Alemtuzumab versus interferón beta 1a para la esclerosis múltiple recurrente‐remitente
Resumen
Antecedentes
El alemtuzumab es un anticuerpo monoclonal humanizado que altera la reserva circulante de linfocitos, y causa linfopenia prolongada, lo cual remodela el repertorio inmunitario que acompaña la reconstitución homeostática de linfocitos. Se ha probado que es más efectivo que el interferón (IFN) 1a para el tratamiento de la esclerosis múltiple recurrente‐remitente (EMRR).
Objetivos
Comparar la eficacia, la tolerabilidad y la seguridad del alemtuzumab versus interferón beta 1a en el tratamiento de los pacientes con EMRR para prevenir la actividad de la enfermedad.
Métodos de búsqueda
Se buscaron todos los ensayos prospectivamente registrados y en curso en el registro de ensayos del Grupo Cochrane de Esclerosis Múltiple y Enfermedades Raras del Sistema Nervioso Central (Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register) (1 de febrero de 2017) que, entre otras fuentes, contiene registros de CENTRAL, MEDLINE, Embase, CINAHL, LILACS, PEDRO y en las bases de datos de registros de ensayos Clinical Trials.gov y la WHO International Clinical Trials Registry Platform para todos los ensayos registrados y en curso.
Criterios de selección
Todos los ensayos controlados, aleatorizados y a doble ciego que comparan el alemtuzumab intravenoso (12 mg por día o 24 mg por día en cinco días consecutivos durante el primer mes y en tres días consecutivos en los meses 12, 24, 36) versus el IFN beta 1a subcutáneo (Rebif), 22 μg o 44 μg tres veces por semana, o el IFN beta 1a (Avonex) por inyección intramuscular 30 μg una vez por semana, en personas de cualquier sexo y edad con EMRR.
Obtención y análisis de los datos
Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane.
Resultados principales
Se incluyeron tres ensayos con 1694 participantes. Todos los ensayos compararon alemtuzumab de 12 mg por día o 24 mg por día versus IFN beta 1a para el tratamiento de la EMRR. En CAMMS223 los participantes recibieron IFN beta 1a de 44 μg subcutáneo tres veces por semana o ciclos intravenosos anuales de alemtuzumab (a una dosis de 12 mg por día o 24 mg por día) durante 36 meses. En CARE‐MS I y CARE‐MS II, los participantes recibieron IFN beta 1a de 44 μg subcutáneo tres veces por semana o ciclos intravenosos anuales de alemtuzumab de 12 mg por día durante 24 meses. Los tres estudios tenían riesgo de sesgo de rendimiento y de desgaste, un estudio tenía un riesgo "poco claro" en el sesgo de selección.
En comparación con el interferón beta 1a, el alemtuzumab administrado en una dosis de 12 mg por día probablemente reduce el riesgo de recaída (riesgo relativo (RR) 0,60, intervalo de confianza (IC) del 95%: 0,52 a 0,70, evidencia de calidad moderada), puede reducir el riesgo de empeoramiento de la discapacidad (RR 0.60, IC del 95% 0,45 a 0,79, evidencia de baja calidad) y el riesgo de desarrollar nuevas lesiones T2 en la resonancia magnética (RR 0,75, IC del 95% 0,61 a 0,93, evidencia de baja calidad) después de 24 y 36 meses de seguimiento. Las puntuaciones de la Escala Expandida de Estado de Discapacidad (EDSS) pueden ser similares entre los regímenes de tratamiento (diferencia de medias (DM) ‐0,35; IC del 95%: ‐0,73 a 0,03; evidencia de baja calidad).
A una dosis de 24 mg por día, el alemtuzumab puede reducir la recaída (RR 0,38; IC del 95%: 0,23 a 0,62; evidencia de baja calidad), el empeoramiento de la discapacidad (RR 0,42; IC del 95%: 0,21 a 0,84; evidencia de baja calidad). Los efectos sobre las puntuaciones del EDSS cuando se comparan con el interferón beta 1a a los tres años son inciertos debido a la muy baja calidad de la evidencia (DM ‐0,83; IC del 95%: ‐1,17 a ‐0,49).
Los tres ensayos informaron eventos adversos y eventos adversos graves. El riesgo de experimentar un evento adverso en los grupos de alemtuzumab 12 mg o de interferón puede ser similar (RR 1,03; IC del 95%: 0,98 a 1,08, evidencia de baja calidad). El riesgo de eventos adversos graves es probablemente similar entre los tratamientos (RR 1,03; IC del 95%: 0,82 a 1,29; evidencia de calidad moderada). El riesgo de cualquier evento adverso puede ser similar entre alemtuzumab 24 mg e interferón (RR 1,02, IC del 95%: 0,96 a 1,08, evidencia de baja calidad). El riesgo de eventos adversos graves es probablemente similar entre los tratamientos (RR 0,95; IC del 95%: 0,70 a 1,31; evidencia de calidad moderada).
