117H trial conducted a further subgroup analysis by age, which only showed a significant improvement in the respiratory domain score for adults in the ivacaftor group and not children (Table 3).
| Overall | 6 ‐ 11 years | ≥18 years | ||||
| Treatment difference | P value | Treatment difference | P value | Treatment difference | P value | |
| Quality of life (CFQ‐R) ‐ respiratory domain (pooled) | 8.4 | 0.009 | ‐6.1 | 0.19 | 12.6 | 0.002 |
| % predicted FEV1 ‐ absolute change from baseline | 2.1 | 0.20 | ‐6.3 | 0.03 | 5.0 | 0.01 |
| % predicted FEV1 ‐ relative change from baseline | 5.0 | 0.06 | ‐6.8 | 0.04 | 0.2 | 0.008 |
| BMI ‐ absolute change from baseline | 0.26 | 0.78 | ‐0.18 | 0.87 | 0.31 | 0.78 |
| Sweat chloride ‐ absolute change from baseline | ‐24.0 | <0.0001 | ‐27.6 | <0.001 | ‐21.9 | <0.001 |
Treatment difference was adjusted for age and % predicted FEV1
BMI: body mass index
CFQ‐R: cystic fibrosis questionnaire ‐ revised
FEV1: forced expiratory volume in one second
3. FEV1 (relative change from baseline)
All included trials reported this outcome (n = 447) (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
At 16 weeks investigators reported no significant difference in the relative change from baseline in FEV1 between groups in the F508del trial, MD 2.40% (95% CI ‐0.95 to 5.75) (DISCOVER 2011) (Analysis 1.1) (moderate‐quality evidence).
At 24 weeks in the phase 3 G551D trials, both children and adults in the ivacaftor group reported significant improvements in the relative change from baseline in FEV1 (ENVISION 2013; STRIVE 2011). For the paediatric trial, only interim data were reported in a conference abstract which were insufficient for inclusion into the meta‐analysis, MD 17.4% (P < 0.0001) (ENVISION 2013); but for the adult trial investigators reported MD 16.90% (95% CI 13.60 to 20.20) (Analysis 2.4). Data at 48 weeks were not reported in the paediatric trial (ENVISION 2013); however, the adult trial reported a significant improvement in the relative change from baseline in FEV1 in the ivacaftor group at 48 weeks, MD 16.80% (95% CI 13.50 to 20.10) (STRIVE 2011) (Analysis 2.4) (moderate‐quality evidence).
Again Accurso reported medians (range) from the phase 2 G551D trial; at four weeks there was a relative improvement from baseline in % predicted FEV1 of 8.7% (2.3 to 31.3) in the 150 mg group, 4.4% (0.0 to 18.3) in the 250 mg group and 7.3% (5.2 to 8.2) in the placebo group (Accurso 2010). Treatment differences between ivacaftor arms and the placebo group were not significant (Accurso 2010) (moderate‐quality evidence).
In the R117H trial, investigators included the relative change from baseline in FEV1 data in a results table; however, the absolute change in FEV1 was a primary outcome and this was the focus of the text (KONDUCT 2015). At 24 weeks investigators reported no significant difference in the relative change from baseline in FEV1 between treatment groups MD 5.00% (95% CI ‐0.24 to 10.24) (Analysis 3.2) (moderate‐quality evidence). Treatment effect was adjusted for continuous baseline values of age and % predicted FEV1 (KONDUCT 2015).
Secondary outcomes
1. Adverse effects
All included trials reported the number of participants who experienced adverse effects (n = 447) (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
The F508del trial reported the number of participants who experienced adverse effects that occurred in at least 5% of participants taking ivacaftor (DISCOVER 2011) (Analysis 1.2). Accurso reported the number of participants who experienced any adverse effect in the phase 2 G551D trial (Accurso 2010); we have pooled data for the 150 mg group and 250 mg group and compared these to the placebo group (Analysis 2.6). Both phase 3 G551D trials reported the number of participants who experienced any serious adverse effect and the number of participants who experienced all adverse effects that occurred in more than 5% of participants in either treatment arm (ENVISION 2013; STRIVE 2011). We have combined the data from both trials (Analysis 2.5). Serious adverse effects were defined as life‐threatening or debilitating, which is consistent with our definition of severe. The R117H trial reported the number of participants with any adverse event, serious adverse events (the authors' definition of a serious adverse event was not present in the text), adverse events leading to discontinuation and adverse events occurring in 15% of participants in any ivacaftor treatment group (KONDUCT 2015) (Analysis 3.3; Analysis 3.4).
For the F508del trial, phase 3 G551D trials and the R117H trial, we have reported on adverse effects that occurred more frequently in either the ivacaftor or placebo groups where there was greater or equal to 5% incidental difference between groups in the number of participants affected (DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011). Given the small sample size in the phase 2 G551D trial by Accurso (n = 19), we have not reported on the most common adverse effects from this trial (Accurso 2010). For all trials we have present below the results that were statistically significant in trial reports. Where numerical data were not provided, we have discussed the results narratively.
a. mild (therapy does not need to be discontinued)
In the F508del trial, episodes of cough, nausea, rash and contact dermatitis were experienced by more participants assigned to ivacaftor compared to those assigned to placebo. Pulmonary exacerbations were more common in participants in the placebo group (DISCOVER 2011) (Analysis 1.2) (low‐quality evidence). In the adult phase 3 G551D trial, more adults in the placebo group experienced episodes of pulmonary exacerbation, cough, haemoptysis, and decreased pulmonary function in comparison to participants in the ivacaftor group. Adverse effects that occurred in more adults in the ivacaftor group were headache, upper respiratory tract infection, nasal congestion, rash, and dizziness (STRIVE 2011) (Analysis 2.5) (low‐quality evidence). In the paediatric phase 3 G551D trial, episodes of cough, productive cough, vomiting, rales, and decreased pulmonary function were experienced by more children in the placebo group in comparison to children in the ivacaftor group. Episodes of oropharyngeal pain, headache, nasopharyngitis, upper respiratory tract infection, otitis media, diarrhoea, and an increased blood eosinophil count were reported in more children in the ivacaftor group (ENVISION 2013) (Analysis 2.5) (low‐quality evidence). In the R117H trial more episodes of nasal congestion, oropharyngeal pain, abdominal pain, wheeze and CF lung pathogen colonisation were experienced in the ivacaftor group compared to the placebo group (KONDUCT 2015) (Analysis 3.4) (low‐quality evidence).
There were no statistically significant differences at the 1% significance level to allow for multiple analyses related to adverse events in any of the included trials (Analysis 2.5; Analysis 2.6, Analysis 1.2; Analysis 3.4).
b. moderate (therapy is discontinued and the adverse effect ceases)
The F508del trial and both phase 3 G551D trials reported the number of participants who experienced adverse effects that required interruption of the intervention (DISCOVER 2011; ENVISION 2013; STRIVE 2011). The R117H trial did not report any participants requiring interruption of the intervention (KONDUCT 2015).
In the F508del trial, two participants in the ivacaftor group (1.8%) stopped receiving the intervention due to elevated liver enzyme values; but the intervention was subsequently restarted as both cases were found to be caused by concurrent pathology (DISCOVER 2011). No trial drug interruption occurred in the placebo group. The difference between groups in number of participants who required trial interruption was not significant, OR 1.29 (95% CI 0.06 to 27.62) (Analysis 1.3) (low‐quality evidence). In the paediatric phase 3 G551D trial, three participants from the placebo group experienced adverse effects requiring interruption of the intervention compared to one participant in the ivacaftor group; but the details of these adverse events were not reported (ENVISION 2013) (low‐quality evidence). In the adult trial, 11 adverse events in the ivacaftor group (13.3%) compared to four in the placebo group (5.1%) required trial drug interruption. Adverse events in the ivacaftor group were: haemoptysis (n = 1); migraine (n = 1); upper respiratory tract infection (n = 1); pulmonary exacerbation (n = 1); increased hepatic enzyme (n = 2); pulmonary exacerbation and anaphylactic shock (n = 1); lymph node pain and gynaecomastia (n = 1); myalgia and diarrhoea (n = 1); decreased weight and pulmonary exacerbation (n = 1); and vulvovaginal mycotic infection, oral candidiasis and two episodes of pulmonary exacerbation (n = 1). Adverse events in the placebo group were: migraine (n = 1); pulmonary exacerbation (n = 1); increased blood lactate dehydrogenase and increased hepatic enzymes (n = 1); and rash, nephrolithiasis and renal colic (n = 1). Investigators reported that five participants in the placebo group required drug interruption; however, one of these participants subsequently withdrew from the trial and will be discussed under 'severe' adverse events (STRIVE 2011) (low‐quality evidence). Combined data for both phase 3 G551D trials showed no significant difference between treatment arms, OR 1.18 (95% CI 0.14 to 9.92) (Analysis 2.7) (low‐quality evidence). Heterogeneity was substantial (I² = 64%) which is possibly due to the difference in ages between the adult and paediatric trials.
c. severe (life‐threatening or debilitating, or which persists even after treatment is discontinued)
All included trials reported the number of participants who developed adverse effects that required discontinuation of the intervention (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
In the F508del trial, three participants in the ivacaftor group (2.7%) discontinued due to asthenia, fatigue and headache (n = 1), arthritis (n = 1) and myopathy (n = 1); a further participant in this group developed fatigue, depression and suicidal ideation that was considered to be life‐threatening (DISCOVER 2011). In comparison, two participants in the placebo group (7.1%) discontinued medication because of abnormal feelings of cognitive disorder (n = 1) and elevated liver enzymes and increased lactate dehydrogenase levels (n = 1). The abnormal liver enzyme profile was considered to be caused by concomitant use of an anabolic steroid like a nutritional supplement (DISCOVER 2011). The number of participants requiring trial drug discontinuation between treatment arms was not significant, OR 0.36 (95% CI 0.06 to 2.25) (Analysis 1.3) (low‐quality evidence).
In the paediatric phase 3 G551D trial, one participant from the placebo group withdrew due to anxiety and psychological issues (ENVISION 2013). In the adult trial, four participants from the placebo group withdrew from the trial; one each due to increased hepatic enzyme levels, atrioventricular block, panic attack and respiratory failure. There was one dropout from the ivacaftor group due to increased hepatic enzymes (STRIVE 2011). Combined data for the phase 3 G551D trials showed no significant difference between treatment arms in the number of participants discontinuing the trial drug, OR 0.25 (95% CI 0.04 to 1.57) (Analysis 2.7) (low‐quality evidence). Likewise, combined data from the two trials for serious adverse effects, did not show an increase with ivacaftor compared with placebo (Analysis 2.8), with the exception of pulmonary exacerbation which will be discussed under other adverse effects of therapy (below).