Conclusiones de los autores
Los ciclos intravenosos anuales de alemtuzumab a una dosis de 12 mg por día probablemente reducen la proporción de participantes que experimentan recaídas, pueden reducir la proporción de participantes que experimentan un empeoramiento de la discapacidad y el desarrollo de nuevas lesiones T2 en la resonancia magnética durante 2 a 3 años en comparación con el IFN beta‐1a subcutáneo 44 μg tres veces por semana. Los ciclos intravenosos anuales de alemtuzumab a una dosis de 24 mg por día pueden reducir la proporción de participantes que experimentan una recaída y una discapacidad que empeora a lo largo de 3 años en comparación con el IFN beta‐1a subcutáneo 44 μg tres veces por semana. En un estudio se observó una reducción media de 0,8 unidades de EDSS con alemtuzumab en comparación con el interferón beta‐1a a una dosis de 24 mg por día.
Las tasas de eventos adversos fueron igualmente altas para ambos tratamientos. Los eventos adversos más frecuentemente notificados para ambos tratamientos fueron reacciones asociadas a la infusión, infecciones y acontecimientos autoinmunes. La administración de alemtuzumab requiere vigilancia cuidadosa para que los efectos adversos potencialmente graves puedan ser tratados de forma temprana y efectiva.
PICOs
Resumen en términos sencillos
Alemtuzumab, un anticuerpo monoclonal humanizado, como un posible tratamiento alternativo al interferón beta 1a en pacientes con EMRR
Antecedentes
La esclerosis múltiple es una enfermedad progresiva del sistema nervioso central en la que el propio cuerpo de la persona destruye la cubierta que protege los nervios. La enfermedad puede entrar en remisión (cuando los síntomas se reducen o detienen) y luego en una recaía (cuando vuelven los síntomas). Esta afección se denomina esclerosis múltiple recurrente‐remitente (EMRR). La medicación denominada anticuerpos monoclonales (como el alemtuzumab) podría ser una posible inmunoterapia alternativa (tratamiento para estimular el sistema inmunológico) al tratamiento con interferón beta (uno de los tratamientos habituales) en pacientes con EMRR. En esta revisión, se intentó comparar los beneficios, los efectos secundarios y la seguridad del alemtuzumab versus el interferón beta 1a en el tratamiento de las personas con EMRR.
Características de los estudios
Se realizaron búsquedas en las bases de datos médicas y se encontraron tres estudios con 1694 participantes (CAMMS223, CARE‐MS I y CARE‐MS II). CAMMS223 incluyó a pacientes con EMRR temprana que no habían recibido tratamiento previo. Los participantes recibieron dosis de interferón beta 1a subcutáneo (bajo la piel) (en una dosis de 44 μg) tres veces por semana o cursos anuales intravenosos (en una vena) de alemtuzumab (en una dosis de 12 mg por día o 24 mg por día) durante 36 meses. CARE‐MS I incluyó a adultos de 18 a 50 años de edad con EMRR que no habían recibido tratamiento previo. Los participantes recibieron cursos anuales intravenosos de alemtuzumab 12 mg al día o de interferón subcutáneo beta 1a 44 μg tres veces por semana durante 24 meses. CARE‐MS II incluyó a adultos de 18 a 55 años de edad con EMRR y al menos una recaída mientras estaban en tratamiento con interferón beta o glatiramero (otro medicamento que altera la respuesta inmunológica). Los participantes recibieron interferón subcutáneo beta 1a 44 μg tres veces por semana, cursos intravenosos anuales de alemtuzumab 12 mg por día o cursos intravenosos anuales de alemtuzumab 24 mg por día durante 24 meses. La evidencia está actualizada hasta el 1 de febrero de 2017.
Resultados clave
La revisión de los ensayos encontró que, en comparación con el interferón subcutáneo beta 1a tres veces por semana, los ciclos intravenosos anuales de alemtuzumab probablemente reducen la proporción de participantes que experimentan recaídas, pueden reducir la proporción de participantes que experimentan un empeoramiento de la discapacidad y el desarrollo de nuevas lesiones T2 en la resonancia magnética. En un estudio, alemtuzumab 24 mg lleva a una puntuación ligeramente mejor de EDSS en comparación con el interferón beta 1a.
Las tasas de eventos adversos fueron igualmente altas para ambos tratamientos. Los eventos adversos más frecuentemente notificados para ambos tratamientos fueron reacciones asociadas a la infusión, infecciones y acontecimientos autoinmunes. La administración de alemtuzumab requiere vigilancia cuidadosa para que los efectos adversos potencialmente graves puedan ser tratados de forma temprana y efectiva.
Calidad de la evidencia
La calidad del conjunto de evidencia obtenida para cada resultado es principalmente baja, excepto en el caso del número de participantes que experimentaron al menos una recaída, en el que la calidad de la evidencia fue moderada.
Authors' conclusions
Summary of findings
| alemtuzumab12 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis | ||||||
| Patient or population: patients with relapsing‐remitting multiple sclerosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Interferon beta 1a | alemtuzumab12 mg | |||||
| Number of participants experiencing at least one relapse | 448 per 1000 | 269 per 1000 | RR 0.6 | 1414 | ⊕⊕⊕⊝ | |
| Number of participants whose disability worsened | 168 per 1000 | 101 per 1000 | RR 0.6 | 1414 | ⊕⊕⊝⊝ | |
| Number of participants with at least one adverse event | 948 per 1000 | 976 per 1000 | RR 1.03 | 1415 | ⊕⊕⊝⊝ | |
| Number of participants with serious adverse events | 192 per 1000 | 197 per 1000 | RR 1.03 | 1415 | ⊕⊕⊕⊝ | |
| Mean Expanded Disability Status Scale score change from baseline | The mean EDSS score in the control groups ranged from ‐0.14 to 0.38 | Mean EDSS score in the intervention groups was 0.35 lower (0.73 lower to 0.03 higher) | 1414 | ⊕⊕⊝⊝ | ||
| Number of participants with new T2‐hyperintense lesions on magnetic resonance imaging | 630 per 1000 | 472 per 1000 | RR 0.75 | 1125 | ⊕⊕⊝⊝ | |
| Number of participants experiencing treatment discontinuation caused by adverse events | 76 per 1000 | 25 per 1000 | RR 0.33 | 1414 | ⊕⊕⊝⊝ | |
| *The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is the median control group risk across studies. CI: Confidence interval; RR: Risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to study limitation (blinding of participants and personnel could not be well performed). 2 Downgraded for one level due to inconsistency (I2 = 66%) | ||||||
| alemtuzumab24 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis | ||||||
| Patient or population: patients with relapsing‐remitting multiple sclerosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Interferon beta 1a | alemtuzumab24 mg | |||||
| Number of participants experiencing at least one relapse | 405 per 1000 | 154 per 1000 | RR 0.38 | 221 | ⊕⊕⊝⊝ | Single study estimate |
| Number of participants whose disability worsened | 216 per 1000 | 91 per 1000 | RR 0.42 | 221 | ⊕⊕⊝⊝ | Single study estimate |
| Number of participants with at least one adverse event | 964 per 1000 | 984 per 1000 | RR 1.02 | 578 | ⊕⊕⊝⊝ | |
| Number of participants with serious adverse events | 220 per 1000 | 209 per 1000 | RR 0.95 | 578 | ⊕⊕⊕⊝ | |
| Mean Expanded Disability Status Scale score change from baseline | Mean EDSS score in the control group was 0.38 higher | Mean EDSS score in the intervention group was 0.45 lower | 221 | ⊕⊝⊝⊝ | Single study estimate | |
| Number of participants experiencing treatment discontinuation caused by adverse events | 89 per 1000 | 30 per 1000 | RR 0.34 (0.10 to 1.16) | 593 | ⊕⊝⊝⊝ | |
| *The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is the median control group risk across studies. CI: Confidence interval; RR: Risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to study limitation (blinding of participants and personnel could not be well performed). 2 Downgraded one level due to imprecision (low number of events). 4 Imprecision (‐2): In view of the low number of participants and the wide confidence intervals, we downgraded by two points. | ||||||
Background
Description of the condition
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system which is characterised by disseminated inflammatory demyelination. It mainly affects young adults, and leads to disability (Montalban 2010). It has high prevalence in western Europe and North America (more than 100 people per 100,000 population); lower prevalence in central and eastern Europe, the Balkans, Australia and New Zealand (50 per 100,000); and lowest prevalence in Asia, the Middle East, Africa and South America (about 10 to 20 per 100,000) (Koch‐Henriksen 2010). Women have approximately a two‐fold increased risk of developing MS than men. After the first attack, known as clinically isolated syndromes, which refers to a first episode of largely reversible neurological dysfunction with features suggestive of MS, 51% of people develop MS within six years (Chard 2011; Miller 2012). Most people with MS have a relapsing‐remitting course, but after 10 years over half of people with MS convert to a secondary progressive phase which is characterised by continuing deterioration without remission (Weinshenker 1989).