No severe adverse effects were reported in any of the participants in the phase 2 G551D trial and all adverse events resolved without discontinuation of the intervention (Accurso 2010) (low‐quality evidence).
The R117H trial reported six (17%) severe adverse events in the placebo group and four (12%) in the ivacaftor group with no participants discontinuing the intervention due to adverse events (KONDUCT 2015). There was no significant difference in the number of serious adverse events between treatment arms, OR 0.64 (95% CI 0.16 to 2.52) (Analysis 3.3) (low‐quality evidence).
d. other adverse effects of therapy (of any severity) that are not classifiable according to these categories
The number of participants who experienced episodes of pulmonary exacerbation was reported by all trials (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011) (low‐quality evidence). In all cases pulmonary exacerbations were protocol‐defined; both phase 3 G551D trials and also the F508del trial employed the same definition (DISCOVER 2011; ENVISION 2013; STRIVE 2011), but this was different to the definition employed by the phase 2 G551D trial (Accurso 2010). The R117H trial reported protocol‐defined pulmonary exacerbations, but the full protocol was not available to determine this definition (KONDUCT 2015). Data for all G551D participants in this review are shown separately (Analysis 2.9). In the adult phase 3 G551D trial, there were minor differences in the number of participants experiencing episodes of pulmonary exacerbations between the full text, supplementary appendix and an online trials database (clinicaltrials.gov). Data were extracted from the online trials database where data for serious and other cases of pulmonary events were reported.
In the phase 2 G551D trial, one participant from each of the treatment arms experienced an exacerbation compared to none in the placebo group (Accurso 2010); when analysed, there was no significant difference in the number of participants who experienced pulmonary exacerbations between the ivacaftor group (combined data from 150 mg and 250 mg groups) and the placebo group at one month, OR 1.67 (95% CI 0.07 to 41.64) (Analysis 2.9). In the phase 3 G551D trials, at 48 weeks significantly fewer participants in the ivacaftor group experienced serious episodes of pulmonary exacerbations compared to participants in the placebo group, OR 0.34 (99% CI 0.13 to 0.88) (Analysis 2.8). Combined data for all exacerbations in these trials was not significant between groups at this time‐point, OR 0.64; 95% CI 0.36 to 1.12) (Analysis 2.9). In the adult trial, the meta‐analysis of all exacerbations shows significantly fewer participants in the ivacaftor group experienced exacerbations than in the placebo group, OR 0.54 (95% CI 0.29 to 1.01) (STRIVE 2011) (Analysis 2.9). In the F508del trial, investigators reported a non‐significant lower frequency of pulmonary exacerbations in the ivacaftor group, OR 0.44 (99% CI 0.14 to 1.41) (Analysis 1.2).
The adult phase 3 G551D trial reported data for the time‐to‐first pulmonary exacerbation (STRIVE 2011). At 24 weeks, a significantly greater proportion of participants in the ivacaftor group (78%) were exacerbation‐free in comparison to participants in the placebo group (51%). This corresponds to a hazard ratio (HR) of 0.46 (95% CI 0.28 to 0.76) (P = 0.002) so within the first 24 weeks, adults receiving ivacaftor were 54% less likely to experience an exacerbation than those assigned to placebo (Analysis 2.10). At 48 weeks, 67% of participants in the ivacaftor group and 41% of participants in the placebo group were exacerbation‐free, HR 0.46 (95% CI 0.29 to 0.73), and the difference between groups remained significant (P < 0.001) (Analysis 2.10) (moderate‐quality evidence). Therefore during the 48‐week trial period, participants receiving ivacaftor were 54% less likely to experience an exacerbation than those assigned to placebo (STRIVE 2011).
The R117H trial reported that at 24 weeks there was no significant difference between treatment groups for the time‐to‐first pulmonary exacerbation, HR 0.93 (95% CI 0.42 to 2.08) (KONDUCT 2015) (Analysis 3.6) (moderate‐quality evidence). Additionally, there was no significant difference between the ivacaftor and placebo groups in the number of participants experiencing a pulmonary exacerbation, OR 0.81 (95% CI 0.30 to 2.19) (Analysis 3.5).
There was no significant difference in the hepatic enzyme profile between groups in either phase 3 G551D trial (Analysis 2.5; Analysis 2.11). The majority of participants in the F508del trial had aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin values less than or equal to two times ULN (DISCOVER 2011).
2. Hospitalisation
The adult phase 3 G551D trial (n = 167) reported on the number of hospitalisations for episodes of pulmonary exacerbation and also on the number of days admitted (STRIVE 2011). The R117H trial reported the number of hospital admissions for episodes of pulmonary exacerbation (KONDUCT 2015).
a. number of days
In the G551D trial, of the episodes of pulmonary exacerbation that required hospitalisations, those occurring in participants in the ivacaftor group required less time in hospital, MD ‐0.23 days (95% CI ‐3.74 to 3.28) (Analysis 2.12). We note this non‐significant summary statistic conflicts with the trial report. The Supplementary table 2B of the supplementary appendix reports a P value of 0.0275 for this difference; however, this has been calculated from a Wilcoxon rank‐sum test, stratified by baseline % predicted FEV1 severity and age group (STRIVE 2011). This is a non‐parametric test used when data are skewed and where values are usually given as medians and ranges. In this trial, however, mean and SDs have been reported. As stated above, after entering these data into Review Manager, we have calculated a different P value of 0.90 which was not significant (Analysis 2.12).
b. number of episodes
Similarly, in the G551D trial significantly fewer episodes of pulmonary exacerbation required hospitalisation in participants in the ivacaftor group, OR 0.37 (95% CI 0.16 to 0.81) (Analysis 2.13) (STRIVE 2011). The R117H trial did not show a significant difference between treatment groups in the number of participants requiring hospital admission for pulmonary exacerbations (Analysis 3.5) (KONDUCT 2015).
3. School or work attendance
No individual data for school or work attendance was reported by any trial (n = 447) (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
4. Other physiological measures of lung function
a. FEV1 (absolute values)
All included trials reported on the absolute change from baseline in FEV1 (n = 447) (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011). For the four phase three trials, this outcome was a primary endpoint (DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011). The data in the paediatric phase 3 G551D trial were adjusted based on the continuous baseline value of % of predicted FEV1 (ENVISION 2013). Data in the R117H trial were adjusted for continuous baseline values of age and % predicted FEV1 (KONDUCT 2015).
Investigators reported no significant differences between groups in the F508del trial for change from baseline of % predicted FEV1 at 16 weeks, MD 1.70% (95% CI ‐0.65 to 4.05) (DISCOVER 2011) (Analysis 1.4) (moderate‐quality evidence).
Both phase 3 G551D trials reported results early (day 15), but we are unable to include these results in our analysis (ENVISION 2013; STRIVE 2011). At this time point, an estimated MD of 13.0% points can be deduced from the graph (Figure 2 in the full paper) for the paediatric trial (ENVISION 2013) and the adult trial reported a significant MD of 9.2% points (P < 0.001) (STRIVE 2011). At 24 weeks combined data from both of these trials show a significant increase in FEV1 (% predicted) from baseline in the ivacaftor group, MD 10.80% (95% CI 8.91 to 12.69) (P < 0.00001) with no heterogeneity (I² = 0%) (Analysis 2.14) (low‐quality evidence). Combined data at 48 weeks still demonstrate a significant change from baseline in FEV1 (% predicted), MD 10.44% (95% CI 8.56 to 12.32), again with no heterogeneity (I² = 0%) (Analysis 2.14) (low‐quality evidence). For the change from baseline in FEV1 (L), combined data at 24 weeks show a significant increase in in the ivacaftor group, MD 0.33 L (95% CI 0.17 to 0.49), but with considerable heterogeneity (I² = 85%) (Analysis 2.15) (low‐quality evidence). At 48 weeks the combined data still demonstrate a significant improvement, MD 0.31 L (95% CI 0.11 to 0.50), but again with considerable heterogeneity (I² = 90%) (Analysis 2.15) (low‐quality evidence). We do not know why the I² values are different between the meta‐analyses of % predicted FEV1 and FEV1 (L); we are not able to infer anything from it as there are only two trials in the analysis (ENVISION 2013; STRIVE 2011).
At four weeks, in the phase 2 G551D trial, investigators reported a median (range) change from baseline in FEV1 of 0.25 L (0.05 to 0.75) in the 150 mg group, 0.17 L (0 to 0.37) in the 250 mg group and 0.20 L (0.12 to 0.33) in the placebo group (low‐quality evidence). Treatment differences between the ivacaftor arms and the placebo arm were not significant (Accurso 2010).
Subgroup analysis of the G551D trials
Improvements in the absolute change from baseline in FEV1 amongst pre‐defined subgroups were reported at 48 weeks by the phase 3 G551D trials (ENVISION 2013; STRIVE 2011).
In the paediatric trial at 48 weeks, children in three subgroups demonstrated significant improvements in the change from baseline in % predicted FEV1 in the ivacaftor group compared to the placebo group:
-
a baseline % predicted FEV1 below 90%, MD 14.90 (95% CI 7.30 to 22.50);
-
were from Europe, MD 24.60 (95% CI 6.40 to 42.80); and
-
were female, MD 13.80 (95% CI 4.20 to 23.40) (ENVISION 2013).
However, there was no significant difference in the change from baseline in % predicted FEV1 between treatment and placebo in the following subgroups:
-
baseline % predicted FEV1 over 90%, MD 6.90% (95% CI ‐3.80 to 17.60);
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from North America, MD 5.80% (95% CI ‐2.60 to 14.20);
-
from Australia, MD 4.20% (95% CI ‐3.70 to 12.10); and
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male, MD 5.20% (95% CI ‐2.20 to 12.60) (ENVISION 2013) (Analysis 2.16).
The adult phase 3 G551D trial reported significant improvements in FEV1 % predicted favouring ivacaftor over placebo in all subgroups (Table 4); insufficient data precludes inclusion of these results in a meta‐analysis (STRIVE 2011).
| Subgroup | Treatment effect | P value |
| Baseline percent of predicted FEV1 of less than 70% | 10.6 | < 0.001 |
| Baseline percent of predicted FEV1 of greater or equal to 70% | 10.3 | < 0.001 |
| Participants from North America | 9.0 | < 0.001 |
| Participants from Europe | 9.9 | < 0.001 |
| Participants from Australia | 11.9 | 0.008 |
| Male | 11.0 | < 0.001 |
| Female | 11.6 | < 0.001 |
| Less than 18 years | 11.4 | 0.005 |
| Greater than or equal to 18 years | 9.9 | < 0.001 |
The treatment effect represents the difference between the ivacaftor group and the placebo group with respect to the absolute change from baseline through week 48.
FEV1: forced expiratory volume at one second
The R117H trial reported that at 24 weeks there was no significant treatment differences in absolute % predicted FEV1 between the ivacaftor and placebo groups, MD 2.10% (95% CI ‐1.13 to 5.33) (Analysis 3.7) (KONDUCT 2015) (low‐quality evidence).
b. FVC (absolute values and change from baseline)
Three trials reported on the change from baseline in FVC (Accurso 2010; DISCOVER 2011; STRIVE 2011). None of the data were included in a meta‐analysis as they were either non‐parametric data (reported as median and ranges) (Accurso 2010) or insufficient data were provided (DISCOVER 2011; STRIVE 2011).
The F508del trial reported no significant differences between groups in FVC, but no numerical data were provided (DISCOVER 2011).
The phase 2 G551D trial reported a relative improvement from baseline FVC at two weeks in all three groups; there was a 9.0% improvement in the 150 mg ivacaftor group, a 7.4% improvement in the 250 mg ivacaftor group and a 1.0% improvement in the placebo group (Accurso 2010). Treatment differences between the ivacaftor groups and the placebo group were not significant. At four weeks a median (range) change from baseline of 0.18 L (‐0.29 to 0.48) in the 150 mg group, 0.09 L (‐0.09 to 0.43) in the 250 mg group and 0.10 L in the placebo group were reported. These values corresponded to relative changes from baseline of 4.6% in the 150 mg group, 2.6% in the 250 mg group and 2.3% in the placebo group. Treatment differences between the ivacaftor groups and the placebo group were not significant (Accurso 2010).
The adult phase 3 G551D trial reported on the absolute change from baseline in FVC in the form of a graph (supplemental figure 4B of the supplementary appendix) (STRIVE 2011). From the graph, an estimated MD between intervention and placebo arms of 11.5% at 24 weeks and 7.0% at 48 weeks can be deduced. These results should be interpreted with caution, as they are not accurate (STRIVE 2011).
5. Extra courses of antibiotics
Three trials reported on extra courses of antibiotics required by participants (n = 376) (DISCOVER 2011; KONDUCT 2015; STRIVE 2011).
The F508del trial reported on the number of new sinopulmonary signs or symptom events that required new or changed antibiotic therapy; however, the route of administration was not stated (DISCOVER 2011). Investigators reported proportionately fewer episodes of new sinopulmonary signs or symptom events requiring antibiotic treatment in the ivacaftor group, OR 0.56 (95% CI 0.24 to 1.30); however, the difference was not significant (Analysis 1.5).
The adult phase 3 G551D trial reported firstly the number of episodes of pulmonary exacerbation that required intravenous antibiotics and secondly the number of days on intravenous antibiotics to treat pulmonary exacerbations (see below) (STRIVE 2011). The R117H trial reported the number of episodes of pulmonary exacerbation requiring intravenous antibiotics (KONDUCT 2015).
a. oral
This outcome was not reported in any trial.
b. intravenous
In the adult phase 3 G551D trial, Ramsey reported significantly fewer episodes of pulmonary exacerbations requiring intravenous antibiotics occurred in participants in the ivacaftor group, OR 0.34 (95% CI 0.18 to 0.64) (P = 0.0009) (Analysis 2.17). In addition, more days of intravenous antibiotic administration were required for exacerbations occurring in participants in the placebo group, MD ‐4.35 (95% CI ‐10.51 to 1.81) (Analysis 2.18). Supplementary table 2B of the supplementary appendix reports a P value of 0.0183 for this difference; however, this has been calculated from a Wilcoxon rank‐sum test, stratified by baseline % predicted FEV1 severity and age group (STRIVE 2011). This is a non‐parametric test used when data are skewed and where values are usually given as medians and ranges. In this trial however, mean and SDs have been reported. After entering these data into Review Manager, we have calculated a different P value of 0.17 which was not significant (Analysis 2.18).
In the R117H trial, investigators reported fewer episodes of pulmonary exacerbation requiring intravenous antibiotics in the ivacaftor group, OR 0.30 (95% CI 0.06 to 1.62), however, this result was not significant (P = 0.16) (Analysis 3.5) (KONDUCT 2015).
c. inhaled
This outcome was not reported in either trial.
6. Radiological measures of lung disease
No trials reported chest radiograph scores or CT scores.
7. Acquisition of respiratory pathogen
No trial reported on the acquisition of any respiratory pathogens (e.g. P aeruginosa, S aureus, H influenzae).
8. Eradication of respiratory pathogens
No trial reported on the eradication of any respiratory pathogens (e.g. P aeruginosa, S aureus, H influenzae).
9. Nutrition and growth
a. weight
Three trials (n = 359) reported the absolute change from baseline in weight (kg) (DISCOVER 2011; ENVISION 2013; STRIVE 2011); one of these additionally reported on weight‐for‐age z score (DISCOVER 2011).
The F508del trial, reported no significant difference in weight gain between the ivacaftor group and the placebo group at 16 weeks, MD ‐0.20 kg (95% CI ‐1.18 to 0.78) (Analysis 1.6). There was also no significance difference between groups in weight‐for‐age z scores (MD 0.43), but insufficient data prevented inclusion of this outcome in the analysis (DISCOVER 2011).
Combined data from the phase 3 G551D trials at 24 weeks demonstrated significant weight gain in the ivacaftor group, MD 2.37 kg (95% CI 1.68 to 3.06) with moderate heterogeneity (I² = 38%) (ENVISION 2013; STRIVE 2011) (Analysis 2.19). Combined data from the same trials at 48 weeks also demonstrated significant weight gain in the ivacaftor group compared to placebo, MD 2.75 kg (95% CI 1.74 to 3.75), but with no heterogeneity (I² = 0%) (ENVISION 2013; STRIVE 2011) (Analysis 2.19).
b. BMI
Four trials reported on the change from baseline in BMI (DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011) and three additionally reported BMI for age z score (DISCOVER 2011; ENVISION 2013; STRIVE 2011), but none of them provided sufficient information for inclusion into a meta‐analysis (DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
In the F508del trial, a lower BMI score was reported in the ivacaftor group in comparison to the placebo group at 16 weeks, MD ‐0.04 mg/m², but the difference between groups was not significant (DISCOVER 2011). In the phase 3 G551D trials, both children and adults in the ivacaftor group scored significantly higher BMI values at 48 weeks, MD 1.09 kg/m² (P = 0.0003) and MD 0.93 kg/m² (P < 0.0001) respectively (ENVISION 2013; STRIVE 2011).
In the F508del trial, at 16 weeks there was no significant difference between the ivacaftor group and the placebo group in BMI‐for‐age z score amongst a subgroup of participants aged 20 years or below, MD 0.75 (DISCOVER 2011). The paediatric phase 3 G551D trial reported significantly higher BMI‐for‐age‐z scores in the ivacaftor group compared to placebo at 24 weeks, MD 0.34 (P ≤ 0.001), and 48 weeks, MD 0.45 (P < 0.001) (ENVISION 2013). At 48 weeks, the adult phase 3 G551D trial reported significantly higher BMI‐for‐age‐z scores in the ivacaftor group amongst a subgroup of 47 participants aged 12 to 20 years, MD 0.33 (P = 0.0490) (STRIVE 2011).
The R117H trial reported a higher BMI score in the ivacaftor group compared to placebo at 24 weeks, MD 0.26 kg/m² (95% CI ‐1.57 to 2.09), but this was not significant (P = 0.1) (KONDUCT 2015) (Analysis 3.8). Treatment effect was adjusted for age and categorical % predicted FEV1 at baseline (KONDUCT 2015).
c. height
Two trials reported on height z scores (ENVISION 2013; STRIVE 2011). The paediatric phase 3 G551D trial reported improvements in the ivacaftor group at both 24 weeks (MD 0.06) and 48 weeks (MD 0.12) (ENVISION 2013). In the adult phase 3 G551D trial reported improvements in the ivacaftor group at 24 weeks (MD 0.05) and 48 weeks (MD 0.06) amongst a subset of 47 participants aged 12 to 20 years (STRIVE 2011).
10. Sweat chloride (change from baseline)
The change from baseline in sweat chloride concentration was reported by all trials (n = 447) (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
In the F508del trial, investigators reported significant reductions in sweat chloride concentration at 16 weeks in the ivacaftor group compared to the placebo group, MD ‐2.90 mmol/L (95% CI ‐5.60 to ‐0.20) (DISCOVER 2011) (Analysis 1.7).
In the phase 2 G551D trial, at four weeks there was a significant difference in the median (range) change from baseline in sweat chloride concentration between the 150 mg group (within group change ‐59.5 mmol/L (‐66.0 to ‐19.0) and the placebo group (within group change 5.0 mmol/L (‐2.0 to 11.0) (P = 0.02); a similar significant difference was seen between the 250 mg group (within group change ‐38.0 mmol/L (‐47.0 to ‐10.5) and placebo group (within group change 5.0 mmol/L (‐2.0 to 11.0) (P = 0.03) (Accurso 2010).