Magnetic resonance imaging (MRI) provides a reflection of the underlying pathology. The MRI measures of disease activity (enhancing demyelinating lesions) and severity (T2‐T1‐weighted lesion burden) are used to monitor the natural evolution of the disease and treatment effects. They have been integrated with clinical data into diagnostic criteria for MS (McDonald 2001; Polman 2005; Polman 2011).
Considering the autoimmune pathogenesis of the disease, the mainstay of treatment is immunomodulatory therapy with interferon (IFN) beta and glatiramer acetate (GA), which are the current standard first‐line treatments for MS. They reduce relapse frequency by about 30% (Brown 2013). Natalizumab, and more recently, fingolimod, have been introduced for people with highly active disease; they are more efficacious but have a more problematic safety profile than IFN and GA (Brown 2013; Pucci 2011).
The social costs associated with MS are high because of its long duration, the early loss of productivity, the need for assistance in activities of daily living, and the use of immunomodulatory treatments and multi‐disciplinary health care (Koutsouraki 2010).
Description of the intervention
IFN beta 1a is a lyophilised glycoprotein produced in mammalian cells using the natural human gene sequence. Two preparations are licensed for the treatment of MS: 30 μg once a week administered by intramuscular injection (Avonex) and 22 μg or 44 μg administered three times a week by subcutaneous injections (Rebif). Their efficacy on disease activity is partial (Brown 2013). IFN therapy has been associated with a high frequency of treatment‐related adverse events, mainly influenza‐like reactions and injection site reactions; most people treated with IFN have leukopenia, lymphopenia, thrombocytopenia and increased plasma hepatic enzymes (Rice 2001). These data suggest the need for alternative MS treatments with less invasive routes of administration and new modes of action to expand the current treatment repertoire, increase patient satisfaction and adherence, and thereby improve efficacy.
alemtuzumab is a humanised monoclonal antibody (mAb), approved by the US Food and Drug Administration (FDA) for the treatment of B‐cell chronic lymphocytic leukaemia (FDA 2000). It binds to CD52, a 12‐amino acid cell surface protein (Hale 2001) that is expressed at high levels on T cells and B cells, and at lower levels on monocytes, macrophages and eosinophils. Cells of the innate immune system are unaffected (Coles 2013). alemtuzumab alters the circulating lymphocyte pool (Cuker 2011), causing prolonged lymphopenia (Thompson 2010). The therapeutic effect of alemtuzumab is mediated by the remoulding of the immune repertoire that accompanies homeostatic lymphocyte reconstitution (Coles 2013). Recovery of B and T lymphocytes to the lower limit of normal after a single course of alemtuzumab takes eight months (B lymphocytes) and three years (T lymphocytes) (Hill‐Cawthorne 2012). alemtuzumab is given as an intravenous infusion of 12 mg/day on five consecutive days during the first month (first cycle) and on three consecutive days at months 12 (second cycle) and 24 (third cycle).
For people with secondary progressive MS, alemtuzumab significantly reduces the mean relapse rate and the risk of new MRI lesions. However, the person's disability continues to deteriorate as their cerebral atrophy progresses. For people with relapsing‐remitting MS (RRMS), unlike the progressive cohort, mean disability scores decrease after alemtuzumab (Coles 2013). In a unique programme of drug development in MS, alemtuzumab has been compared in one phase II trial and two phase III trials with the active comparator IFN beta 1a. In these trials, alemtuzumab was more effective in suppressing relapses compared to IFN beta 1a. Indeed, alemtuzumab treatment led to an improvement in disability and a reduction in cerebral atrophy (Coles 2013).
However, alemtuzumab use was associated with an increased occurrence of autoimmune disorders, such as immune thrombocytopenia, thyroid disease and antiglomerular basement membrane disease (Cuker 2011). Moreover, in 2005, three people with MS developed severe idiopathic thrombocytopenic purpura while participating in a clinical study of alemtuzumab (Campath) (FDA 2005). One of these people died.
How the intervention might work
The pathology of MS suggests an autoimmune aetiology and includes infiltration of T cells, B cells and macrophages in active MS brain lesions (Ode 2012). alemtuzumab causes rapid and prolonged lymphocyte depletion, finally resulting in immunosuppression and decreased central nervous system immunosurveillance (Bielekova 2010). After alemtuzumab therapy, the consequent homeostatic reconstitution leads to a radically reformed lymphocyte pool with a relative increase in regulatory T cells and expansion of autoreactive T cells (Coles 2013). In theory, these repertoire changes induced by alemtuzumab may improve long‐term efficacy, but it could also underlie development of antibody‐mediated autoimmune complications (Bielekova 2010).