In the phase 3 G551D trials, reduced sweat chloride concentrations were reported early (day 15) in children, MD ‐50 mmol/L (estimated from a graph) (ENVISION 2013) and in adults, MD ‐47.1 mmol/L (P < 0.001) (STRIVE 2011). Combined data from these trials demonstrated significant reductions in sweat chloride concentration at 24 weeks, MD ‐50.19 mmol/L (95% CI ‐56.20 to ‐44.18) with a moderate level of heterogeneity (I² = 57%) (Analysis 2.20), and at 48 weeks, MD ‐49.74 mmol/L (95% CI ‐54.61 to ‐44.87) with a moderate level of heterogeneity (I² = 40%) (Analysis 2.20). Secondary analysis of combined data from these trials reported that the number needed to treat (NNT) for a reduction of 20 mmol/L in sweat chloride concentration was 1.03. Data from each phase 3 G551D trial demonstrated that significant changes in sweat chloride were reported regardless of whether participants were FEV1 responders (5% point improvement) or minimal responders (less than 5% point improvement) (ENVISION 2013; STRIVE 2011) (Table 5).
| Paediatric phase 3 G551D study(ENVISION 2013) | Adult phase 3 G551D study(STRIVE 2011) | |||
| Treatment difference (mmol/L) | P value | Treatment difference (mmol/L) | P value | |
| Minimal responders (less than 5% point improvement) | ‐55.8 | <0.0001 | ‐46.1 | < 0.0001 |
| FEV1 responders (5% point improvement) | ‐53.9 | <0.0001 | ‐49.7 | < 0.0001 |
FEV1: forced expiratory volume at one second
In the R117H trial, at 24 weeks a significant reduction in sweat chloride concentrations was reported in the ivacaftor group compared to placebo group, MD ‐24.00 mmol/L (95% CI ‐28.01 to ‐19.99) (P = <0.0001) (KONDUCT 2015) (Analysis 3.9). Treatment effect was adjusted for continuous baseline values of age and % predicted FEV1 (KONDUCT 2015). In addition, age subgroup analysis showed significant reductions in sweat chloride concentrations for both participants aged 6 to 11 years and 18 years and over (Table 3).
11. Cost of treatment
No trials reported on the cost of ivacaftor treatment.
Discussion
Summary of main results
The CFTR protein product of a class III mutation is transported to the cell membrane, but displays defective chloride ion gating and dysregulation of sodium channels resulting in a severe CF phenotype; characterised by chronic airway infection and inflammation and pancreatic insufficiency. Agents that repair the underlying gating defects (CFTR potentiators) restore CFTR function for class III mutations and correct the abnormal transmembrane salt transport in cell and animal models (Van Goor 2009). These CFTR potentiators may also have a role in repairing the underlying gating defect in the minimal amounts of class II CFTR that are transported to the cell membrane and for the restrictive movement of chloride ions in class IV CFTR.
This review examines whether CFTR potentiators improve clinically relevant endpoints in CF. Five trials with 447 participants met the inclusion criteria for this review; one compared 150 mg and 250 mg doses of ivacaftor (a potentiator) to placebo (Accurso 2010) and four compared 150 mg of ivacaftor to placebo (DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011). Three trials examined the impact of ivacaftor on people with a class III mutation (G551D) (Accurso 2010; ENVISION 2013; STRIVE 2011). One trial enrolled participants with a class II mutation (F508del) (DISCOVER 2011) and one enrolled participants with a class IV mutation (R117H) (KONDUCT 2015).
The trial that evaluated ivacaftor for people with F508del enrolled participants aged 12 years or over (n = 140) for a duration of 16 weeks (DISCOVER 2011). The first G551D trial was a phase 2 trial enrolling participants 18 years and over and measuring a number of outcomes at 14 and 28 days (Accurso 2010). This was followed by two phase 3 trials, the first enrolling participants aged 12 years and older (n = 167) (STRIVE 2011) and the second enrolled participants aged 6 to 11 years (n = 52) (ENVISION 2013). These trials reported outcomes at 24 and 48 weeks. The R117H trial enrolled participants over six years of age (n = 69) and measured outcomes at 24 weeks (KONDUCT 2015).
The primary end points for these trials were safety (Accurso 2010) or change in FEV1 (ENVISION 2013; KONDUCT 2015; STRIVE 2011) or both (DISCOVER 2011). With respect to this review's primary outcomes, there were no deaths reported in any of the trials and the length and size of the trials precluded valid assessment of the impact of ivacaftor on survival. For CFQ‐R scores, no significant difference was reported in the F508del trial (DISCOVER 2011). The adults randomised to ivacaftor in the phase 2 G551D trial did not report significantly higher CFQ‐R respiratory domain scores 28 days (Accurso 2010). However, adults in the phase 3 G551D trial reported significantly higher CFQ‐R respiratory scores at 24 weeks, MD 8.10 (95% CI 4.63 to 11.57) and at 48 weeks, MD 8.70 (95% CI 5.51 to 11.89) (Analysis 2.3). This finding was not reproduced in the paediatric participants (ENVISION 2013). The R117H trial reported significantly higher CFQ‐R scores at 24 weeks in participants randomised to ivacaftor, MD 8.40 (95% CI 2.17 to 14.63) (Analysis 3.1) (KONDUCT 2015). Again, for relative change in FEV1, no significant improvement was reported in the F508del trial (DISCOVER 2011). The phase 2 G551D trial did not report treatment with ivacaftor resulted in a significant improvement in relative change in FEV1 (Accurso 2010). However, in the adult G551D phase 3 trial, significant improvements in relative change in FEV1 were seen early (after 15 days) and maintained through to 48 weeks, MD 16.80% (95% CI 13.50 to 20.10) (STRIVE 2011). Significant improvements in this outcome were also seen at 24 weeks in the paediatric trial, MD 17.4% (P < 0.0001), but results at 48 weeks were not published (ENVISION 2013). The R117H did not report any significant improvement in relative change in FEV1 (KONDUCT 2015).
We compared the number of participants experiencing adverse effects between the ivacaftor group and the placebo group. Combined data from both G551D phase 3 trials demonstrated a reduced reporting of cough, OR 0.57 (95% CI 0.33 to 1.00) and reduced episodes of decreased pulmonary function, OR 0.29 (95% CI 0.10 to 0.82) in the ivacaftor group (Analysis 2.5). Increased reports of dizziness were recorded in participants receiving ivacaftor in the adult G551D trial (STRIVE 2011), but this adverse effect was not reported by any other trial (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015). Data from the R117H trial showed increased reporting of adverse effects in the ivacaftor group except for pulmonary exacerbation, OR 0.93 (95% CI 0.35 to 2.44), however, these results were not significant (KONDUCT 2015) (Analysis 3.4). No trial reported a significant increase in adverse effects leading to interruption or termination of the trial drug (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
Combined data from the phase 3 G551D trials demonstrated significantly fewer participants experienced 'serious' cases of pulmonary exacerbation in the ivacaftor group, OR 0.34 (95% CI 0.17 to 0.70) (Analysis 2.13). When considering all data for exacerbations, fewer adults in the ivacaftor group reported exacerbations in the adult phase 3 G551D trial, OR 0.54 (95% CI 0.29 to 1.01) (Analysis 2.9); also, more participants in the placebo group required hospitalisation and IV antibiotics for pulmonary exacerbations and a greater proportion of participants in the ivacaftor group were exacerbation‐free at the 24 and 48 week time points (Analysis 2.10) (STRIVE 2011). In the R117H trial fewer participants in the ivacaftor group experienced pulmonary exacerbations, hospitalisation and IV antibiotics for the exacerbation, but results were not significant (Analysis 3.5) (KONDUCT 2015). This effect was not reported by the remaining three trials (Accurso 2010; DISCOVER 2011; ENVISION 2013).
The adverse effects profile of ivacaftor should be interpreted with caution as it was based on small numbers of participants. Furthermore, none of the included trials were powered to assess this outcome (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011).
No significant weight gain or change in BMI scores were reported in the F508del or R117H trials (DISCOVER 2011; KONDUCT 2015). Participants in both phase 3 G551D trials demonstrated significant weight gain on ivacaftor at 24 weeks, MD 2.37 kg (95% CI 1.68 to 3.06) and 48 weeks, MD 2.75 kg (95% CI 1.74 to 3.75) (Analysis 2.19). These two trials also reported that significantly higher BMI scores were achieved in the ivacaftor group; for children, MD 1.09 kg/m² (P = 0.0003) and for adults, MD 0.93 kg/m² (P < 0.0001). Significantly higher BMI for age z scores were reported for children in the ivacaftor group at 24 weeks, MD 0.34 (P ≤ 0.001) and at 48 weeks, MD 0.45 (P < 0.001) (ENVISION 2013). In a subset of participants aged 12 to 20 years old from the adult trial, a higher BMI for age Z score was reported at 48 weeks, MD 0.33 (P = 0.0490) (STRIVE 2011).
All trials reported significant reductions in sweat chloride concentrations (Accurso 2010; DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011). The F508del trial reported a MD of ‐2.90 mmol/L (95% CI ‐5.60 to ‐0.20) (DISCOVER 2011). The phase 2 G551D trial reported median values at 28 days; in the 150 mg ivacaftor group, median ‐64.5 mmol/L (P = 0.02) and in the 250 mg ivacaftor group, median ‐43.0 mmol/L (P = 0.03) (Accurso 2010). Combined data from the phase 3 G551D trials demonstrated significant reductions in sweat chloride concentration in participants on ivacaftor at 24 weeks, MD ‐50.19 mmol/L (95% CI ‐56.20 to ‐44.18) and 48 weeks, MD ‐49.74 mmol/L (95% CI ‐54.61 to ‐44.87) (Analysis 2.20). Similarly, the ivacaftor group in the R117H trial reported a significant reduction in sweat chloride concentration at 24 weeks, MD ‐24.00 mmol/L (95% CI ‐28.01 to ‐19.99) (Analysis 3.9).
Overall completeness and applicability of evidence
The DISCOVER trial recruited 140 participants homozygous for the F508del mutation, who were a representative sample for people with this mutation aged from 12 years upwards. This trial was included because it evaluated ivacaftor, although on a population with class II mutations in which a minimal amount of CFTR is able to reach the cell surface. In light of the results that failed to reach statistical significance in this population, trials with younger participants with F508del are not appropriate (DISCOVER 2011).
Three trials recruited 238 participants with the G551D mutation representing a significant proportion of all people with this mutation in the countries where the trials were undertaken (Accurso 2010; ENVISION 2013; STRIVE 2011). It can be assumed that the results are applicable to those with the G551D mutation not included in the trials; however, current trials have not enrolled children under six years of age or pregnant women. There are insufficient data for some outcomes, which we considered to be important for this review: school or work attendance; radiological measures of lung disease; acquisition of respiratory pathogens; and cost of treatment. One G551D trial reported on hospitalisations and extra courses of antibiotics (STRIVE 2011).
The R117H trial recruited 69 participants with the R117H mutation. Results are not applicable to individuals with other class IV mutations and the small sample size reduces the applicability of this evidence to people with cystic fibrosis who carry the R117H mutation (KONDUCT 2015).