Studies have demonstrated the efficacy of IFN beta 1a in people with RRMS (Panitch 2002; PRISMS 1998; Schwid 2007), and it has been commonly used in clinical practice. The mechanism of action of these therapeutic agents remains undefined. Several modes of action have been proposed, including: inhibition of T‐cell activation and proliferation; apoptosis of autoreactive T cells; induction of regulatory T cells; inhibition of leukocyte migration across the blood‐brain barrier; cytokine modulation and potential antiviral activity. Endogenously produced IFN in the injured brain is also now believed to contribute to mediation of anti‐inflammatory and regenerative effects (Dhib‐Jalbut 2002; Dhib‐Jalbut 2010).
Why it is important to do this review
mAbs have gained relevance in the treatment of MS. Trials demonstrated that alemtuzumab is more effective than IFN beta 1a, significantly reducing the relapse rate, risk for sustained accumulation of disability and mean Expanded Disability Status Scale (EDSS) score at month 36 after treatment. However, 30% of people develop autoimmunity (Thompson 2010). Marketing authorisation for alemtuzumab has been filed, and whilst trial data suggest that its efficacy outperforms both licensed drugs and others in development, there is a significant risk of adverse events, such as infusion‐associated reactions, mild‐to‐moderate infections and autoimmunity (Ali 2013; Coles 2013). While the European Medicines Agency (EMA) has already approved it for RRMS (EMA 2013), it has not been approved by the FDA (FDA 2013; Thompson 2013).
A systematic review is warranted to assess the efficacy, tolerability and safety profile of alemtuzumab versus IFN beta 1a.
Objectives
To compare the benefit, tolerability and safety of alemtuzumab versus IFN beta 1a in the treatment of people with RRMS to prevent disease activity.
Methods
Criteria for considering studies for this review
Types of studies
Double‐blind, randomised, controlled trials (RCTs). We excluded uncontrolled, non‐randomised and quasi‐randomised trials.
Types of participants
We included participants of any gender and age with RRMS fulfilling Poser criteria (Poser 1983), or original or revised McDonald criteria (McDonald 2001; Polman 2005; Polman 2011). We excluded participants with: a progressive disease course; previous immunosuppressive, investigational or monoclonal antiboby therapy and clinically significant autoimmune disorder other than MS.
Types of interventions
Experimental intervention: intravenous alemtuzumab 12 mg per day or 24 mg per day on five consecutive days during the first month and on three consecutive days at months 12 and 24.
Control intervention: subcutaneous IFN beta 1a (Rebif) 22 μg or 44 μg three times per week or intramuscular IFN beta 1a (Avonex) 30 μg once a week.
Types of outcome measures
Primary outcomes
Benefit:
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number of participants experiencing at least one relapse at 24 and 36 months. Relapse was defined as new or worsening pre‐existing neurological symptoms, without fever, that lasted for 48 hours or more and that were accompanied by a change in Functional Score on Kurtzke's EDSS scale assessed by the examining physician. One or more of the following changes compared with baseline was required for relapse confirmation: an increase in total EDSS by 0.5 points; an increase of at least 1 point in two functional‐systems scores, or of at least 2 points in one functional‐system score. Other less stringent criteria were accepted.
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number of participants whose disability worsened at 24 and 36 months, defined as an increase of at least 1.5 points on the EDSS scale for participants with a baseline score of 0, of at least 1.0 point for participants with a baseline score of 1.0 or more, and of at least 0.5 point for participants with a baseline score of 5.5 or more, sustained for six months (Kurtzke 1983).
Safety:
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number of participants with at least one adverse event, including serious adverse events.
Secondary outcomes
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mean EDSS score change from baseline at 24 and 36 months.
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number of participants with new T2‐hyperintense lesions on MRI at 24 and 36 months.
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number of participants experiencing treatment discontinuation caused by adverse events.
Search methods for identification of studies
We conducted a systematic search without language restrictions to identify all relevant published and unpublished RCTs.
Electronic searches
The Information Specialist searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, which, among other sources, contains trials from:
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Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 1);
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MEDLINE (PubMed) (1966 to 1 February 2017);
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Embase (Embase.com) (1974 to 1 February 2017);
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Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCOhost) (1981 to 1 February 2017);
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Latin American and Caribbean Health Science Information Database (LILACS) (Bireme) (1982 to 1 February 2017);
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ClinicalTrials.gov (www.clinicaltrials.gov);
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World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch).
The keywords for this review are listed in Appendix 1.
Information on the Trials Register or the Review Group and details of the search strategies used to identify trials can be found in the 'Specialised Register' section within the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group module.
In addition, the review authors searched the following three Chinese databases using the search terms (duofaxingyinghua) AND (alundankang) AND (β‐ganraosu):
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China Biological Medicine Database (CBM‐disc) (1979 to 1 February 2017);
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Chinese National Knowledge Infrastructure Database (CNKI) (1979 to 1 February 2017);
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VIP Chinese Science and Technique Journals Database (1979 to 1 February 2017).
Searching other resources
In addition, we used the following methods.
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We screened reference lists of relevant review articles and primary studies found.
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We contacted experts in the field to identify further published or unpublished trials.
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we handsearched congress reports and conference proceedings (from 1994 to 1 February 2017) from the most important neurological associations and MS Societies (e.g. American Academy of Neurology, American Neurological Association, American Committee for Treatment and Research in MS, the European Committee for Treatment and Research in MS) and contact pharmaceutical companies.
Data collection and analysis
Selection of studies
Three review authors (JZ, YX, JL) independently screened titles and abstracts of the citations retrieved by the literature search. We selected the full text of potentially relevant studies for further assessment. We independently evaluated the eligibility of these studies on the basis of information available in the published data. Any disagreement regarding inclusion was resolved by discussion among all review authors.
We collated multiple reports of the same study, so that each study rather than each report, was the unit of interest in the review.
Data extraction and management
Three review authors (JZ, YX, JL) independently extracted the following data.
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Participants: diagnostic criteria, number in each group, age, gender, baseline comparability between groups, length of follow‐up, withdrawals or losses to follow‐up.
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Methods: study design; randomisation method; allocation concealment method; blinding methods of participants, personnel and outcome assessors.
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Interventions: details of alemtuzumab and IFN beta 1a, such as administration method, dosage and duration, treatment period, cointervention(s).
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Outcomes: primary and secondary outcomes.
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Other: country and setting, publication year, sources of funding, intention‐to‐treat (ITT) analysis.
Any disagreements were resolved by discussion among all the review authors.
Assessment of risk of bias in included studies
Two review authors (JZ, JL) independently assessed the risk of bias of the included studies using the checklist recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We assessed the risk of bias according the following domains: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and other bias. Each domain was classified as 'low,' 'high' or 'unclear' risk of bias (Higgins 2011b). For each entry, the judgement ('low risk' of bias, 'high risk' of bias, or 'unclear risk' of bias) was followed by a text box for a description of the design, conduct or observations that supported the judgement. There was no disagreement in assessing the risk of bias among the review authors. The final results were recorded in Review Manager 5 (RevMan 2014).
Measures of treatment effect
Data were managed according to the ITT principle. For each outcome, we calculated a summarised estimate of treatment effect (with 95% confidence interval (CI)) for each comparison. For dichotomous outcomes (e.g. relapses, disease progression), we used risk ratios (RR) and for continuous data (e.g. EDSS score), we used mean differences (MD).
Unit of analysis issues
Cluster and cross‐over trials have not been carried out to evaluate alemtuzumab treatments for MS. We combined outcome data for participants who had relapses at 24 and 36 months and disability worsening at 24 and 36 months. When studies had multiple arms, we did not combine arms, and compared relevant arms separately in different analyses, to avoid double counting.
Dealing with missing data
We contacted authors of identified studies to obtain additional information. If additional information was not obtained, we analysed the available data.
Assessment of heterogeneity
We evaluated clinical and methodological heterogeneity across included studies by comparing characteristics of participants, interventions and study designs.
We evaluated statistical heterogeneity among included studies using a Chi² test with an alpha of 0.1, and with the I² test. A P value of less than 0.1 and an I² statistic more than 50% was an indication of substantial statistical heterogeneity (Higgins 2011a); we examined potential sources of clinical and methodological heterogeneity.
Assessment of reporting biases
We did not use funnel plots to explore possible publication bias due to an insufficient number of included studies.
Data synthesis
We used Review Manager 5 software to conduct formal meta‐analysis (RevMan 2014). The selection of a fixed‐effect or random‐effects model was mainly based on the results of the Chi² test and I² statistic for heterogeneity (Higgins 2011a). If the I² statistic indicated substantial statistical heterogeneity, we explored potential causes of heterogeneity first, to determine whether a subgroup analyses was needed. If the substantial heterogeneity still could not be explained, we adopted a random‐effects model. If the I² statistic indicated no significant statistical heterogeneity, we used a fixed‐effect model.
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroups analyses.
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Different dosages of alemtuzumab versus IFN beta 1a.
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Different duration of treatment.
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Different cointerventions.
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Different types of IFN beta 1a.
However, because of the limited number of studies, we could not perform all the analyses.
Sensitivity analysis
We planned to perform the following sensitivity analyses.
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Excluding studies at high risk of bias (i.e. non‐random sequence generation and inadequate allocation concealment, lack of blinded outcome assessor, lack of blinded participants/personnel, or a combination of these).
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Using a random‐effects model if a fixed‐effect model was used previously.
However, because of the limited number of studies, we could not perform all the analyses.