There is no current evidence to support the use of CFTR potentiators in people with other class III to V mutations (not G551D). While there are trials recruiting people with other class III to V mutations, these have not be included in this review due to their cross‐over trial design (KONNECTION 2013; NCT01685801; NCT01784419).
Quality of the evidence
All the included trials were RCTs which represent the highest quality with regards to trial design.
The overall risk of bias across the included trials was judged to be moderate. Random sequence generation, allocation concealment and blinding of trial personnel were well‐documented. Blinding of participants was less clear, as details of ivacaftor and placebo tablets (such as taste, colour and consistency) were not provided. Participant data were excluded from the analysis in four trials (DISCOVER 2011; ENVISION 2013; KONDUCT 2015; STRIVE 2011). The risk of selective reporting was generally high as trials did not always report on outcomes outlined in the protocol, or present data for all outcomes and report on outcomes considered important by the review authors.
The quality of the evidence in this review is judged to be moderate to low, mainly due to risk of bias from incomplete outcome data and selective reporting and imprecision of results, particularly where few individuals have experienced adverse events (summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3).
Potential biases in the review process
The review authors conducted a comprehensive literature search of online journal databases using the Cystic Fibrosis and Genetic Disorders Review Group's Cystic Fibrosis Trials Register and online trials databases (Appendix 1) and also of manual searching of journal conference abstracts. Two authors independently applied the inclusion and exclusion criteria to the resultant literature and extracted relevant trials. The authors independently extracted data and assessed the risk of bias of the included trials. If they failed to reach a consensus on the risk of bias in a trial, a third author (KWS) arbitrated. The initial analyses were undertaken by one review author (SP) and checked for appropriateness by the review statistician (KD). MS completed the analysis for the update of the review. This methodological approach ensured that risks of bias in the review process were kept to a minimum.
This review has assessed all available published trial data. Trial authors were contacted for relevant unpublished information and individual participant data. To date, a protocol synopsis and summary of product characteristics have been provided with regards to information requested for the R117H trial (KONDUCT 2015). We are not aware of any unpublished trials, although we have highlighted issues with selective reporting in the included trials.
Agreements and disagreements with other studies or reviews
We are aware of one other published review of ivacaftor for people with CF which included the phase 3 G551D trials and data from the open‐label extensions to these trials (Whiting 2014). In line with this Cochrane Review, the Whiting review also concluded that ivacaftor has a clinically relevant impact on people with CF with the G551D mutation. We identified disagreements between the two reviews concerning the methodological quality and risk of bias assessments for the phase 3 G551D trials, although both reviews have used the Cochrane risk of bias tool. In the Whiting review, the authors judged the risk of bias for all methodological aspects of the adult phase 3 G551D trial to be low; whereas we judged this trial to have an unclear risk of detection bias and high risks of attrition bias and selective reporting bias (STRIVE 2011). With regards to the paediatric phase 3 G551D trial, disagreements were identified for participant and outcome assessor blinding, incomplete outcome data and selective reporting. The Whiting review judged this trial to have a low risk of detection bias, performance bias and selective outcome reporting bias and an unclear risk of attrition bias; while we judged the trial to have an unclear risk of detection and performance bias and a high risk of attrition bias and selective outcome reporting bias (ENVISION 2013). The overall methodological quality of the phase 3 G551D trials was assessed to be higher in the Whiting review than in this review.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. This Figure demonstrates the high proportion of trials that were judged to have a high risk of attrition bias (incomplete outcome data addressed) and selective reporting bias.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Ivacaftor (VX‐770) versus placebo in people with the F508del CFTR mutation, Outcome 1 FEV1 ‐ relative change from baseline.
Comparison 1 Ivacaftor (VX‐770) versus placebo in people with the F508del CFTR mutation, Outcome 2 Adverse effects.
Comparison 1 Ivacaftor (VX‐770) versus placebo in people with the F508del CFTR mutation, Outcome 3 Severity of adverse effects of therapy with regards to study drug interruption (moderate) or discontinuation (severe).
Comparison 1 Ivacaftor (VX‐770) versus placebo in people with the F508del CFTR mutation, Outcome 4 FEV1 % predicted ‐ absolute change from baseline.
Comparison 1 Ivacaftor (VX‐770) versus placebo in people with the F508del CFTR mutation, Outcome 5 Antibiotic treatment of sinopulmonary signs or symptoms.
Comparison 1 Ivacaftor (VX‐770) versus placebo in people with the F508del CFTR mutation, Outcome 6 Weight (kg) ‐ change from baseline.
Comparison 1 Ivacaftor (VX‐770) versus placebo in people with the F508del CFTR mutation, Outcome 7 Sweat chloride concentration ‐ change from baseline.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 1 CFQ‐R score (respiratory domain, child version) ‐ adjusted change from baseline.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 2 CFQ‐R score (respiratory domain score, parent/caregiver version) ‐ adjusted change from baseline.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 3 CFQ‐R score (respiratory domain score, pooled) ‐ absolute change from baseline.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 4 FEV1 ‐ mean relative change from baseline.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 5 Adverse events occurring in greater than or equal to 5% of trial participants.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 6 All adverse events.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 7 Severity of adverse effects of therapy with regards to study drug interruption (moderate) or discontinuation (severe).
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 8 Serious adverse events.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 9 The number of G551D participants who developed episodes of pulmonary exacerbation.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 10 Time to first pulmonary exacerbation.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 11 Maximum liver function test abnormalities in adolescents/adults at 48 weeks.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 12 Duration of hospitalisation for pulmonary exacerbation.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 13 Number of hospitalisations for pulmonary exacerbations.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 14 FEV1 (% predicted) ‐ mean absolute change from baseline.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 15 FEV1 (litres) ‐ mean absolute change from baseline.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 16 Change from baseline through week 24 in percent of predicted FEV1 according to subgroup.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 17 Number of pulmonary exacerbations requiring intravenous antibiotics.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 18 Days with intravenous antibiotics administered for pulmonary exacerbations.
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 19 Weight ‐ change from baseline (kg).
Comparison 2 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 20 Sweat chloride level ‐ change from baseline.
Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 1 CFQ‐R score (respiratory domain score, pooled) ‐ absolute change from baseline.
Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 2 FEV1 relative change from baseline.
Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 3 Adverse events.
Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 4 Adverse events in > 15% of participants.
Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 5 Summary of pulmonary exacerbations.
Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 6 Time to first pulmonary exacerbation.
Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 7 FEV1 predicted % absolute change from baseline.
Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 8 BMI absolute change from baseline.
Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 9 Sweat chloride concentration ‐ change from baseline.
| Ivacaftor compared with placebo for cystic fibrosis with the F508del CFTR mutation | ||||||
| Patient or population: adults and children with cystic fibrosis and with the F508del CFTR mutation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Ivacaftor | |||||
| Survival Follow‐up: 16 weeks | No deaths reported. | No deaths reported. | NA | 140 (1 study) | NA | |
| QoL Total score Follow‐up: NA | Not reported. | NA | NA | NA | ||
| QoL (CFQ‐R) Respiratory domain Follow‐up: 16 weeks | See comment.1 | See comment.1 | NA | 140 | ⊕⊕⊕⊝ | There was no significant difference between groups at 16 weeks. |
| FEV1 % predicted Relative change from baseline Follow‐up:16 weeks | Not reported.2 | The mean FEV1 (% predicted) was 2.4% higher (0.95% lower to 5.75% higher) in the ivacaftor group. | NA | 140 | ⊕⊕⊕⊝ | There was no significant difference between groups at 16 weeks. |
| FEV1 % predicted Absolute change from baseline Follow‐up: 16 weeks | Not reported.2 | The mean FEV1 (% predicted) was 1.7% higher (0.65% lower to 4.05% higher) in the ivacaftor group. | NA | 140 | ⊕⊕⊕⊝ | There was no significant difference between groups at 16 weeks. |
| Adverse events Follow‐up:16 weeks | The most commonly reported adverse events in the placebo group were: pulmonary exacerbation, cough, oropharyngeal pain and fatigue. | The most commonly reported adverse events in the ivacaftor group were: cough, pulmonary exacerbation, upper respiratory tract infection and nasal congestion. | NA | 140 | ⊕⊕⊝⊝ | There was no significant difference between groups in terms of any other adverse events. |
| Time to first pulmonary exacerbation Follow‐up: 16 weeks | Not reported. | NA | NA | NA | ||
| *The basis for the assumed risk is the mean placebo group risk across studies, unless otherwise stated. The corresponding risk (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 | ||||||
| 1. Presentation of the data prevented including data in analysis therefore results are presented narratively. | ||||||
| Ivacaftor compared with placebo for cystic fibrosis with at least one G551D CFTR mutation | ||||||
| Patient or population: adults and children with cystic fibrosis and with at least one G551D CFTR mutation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Ivacaftor | |||||
| Survival Follow‐up: 2 ‐ 48 weeks | No deaths reported. | No deaths reported. | NA | 238 | NA | |
| QoL Total score Follow‐up: NA | Not reported. | NA | NA | NA | ||
| QoL (CFQ‐R) Respiratory domain Follow‐up: 2 ‐ 48 weeks | See comment.1 | See comment.1 | NA | 222 (3 studies) | ⊕⊕⊕⊝ | A small phase 2 trial (n = 19) showed no significant difference at 2 or 4 weeks. A phase 3 trial (n = 151) in adults showed significantly higher quality of life in the ivacaftor group compared to placebo at 48 weeks A phase 3 trial (n = 52) showed no significant difference at 24 or 48 weeks in the child version of the CFQ‐R. The same trial showed a significantly higher quality of life in the ivacaftor group compared to placebo at 48 weeks in the parent / caregiver version at 24 weeks but not at 48 weeks.5 |
| FEV1 % predicted Relative change from baseline Follow‐up: 2 ‐ 48 weeks | See comment.1 | See comment.1 | NA | 232 (3 studies) | ⊕⊕⊕⊝ | A small phase 2 trial (n = 19) showed no significant difference at 2 or 4 weeks. Two phase 3 trials (n = 213) showed a significant improvement in FEV1 at 24 weeks (MD ranged between 16.9% to 17.4%) One phase 3 trial (n = 161) showed a significant improvement in FEV1 at 48 weeks (MD 16.8%). 6 |
| FEV1 L and % predicted Absolute change from baseline Follow‐up: 2 to 48 weeks | See comment.1 | See comment.1 | NA | 232 (3 studies) | ⊕⊕⊝⊝ | A small phase 2 trial (n = 19) showed no significant difference at 2 or 4 weeks. Two phase 3 trials (n = 213) showed a significant improvement in FEV1 (L and % predicted) at 24 weeks and 48 weeks.7 |
| Adverse events Follow‐up: 2 ‐ 48 weeks | The most commonly reported adverse events in the placebo group were: pulmonary exacerbation, cough, oropharyngeal pain and headache. | The most commonly reported adverse events in the ivacaftor group were: cough, pulmonary exacerbation, upper respiratory tract infection and headache. | NA | 232 (3 studies) | ⊕⊕⊝⊝ | Pulmonary exacerbations were significantly more common in the placebo group. There was no significant difference between groups in terms of any other adverse events.8 |
| Time to first pulmonary exacerbation Follow‐up: 48 weeks | 41% of the placebo group were exacerbation free at 48 weeks. | 67% of the ivacaftor group were exacerbation free at 48 weeks. | HR 0.46 (95% CI 0.29 to 0.73) | 161 (1 study) | ⊕⊕⊕⊝ | There was also a statistically significant difference between groups at 24 weeks; 78% and 51% of the ivacaftor and placebo groups were exacerbation free respectively; HR 0.46 (95% CI 0.28 to 0.76). |
| *The basis for the assumed risk is the mean placebo group risk across studies, unless otherwise stated. The corresponding risk (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 | ||||||
| 1. Presentation of the data prevented pooling the data from all three studies therefore results are summarised narratively. | ||||||
| Ivacaftor compared with placebo for cystic fibrosis with at least one R117H CFTR mutation | ||||||
| Patient or population: adults and children with cystic fibrosis and with at least one R117H CFTR mutation Settings: outpatients Intervention: ivacaftor Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Ivacaftor | |||||
| Survival Follow‐up: 2 ‐ 24 weeks | No deaths reported. | No deaths reported. | NA | 69 (1 study) | NA | |
| QoL Total score Follow‐up: NA | Not reported. | NA | NA | NA | ||
| QoL (CFQ‐R) Respiratory domain Follow‐up: 2 ‐ 24 weeks | Not reported. | The mean adjusted CFQ‐R respiratory domain score was 8.40% higher (2.17% higher to 14.63% higher) in the ivacaftor group. | NA | 69 (1 study) | ⊕⊕⊕⊝ | There was a significant improvement in CFQ‐R respiratory domain scores at 24 weeks.3 |
| FEV1 % predicted Relative change from baseline Follow‐up: 2 ‐ 24 weeks | See comment.1 | The mean adjusted FEV1 (% predicted) was 5.00% higher (0.24% lower to 10.24% higher) in the ivacaftor group. | NA | 69 (1 study) | ⊕⊕⊕⊝ | There was no significant difference between groups at 24 weeks.3 |
| FEV1 L and % predicted Absolute change from baseline Follow‐up: 2 ‐ 24 weeks | See comment.1 | The mean adjusted FEV1 (% predicted) was 2.10% higher (1.13% lower to 5.33% higher) in the ivacaftor group. | NA | 69 (1 study) | ⊕⊕⊕⊝ | There was no significant difference between groups at 24 weeks.3 |
| Adverse events Follow‐up: 2 ‐ 24 weeks | The most commonly reported adverse events in the placebo group were: pulmonary exacerbation and cough. | The most commonly reported adverse events in the ivacaftor group were: pulmonary exacerbation, cough, headache, nasal congestion, oropharyngeal pain, diarrhoea and increased sputum. | NA | 69 (1 study) | ⊕⊕⊝⊝ | There was no significant difference between groups in terms of any other adverse events. |
| Time to first pulmonary exacerbation Follow‐up: 24 weeks | 63% of the placebo group were exacerbation free at 24 weeks. | 68% of the ivacaftor group were exacerbation free at 24 weeks. | HR 0.93 (95% CI 0.42 to 2.08) | 69 (1 study) | ⊕⊕⊕⊝ | There was no significant difference between groups at 24 weeks. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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 | ||||||
| 1. Presentation of the data prevented including data in analysis therefore results are presented narratively. | ||||||
| Class | Example mutation | Impact on CFTR structure and function |
| I | G542X | Synthesis of CFTR is critically impaired, and no functional protein is produced. This is due to the presence of a premature stop codon in the nucleotide sequence. Individuals have minimal CFTR function. |
| II | ΔF508 | A full length of CFTR is produced, but this is structurally abnormal and destroyed by the cell before it reaches the cell membrane. This is called a defect in the intracellular trafficking pathway. Minimal amounts of CFTR can escape being destroyed and be transported to the cell membrane. However here, class II CFTR products display defective ion transport. Individuals have minimal CFTR function. |
| III | G551D | CFTR is produced and embedded in the cell membrane, but the chloride channel does not respond (‘switch on’) to normal stimulation from the cell. This means there is no significant ion transport across the protein. Individuals have some residual CFTR function. |
| IV | R347P | CFTR is transported to the outer cell membrane, and responds to normal stimulation, but functions at a low level because chloride ions do not cross the channel appropriately. Individuals have some residual CFTR function. |
| V | A455E | Normal CFTR is produced, but the amount of protein is reduced. Individuals have some residual CFTR function. |
| CFTR: cystic fibrosis transmembrane conductance regulator | ||
| Domain | Day 14 | Day 28 | ||||
| Placebo (n = 4) | VX‐770 150 mg (n = 8) | VX‐770 250 mg (n = 7) | Placebo (n = 4) | VX‐770 150 mg (n = 8) | VX‐770 250 mg (n = 7) | |
| Body image | 0 (‐11.1 to 22.2) | 0 | 0 | ‐5.6 | 0 (‐22.2 to 11.1) | 0 |
| Digestive symptoms | ‐5.6 | 0 | 0 | 0 | 5.6 (0 to 22.2) | 0 |
| Eating disturbances | 0 | 0 | 0 | ‐5.6 | 0 (0 to 0) | 0 |
| Emotional functioning | 13.3 | 0 | 0 | 3.3 | 0 | 6.7 |
| Health perceptions | 5.6 | 0 | 0 | 0 | 0 (‐22.2 to 22.2) | 0 |
| Physical functioning | 0 | 2.1 | 4.2 | 2.1 (0 to 4.2) | 4.2 (‐8.3 to 25.0) | 0 (0 to 12.5) |
| Respiratory symptoms | 2.8 | 5.6 | 5.6 | 2.8 | 8.3 | 11.1 |
| Role | 0 | 0 | 0 | 0 | 0 (‐8.3 to 8.3) | 0 |
| Social | 2.8 | 0 | ‐5.6 | 2.8 | 0 (‐11.1 to 5.6) | 0 |
| Treatment burden | 0 | ‐5.6 | 0 | 0 | ‐5.6 | 0 |
| Vitality | 4.2 | 4.2 | 0 | ‐8.3 | 0 (‐16.7 to 25.0) | 0 |
| Weight | 0 | 0 | 0 | 0 (0 to 33.3) | 0 (0 to 33.3) | 0 (‐33.3 to 33.3) |
| CFQ‐R: Cystic Fibrosis Questionnaire‐Revised | ||||||
| Overall | 6 ‐ 11 years | ≥18 years | ||||
| Treatment difference | P value | Treatment difference | P value | Treatment difference | P value | |
| Quality of life (CFQ‐R) ‐ respiratory domain (pooled) | 8.4 | 0.009 | ‐6.1 | 0.19 | 12.6 | 0.002 |
| % predicted FEV1 ‐ absolute change from baseline | 2.1 | 0.20 | ‐6.3 | 0.03 | 5.0 | 0.01 |
| % predicted FEV1 ‐ relative change from baseline | 5.0 | 0.06 | ‐6.8 | 0.04 | 0.2 | 0.008 |
| BMI ‐ absolute change from baseline | 0.26 | 0.78 | ‐0.18 | 0.87 | 0.31 | 0.78 |
| Sweat chloride ‐ absolute change from baseline | ‐24.0 | <0.0001 | ‐27.6 | <0.001 | ‐21.9 | <0.001 |
| Treatment difference was adjusted for age and % predicted FEV1 BMI: body mass index | ||||||
| Subgroup | Treatment effect | P value |
| Baseline percent of predicted FEV1 of less than 70% | 10.6 | < 0.001 |
| Baseline percent of predicted FEV1 of greater or equal to 70% | 10.3 | < 0.001 |
| Participants from North America | 9.0 | < 0.001 |
| Participants from Europe | 9.9 | < 0.001 |
| Participants from Australia | 11.9 | 0.008 |
| Male | 11.0 | < 0.001 |
| Female | 11.6 | < 0.001 |
| Less than 18 years | 11.4 | 0.005 |
| Greater than or equal to 18 years | 9.9 | < 0.001 |
| The treatment effect represents the difference between the ivacaftor group and the placebo group with respect to the absolute change from baseline through week 48. FEV1: forced expiratory volume at one second | ||
| Paediatric phase 3 G551D study(ENVISION 2013) | Adult phase 3 G551D study(STRIVE 2011) | |||
| Treatment difference (mmol/L) | P value | Treatment difference (mmol/L) | P value | |
| Minimal responders (less than 5% point improvement) | ‐55.8 | <0.0001 | ‐46.1 | < 0.0001 |
| FEV1 responders (5% point improvement) | ‐53.9 | <0.0001 | ‐49.7 | < 0.0001 |
| FEV1: forced expiratory volume at one second | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 FEV1 ‐ relative change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 1.1 At 16 weeks | 1 | 140 | Mean Difference (Fixed, 95% CI) | 2.4 [‐0.95, 5.75] |
| 2 Adverse effects Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Pulmonary exacerbation | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.14, 1.41] |
| 2.2 Upper respiratory tract infection | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.42 [0.18, 11.10] |
| 2.3 Cough | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.62 [0.59, 11.59] |
| 2.4 Productive cough | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.36 [0.15, 37.71] |
| 2.5 Headache | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.42 [0.18, 11.10] |
| 2.6 Nasal congestion | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.71 [0.22, 13.09] |
| 2.7 Sinusitis | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.08 [0.13, 33.75] |
| 2.8 Oropharyngeal pain | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.14, 4.90] |
| 2.9 Upper abdominal pain | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.8 [0.11, 29.87] |
| 2.10 Nausea | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.65 [0.17, 41.76] |
| 2.11 Diarrhea | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.08, 6.49] |
| 2.12 Contact dermatitis | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.48 [0.08, 158.51] |
| 2.13 Rash | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.23 [0.12, 228.54] |
| 2.14 Fatigue | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.12, 4.45] |
| 2.15 Pyrexia | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.14, 9.20] |
| 2.16 Increase in C‐reactive protein | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.53 [0.09, 26.08] |
| 3 Severity of adverse effects of therapy with regards to study drug interruption (moderate) or discontinuation (severe) Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Adverse effect requiring study drug interruption (moderate) | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.06, 27.62] |
| 3.2 Adverse effect requiring study drug discontinuation (severe) | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.06, 2.25] |
| 4 FEV1 % predicted ‐ absolute change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 4.1 At 16 weeks | 1 | 140 | Mean Difference (Fixed, 95% CI) | 1.70 [‐0.65, 4.05] |
| 5 Antibiotic treatment of sinopulmonary signs or symptoms Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 At 16 weeks | 1 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.24, 1.30] |
| 6 Weight (kg) ‐ change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 6.1 At 16 weeks | 1 | 140 | Mean Difference (Fixed, 95% CI) | ‐0.2 [‐1.18, 0.78] |
| 7 Sweat chloride concentration ‐ change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 7.1 At 16 weeks | 1 | 140 | Mean Difference (Fixed, 95% CI) | ‐2.9 [‐5.60, ‐0.20] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 CFQ‐R score (respiratory domain, child version) ‐ adjusted change from baseline Show forest plot | 2 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 1.1 At 24 weeks | 2 | 51 | Mean Difference (Fixed, 95% CI) | 6.1 [‐1.35, 13.55] |