Summary of Findings
We presented the main results of the review in two 'Summary of findings' (SoF) tables, one reporting data for alemtuzumab 12 mg and one for alemtuzumab 24 mg, according to recommendations described in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0) (Schünemann 2011). We provided estimates from the pairwise meta‐analysis based on the methodology developed from the GRADE Working Group (GRADE Working Group 2004). We included an overall grading of the evidence for seven patient‐important outcomes:
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Number of participants experiencing at least one relapse
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Number of participants whose disability worsened
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Number of participants with at least one adverse events
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Number of participants with serious adverse events
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Mean Expanded Disability Status Scale score change from baseline
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Number of participants with new T2‐hyperintense lesions on magnetic resonance imaging
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Number of participants experiencing treatment discontinuation caused by adverse events
We graded the quality of evidence for each outcome considering study limitations, indirectness, inconsistency, imprecision of effect estimates, and risk of reporting bias, assigning four levels of quality of evidence: high, moderate, low, and very low.
Results
Description of studies
Results of the search
The search strategies retrieved 316 references. After screening of titles and abstracts, we obtained 19 full papers (three studies) and assessed them for eligibility (Figure 1).
Study flow diagram.
Included studies
We included three studies involving 1694 participants in the review. All three studies were multicentric RCTs comparing alemtuzumab versus IFN beta 1a in the treatment of people with RRMS. CAMMS223 2008 and CARE‐MS II are three‐arm trials. We did not merge multi‐arm trials involving alemtuzumab at different doses compared to Interferon Beta treatment and presented separate data for each arm.
CAMMS223 2008 involved participants with previously untreated, early RRMS. Participants received either subcutaneous IFN beta 1a 44 μg three times per week or annual intravenous cycles of alemtuzumab at either 12 mg per day or 24 mg per day.
CARE‐MS I enrolled adults aged 18 to 50 years with previously untreated RRMS. Participants received annual intravenous cycles of alemtuzumab 12 mg per day or subcutaneous IFN beta 1a 44 μg three times per week.
CARE‐MS II enrolled adults aged 18 to 55 years with RRMS and at least one relapse on IFN beta or glatiramer. Participants received subcutaneous IFN beta 1a 44 μg three times per week, annual intravenous cycles of alemtuzumab 12 mg per day or annual intravenous cycles of alemtuzumab 24 mg per day. The 24 mg per day group was discontinued to aid recruitment, data were included for safety assessments, but data for benetif outcomes were not provided.
Excluded studies
We excluded none of the potentially eligible studies.
Risk of bias in included studies
The risk of bias summaries are provided in Figure 2 and Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
All three included trials were reported as randomised; CAMMS223 2008 used the Pocock and Simon minimisation algorithm, while CARE‐MS I and CARE‐MS II used an interactive voice response system. Thus, the three studies were at low risk of bias for random sequence generation.
For allocation concealment, CARE‐MS I and CARE‐MS II used an interactive voice response system, thus we assessed them at low risk of bias. CAMMS223 2008 did not mention allocation concealment, thus, we assessed it at unclear risk of bias.
Blinding
We considered all studies at high risk of bias of performance bias (participants and personnel) because both drugs (intervention and comparator) had adverse effects that precluded masking.
Incomplete outcome data
All three trials provided sufficient details about the number of, and the reasons for, dropout. In CAMMS223 2008, the dropout rate was unbalanced between the alemtuzumab group (17%) and the IFN beta 1a group (41%), therefore, we classified the trial at high risk. In CARE‐MS I, the percentage of dropout was unbalanced between alemtuzumab group (6%) and IFN beta 1a group (16%), therefore, we classified the trial at high risk of incomplete outcome data bias. In CARE‐MS II, the percentage of dropout was unbalanced between alemtuzumab group (2.1%) and IFN beta 1a group (12.6%), therefore, we classified the trial at high risk of incomplete outcome data bias.
Selective reporting
All three trials were at low risk of reporting bias as they reported all specified primary and secondary outcomes.
Other potential sources of bias
We did not find any other potential souce of bias.
Effects of interventions
See: Summary of findings for the main comparison Alemtuzumab 12 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis; Summary of findings 2 Alemtuzumab 24 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis
Primary outcomes
Number of participants experiencing at least one relapse at 24 and 36 months
All three trials assessed the number of participants experiencing at least one relapse at 24 and 36 months (CAMMS223 2008; CARE‐MS I; CARE‐MS II). CAMMS223 2008 reported alemtuzumab 12/24 mg versus IFN beta 1a at 36 months. CARE‐MS I and CARE‐MS II reported alemtuzumab 12 mg versus IFN beta 1a at 24 months. In the alemtuzumab 12 mg comparison, there was significant difference in favour of alemtuzumab at 24 months (RR 0.62, 95% CI 0.53 to 0.72), 36 months (RR 0.53, 95% CI 0.35 to 0.80) and overall (RR 0.60, 95% CI 0.52 to 0.70). There was no significant heterogeneity (I² = 9%), so we applied the fixed‐effect model was applied (Analysis 1.1). Only one trial reported alemtuzumab 24 mg versus IFN beta 1a at 36 months (CAMMS223 2008). There was a significant difference in favour of alemtuzumab (RR 0.38, 95% CI 0.23 to 0.62) (see Analysis 1.2).