| 1.2 At 48 weeks | 1 | 51 | Mean Difference (Fixed, 95% CI) | 5.1 [‐1.56, 11.76] |
| 2 CFQ‐R score (respiratory domain score, parent/caregiver version) ‐ adjusted change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 2.1 At 24 weeks | 1 | 52 | Mean Difference (Fixed, 95% CI) | 5.9 [0.41, 11.39] |
| 2.2 At 48 weeks | 1 | 52 | Mean Difference (Fixed, 95% CI) | 4.9 [‐0.39, 10.19] |
| 3 CFQ‐R score (respiratory domain score, pooled) ‐ absolute change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 3.1 At 24 weeks | 1 | 151 | Mean Difference (Fixed, 95% CI) | 8.1 [4.77, 11.43] |
| 3.2 At 48 weeks | 1 | 151 | Mean Difference (Fixed, 95% CI) | 8.6 [5.27, 11.93] |
| 4 FEV1 ‐ mean relative change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 4.1 24 weeks | 1 | 161 | Mean Difference (Fixed, 95% CI) | 16.9 [13.60, 20.20] |
| 4.2 48 weeks | 1 | 161 | Mean Difference (Fixed, 95% CI) | 16.8 [13.50, 20.10] |
| 5 Adverse events occurring in greater than or equal to 5% of trial participants Show forest plot | 2 | Odds Ratio (M‐H, Fixed, 99% CI) | Subtotals only | |
| 5.1 Pulmonary exacerbation | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.64 [0.30, 1.33] |
| 5.2 Cough | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.57 [0.27, 1.19] |
| 5.3 Productive Cough | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.81 [0.29, 2.24] |
| 5.4 Pulmonary function test decreased | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.29 [0.07, 1.14] |
| 5.5 Wheezing | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.12 [0.28, 4.52] |
| 5.6 Rales | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.86 [0.28, 2.69] |
| 5.7 Oropharyngeal pain | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.26 [0.52, 3.05] |
| 5.8 Nasal congestion | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.39 [0.55, 3.53] |
| 5.9 Nasopharyngitis | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.32 [0.46, 3.76] |
| 5.10 Upper respiratory tract infection | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.91 [0.74, 4.90] |
| 5.11 Bronchitis | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.57 [0.13, 18.48] |
| 5.12 Otitis media | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 4.55 [0.23, 89.19] |
| 5.13 Rhinorrhoea | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.65 [0.17, 2.45] |
| 5.14 Sinusitis | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.75 [0.21, 2.68] |
| 5.15 Ear Infection | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.18 [0.00, 10.67] |
| 5.16 Pharyngitis streptococcal | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 5.41 [0.09, 312.04] |
| 5.17 Rhinitis | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.86 [0.40, 8.70] |
| 5.18 Viral Infection | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.36 [0.04, 3.24] |
| 5.19 Sinus Headache | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.44 [0.26, 8.01] |
| 5.20 Headache | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.60 [0.66, 3.92] |
| 5.21 Dizziness | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 10.55 [0.69, 162.40] |
| 5.22 Pyrexia | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.96 [0.35, 2.60] |
| 5.23 Fatigue | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.83 [0.23, 3.07] |
| 5.24 Abdominal pain upper | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.87 [0.26, 2.91] |
| 5.25 Abdominal pain | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.29 [0.46, 3.59] |
| 5.26 Constipation | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.34 [0.06, 2.05] |
| 5.27 Diarrhea | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.36 [0.45, 4.11] |
| 5.28 Vomiting | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.58 [0.20, 1.68] |
| 5.29 Nausea | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.13 [0.37, 3.40] |
| 5.30 Gastrooesophageal reflux disease | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 5.41 [0.09, 312.04] |
| 5.31 Weight decreased | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.46 [0.05, 4.42] |
| 5.32 Asparate aminotransferase increased | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.02 [0.40, 10.31] |
| 5.33 Alanine aminotransferase increased | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.83 [0.21, 3.31] |
| 5.34 Eosinophil count increased | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 3.26 [0.15, 69.97] |
| 5.35 C‐reactive protein increased | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.74 [0.12, 4.37] |
| 5.36 Blood glucose increased | 1 | 166 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.71 [0.25, 11.72] |
| 5.37 Hypoglycaemia | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.69 [0.09, 5.18] |
| 5.38 white blood cell count decreased | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 5.41 [0.09, 312.04] |
| 5.39 Bacteria sputum Identified | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.02 [0.39, 10.32] |
| 5.40 Joint Sprain | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.10 [0.00, 4.71] |
| 5.41 Breath Sounds abnormal | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.35 [0.05, 2.49] |
| 5.42 Arthralgia | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.34 [0.28, 6.44] |
| 5.43 Myalgia | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 5.41 [0.09, 312.04] |
| 5.44 Back pain | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.94 [0.17, 5.03] |
| 5.45 Neck pain | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 5.41 [0.09, 312.04] |
| 5.46 Haemoptysis | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.51 [0.16, 1.65] |
| 5.47 Respiratory tract congestion | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.71 [0.18, 2.86] |
| 5.48 Sinus Congestion | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.97 [0.39, 10.10] |
| 5.49 Dyspnoea | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.36 [0.04, 3.24] |
| 5.50 Pleutiric pain | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.44 [0.27, 21.87] |
| 5.51 Respiration abnormal | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.46 [0.05, 4.42] |
| 5.52 Pharyngeal erythema | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 5.41 [0.09, 312.04] |
| 5.53 Culture throat positive | 1 | 51 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.17 [0.09, 55.58] |
| 5.54 Rash | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.03 [0.58, 7.06] |
| 5.55 Acne | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.95 [0.30, 12.62] |
| 5.56 Lymphadenopathy | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.48 [0.02, 12.25] |
| 5.57 Excoriation | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.48 [0.02, 12.25] |
| 5.58 Neutrophil count decreased | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 5.41 [0.09, 312.04] |
| 5.59 Forced expiratory volume decreased | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 5.41 [0.09, 312.04] |
| 5.60 Seasonal allergy | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.48 [0.02, 12.25] |
| 5.61 Allergic rhinitis | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 5.41 [0.09, 312.04] |
| 6 All adverse events Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 99% CI) | Subtotals only | |
| 6.1 Cardiac Murmur | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.2 Chest discomfort | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.08 [0.00, 6.60] |
| 6.3 Pulmonary exacerbation | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.4 Upper respiratory tract infection | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.5 Respiratory tract congestion | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.6 Cough | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.09 [0.04, 30.57] |
| 6.7 Cough decreased | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.8 Productive cough | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.21 [0.00, 11.63] |
| 6.9 Sputum abnormal | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.10 Sputum decreased | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.11 Sputum discolored | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.12 Increased upper airway secretion | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.13 Increased bronchial secretion | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.14 Rhonchi | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.15 Headache | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.16 Tension headache | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.17 Sinus headache | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.18 Sinusitis | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.19 Chronic sinusitis | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.08 [0.00, 6.60] |
| 6.20 Sinus congestion | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.21 Nasal congestion | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.22 Nasal oedma | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.23 Nasal dryness | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.24 Nasal turbinate abnormality | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.25 Nasal septum disorder | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.26 Mucosal erosion | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.27 Epistaxis | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.28 Oral candidiasis | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.29 Pharyngeal oedema | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.30 Pharyngeal erythema | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.31 Pharyngolaryngeal pain | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.32 Tonsillar hypertrophy | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.08 [0.00, 6.60] |
| 6.33 Abdominal distension | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.08 [0.00, 6.60] |
| 6.34 Upper abdominal pain | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.35 Decreased appetite | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.08 [0.00, 6.60] |
| 6.36 Nausea | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.37 Vomiting | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.38 Diarrhoea | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.46 [0.01, 16.23] |
| 6.39 Flatulence | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.08 [0.00, 6.60] |
| 6.40 Pyuria | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.41 White blood cells in urine | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.42 Rash | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.67 [0.02, 114.48] |
| 6.43 Contact dermatitis | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.08 [0.00, 6.60] |
| 6.44 Erythema | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.45 Excoriation | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.46 Pruritis | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.47 Genital pruritis (female) | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.48 Vulvovaginal mycotic infection | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.49 Photosensitivity reaction | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.50 Allergy to arthropod bite | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.51 Skin laceration | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.52 Injection site oedema | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.53 Fatigue | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.54 Somnolence | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.55 Joint crepitation | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.56 Lymphadenopathy | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 6.57 Blood creatinine increased | 1 | 19 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.93 [0.01, 78.14] |
| 7 Severity of adverse effects of therapy with regards to study drug interruption (moderate) or discontinuation (severe) Show forest plot | 3 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 7.1 Adverse effect requiring study drug interruption (moderate) | 2 | 213 | Odds Ratio (M‐H, Random, 95% CI) | 1.18 [0.14, 9.92] |
| 7.2 Adverse effect requiring study drug discontinuation (severe) | 3 | 232 | Odds Ratio (M‐H, Random, 95% CI) | 0.25 [0.04, 1.57] |
| 8 Serious adverse events Show forest plot | 3 | Odds Ratio (M‐H, Fixed, 99% CI) | Subtotals only | |
| 8.1 Haemoptysis | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.23 [0.01, 4.14] |
| 8.2 Hypoglycaemia | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.18 [0.00, 10.12] |
| 8.3 Complete atrioventricular block | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.4 Pulmonary exacerbation | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.34 [0.13, 0.88] |
| 8.5 Gastrooesophageal reflux | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.6 Pancreatic pseudocyst | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.7 Pancreatitis | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.8 Vomiting | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.9 Abdominal pain | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 3.12 [0.04, 222.22] |
| 8.10 Constipation | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.32 [0.00, 22.86] |
| 8.11 Weight decreased | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.12 Anaphylactic shock | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.13 Catheter related complication | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.14 Implant site infection | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.15 Influenza | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.16 Pseudomonal lung infection | 2 | 213 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.02, 6.34] |
| 8.17 Pneumonia | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.18 Sinusitis | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.19 Cough | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.20 Pleuritic pain | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.21 Pulmonary embolism | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.22 Respiratory distress | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.23 Productive cough | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 1.0 [0.02, 41.06] |
| 8.24 Respiratory failure | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.25 Pulmonary function test decreased | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.32 [0.00, 22.86] |
| 8.26 Lung consolidation | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.32 [0.00, 22.86] |
| 8.27 Myringitis bullous | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.28 Hepatic enzyme increased | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.29 Cervix carcinoma | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.30 Musculoskeletal chest pain | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.31 Pain in extremity | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.32 Spontaneous abortion | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.33 Haematuria | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.34 IgA nephropathy | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 2.85 [0.04, 195.35] |
| 8.35 Nephrolithiasis | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.36 Renal Colic | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.37 Testicular torsion | 1 | 161 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.31 [0.00, 21.17] |
| 8.38 Pyrexia | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 3.12 [0.04, 222.22] |
| 8.39 Muscle strain | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 3.12 [0.04, 222.22] |
| 8.40 Hepatic enzyme increased | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 3.12 [0.04, 222.22] |
| 8.41 Adjustment disorder | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.32 [0.00, 22.86] |
| 8.42 Anxiety | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.32 [0.00, 22.86] |
| 8.43 Affective disorder | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 0.32 [0.00, 22.86] |
| 8.44 Conversion disorder | 1 | 52 | Odds Ratio (M‐H, Fixed, 99% CI) | 3.12 [0.04, 222.22] |
| 9 The number of G551D participants who developed episodes of pulmonary exacerbation Show forest plot | 3 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.1 At 1 month | 1 | 19 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.07, 41.64] |
| 9.2 At 48 weeks | 2 | 213 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.64 [0.36, 1.12] |
| 10 Time to first pulmonary exacerbation Show forest plot | 1 | Hazard Ratio (Fixed, 95% CI) | Subtotals only | |
| 10.1 At 24 weeks | 1 | 161 | Hazard Ratio (Fixed, 95% CI) | 0.46 [0.28, 0.76] |
| 10.2 At 48 weeks | 1 | 161 | Hazard Ratio (Fixed, 95% CI) | 0.46 [0.29, 0.73] |
| 11 Maximum liver function test abnormalities in adolescents/adults at 48 weeks Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 11.1 2x to 3x ULN AST | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.97 [0.57, 6.84] |
| 11.2 2x to 3x ULN ALT | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.23, 2.63] |
| 11.3 2x to 3x ULN Bilirubin | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.90 [0.17, 21.39] |
| 11.4 3x to 5x ULN AST | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.04, 5.21] |
| 11.5 3x to 5x ULN ALT | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.18 [0.01, 3.88] |
| 11.6 3x to 5x ULN Bilirubin | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 11.7 5x to 8x ULN AST | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.85 [0.11, 71.12] |
| 11.8 5x to 8x ULN ALT | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.31 [0.01, 7.71] |
| 11.9 5x to 8x ULN Bilirubin | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 11.10 8x AST | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.06, 15.28] |
| 11.11 8x ALT | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 6.83 [0.35, 134.32] |
| 11.12 8x Bilirubin | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 12 Duration of hospitalisation for pulmonary exacerbation Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 12.1 At 48 weeks | 1 | 161 | Mean Difference (IV, Fixed, 95% CI) | ‐0.23 [‐3.74, 3.28] |
| 13 Number of hospitalisations for pulmonary exacerbations Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 13.1 At 48 weeks | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.37 [0.16, 0.81] |
| 14 FEV1 (% predicted) ‐ mean absolute change from baseline Show forest plot | 2 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 14.1 24 weeks | 2 | 213 | Mean Difference (Fixed, 95% CI) | 10.80 [8.91, 12.69] |
| 14.2 48 weeks | 2 | 213 | Mean Difference (Fixed, 95% CI) | 10.44 [8.56, 12.32] |
| 15 FEV1 (litres) ‐ mean absolute change from baseline Show forest plot | 2 | Mean Difference (Random, 95% CI) | Subtotals only | |
| 15.1 24 weeks | 2 | 212 | Mean Difference (Random, 95% CI) | 0.33 [0.17, 0.49] |
| 15.2 48 weeks | 2 | 212 | Mean Difference (Random, 95% CI) | 0.31 [0.11, 0.50] |
| 16 Change from baseline through week 24 in percent of predicted FEV1 according to subgroup Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 16.1 Subgroup 1: Baseline FEV1 of less than or equal to 90% predicted | 1 | 30 | Mean Difference (Fixed, 95% CI) | 14.9 [7.30, 22.50] |
| 16.2 Subgroup 2: Baseline FEV1 of more than 90% predicted | 1 | 21 | Mean Difference (Fixed, 95% CI) | 6.9 [‐3.80, 17.60] |
| 16.3 Subgroup 3: North America | 1 | 26 | Mean Difference (Fixed, 95% CI) | 5.8 [‐2.60, 14.20] |
| 16.4 Subgroup 4: Europe | 1 | 11 | Mean Difference (Fixed, 95% CI) | 24.60 [6.40, 42.80] |
| 16.5 Subgroup 5: Australia | 1 | 14 | Mean Difference (Fixed, 95% CI) | 4.2 [‐3.70, 12.10] |
| 16.6 Subgroup 6: Male | 1 | 24 | Mean Difference (Fixed, 95% CI) | 5.2 [‐2.20, 12.60] |
| 16.7 Subgroup 7: Female | 1 | 27 | Mean Difference (Fixed, 95% CI) | 13.8 [4.20, 23.40] |
| 17 Number of pulmonary exacerbations requiring intravenous antibiotics Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 17.1 At 48 weeks | 1 | 161 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.34 [0.18, 0.64] |
| 18 Days with intravenous antibiotics administered for pulmonary exacerbations Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 18.1 At 48 weeks | 1 | 161 | Mean Difference (IV, Fixed, 95% CI) | ‐4.35 [‐10.51, 1.81] |
| 19 Weight ‐ change from baseline (kg) Show forest plot | 2 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 19.1 At 24 weeks | 2 | 213 | Mean Difference (Fixed, 95% CI) | 2.37 [1.68, 3.06] |
| 19.2 at 48 weeks | 2 | 213 | Mean Difference (Fixed, 95% CI) | 2.75 [1.74, 3.75] |
| 20 Sweat chloride level ‐ change from baseline Show forest plot | 2 | Mean Difference (Random, 95% CI) | Subtotals only | |
| 20.1 At 24 weeks | 2 | 213 | Mean Difference (Random, 95% CI) | ‐50.19 [‐56.20, ‐44.18] |
| 20.2 At 48 weeks | 2 | 213 | Mean Difference (Random, 95% CI) | ‐49.74 [‐54.61, ‐44.87] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 CFQ‐R score (respiratory domain score, pooled) ‐ absolute change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 1.1 At 24 weeks | 1 | 69 | Mean Difference (Fixed, 95% CI) | 8.4 [2.17, 14.63] |
| 2 FEV1 relative change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 2.1 At 24 weeks | 1 | 69 | Mean Difference (Fixed, 95% CI) | 5.0 [‐0.24, 10.24] |
| 3 Adverse events Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Any adverse event | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.18 [0.01, 3.96] |
| 3.2 Serious adverse event | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.64 [0.16, 2.52] |
| 3.3 Adverse event leading to discontinuation | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 4 Adverse events in > 15% of participants Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 Pulmonary exacerbation | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.35, 2.44] |
| 4.2 Cough | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.20 [0.42, 3.47] |
| 4.3 Headache | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.35, 4.69] |
| 4.4 Increased sputum | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.34 [0.33, 5.47] |
| 4.5 Nasal congestion | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.34 [0.33, 5.47] |
| 4.6 Oropharyhgeal pain | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.84 [0.51, 15.79] |
| 4.7 Diarrhoea | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.34 [0.33, 5.47] |
| 4.8 Abdominal pain | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 10.48 [0.54, 202.47] |
| 4.9 Wheezing | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 4.53 [0.48, 42.82] |
| 4.10 Cystic fibrosis lung pathogen colonisation | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.29 [0.32, 33.31] |
| 5 Summary of pulmonary exacerbations Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 All pulmonary exacerbations | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.30, 2.19] |
| 5.2 Number of hospitalisations for pulmonary exacerbation | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.30 [0.06, 1.62] |
| 5.3 Number of pulmonary exacerbations requiring intravenous antibiotics | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.30 [0.06, 1.62] |
| 6 Time to first pulmonary exacerbation Show forest plot | 1 | Hazard Ratio (Fixed, 95% CI) | Subtotals only | |
| 6.1 At 24 weeks | 1 | 69 | Hazard Ratio (Fixed, 95% CI) | 0.93 [0.42, 2.08] |
| 7 FEV1 predicted % absolute change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 7.1 At 24 weeks | 1 | 69 | Mean Difference (Fixed, 95% CI) | 2.1 [‐1.13, 5.33] |
| 8 BMI absolute change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 8.1 At 24 weeks | 1 | 69 | Mean Difference (Fixed, 95% CI) | 0.26 [‐1.57, 2.09] |
| 9 Sweat chloride concentration ‐ change from baseline Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 9.1 At 24 weeks | 1 | 69 | Mean Difference (Fixed, 95% CI) | ‐22.00 [‐28.01, ‐19.99] |