Number of participants whose disease progressed at 24 and 36 months
All three trials assessed the number of participants who experienced disease progression at 24 and 36 months (CAMMS223 2008; CARE‐MS I; CARE‐MS II).
CAMMS223 2008 reported alemtuzumab 12/24 mg versus IFN beta 1a at 36 months; CARE‐MS I and CARE‐MS II reported alemtuzumab 12 mg versus IFN beta 1a at 24 months. In the alemtuzumab 12 mg comparison, there was significant difference in favour of alemtuzumab at 24 months (RR 0.68, 95% CI 0.50 to 0.92), 36 months (RR 0.33, 95% CI 0.16 to 0.70) and overall (RR 0.60, 95% CI 0.45 to 0.79). There was no significant heterogeneity (I² = 37%), therefore, we applied the fixed‐effect model (Analysis 2.1). One trial reported alemtuzumab 24 mg versus IFN beta 1a (CAMMS223 2008). There was significant difference in favour of alemtuzumab at 36 months (RR 0.42, 95% CI 0.21 to 0.84) (Analysis 2.2).
Number of participants with at least one adverse event, including serious adverse events
All three trials reported adverse events and serious adverse events (CAMMS223 2008; CARE‐MS I; CARE‐MS II).
CAMMS223 2008 reported alemtuzumab 12/24 mg versus IFN beta 1a at 36 months; CARE‐MS I reported alemtuzumab 12 mg versus IFN beta 1a at 24 months; and CARE‐MS II reported alemtuzumab 12/24 mg versus IFN beta 1a at 24 months.
In the alemtuzumab 12 mg group, 897/919 (98%) participants experienced any adverse event and in the IFN beta 1a group, 470/496 (95%) participants experienced any adverse events (RR 1.03, 95% CI 0.98 to 1.08) (Analysis 3.1). In the alemtuzumab 12 mg group, 178/919 (19.3%) participants experienced serious adverse events and in the IFN beta 1a group, 95/496 (19.2%) participants experienced serious adverse events (RR 1.03, 95% CI 0.82 to 1.29) (Analysis 4.1).
In the alemtuzumab 24 mg group, 266/269 (99%) participants experienced any adverse event and in the IFN beta 1a group, 298/309 (96%) participants experienced any adverse events (RR 1.02, 95% CI 0.96 to 1.08) (Analysis 3.2). In the alemtuzumab 24 mg group, 57/269 (21.2%) participants experienced serious adverse events and in the IFN beta 1a group, 68/309 (22.0%) participants experienced serious adverse events (RR 0.95, 95% CI 0.70 to 1.31) (Analysis 4.2).
Secondary outcomes
Mean EDSS score change from baseline at 24 and 36 months
All three trials reported mean EDSS score change from baseline at 24 and 36 months (CAMMS223 2008; CARE‐MS I; CARE‐MS II).
CAMMS223 2008 reported alemtuzumab 12/24 mg versus IFN beta 1a at 36 months. CARE‐MS I and CARE‐MS II reported alemtuzumab 12 mg versus IFN beta 1a at 24 months. Evidence for an effect of decreased disability worsening, as measured by the Expanded Disability Status Scale (EDSS) with alemtuzumab 12 mg compared with IFN beta 1a at 24 months in two studies, was imprecise and with high level of statistical heterogeneity (MD ‐0.20, 95% CI ‐0.60 to 0.20; I2=88%; Analysis 5.1.1). EDSS was reported by CAMMS223 2008 that found significant difference in favour of alemtuzumab 12 mg compared to IFB beta 1a at 36 months of treatment (MD ‐0.70, 95% CI ‐1.04 to ‐0.36; Analysis 5.1.2). The pooled result did not favour alemtuzumab 12 mg compared to IFN beta 1a ( MD ‐0.35, 95% CI ‐0.73 to 0.03; Analysis 5.1; summary of findings Table for the main comparison). One trial comparing alemtuzumab 24 mg versus IFN beta 1a (CAMMS223 2008) found significant difference in favour of alemtuzumab at 36 months but with a wide confidence interval (MD ‐0.83, 95% CI ‐1.17 to ‐0.49; Analysis 5.2).
Number of participants with new T2‐hyperintense lesions on magnetic resonance imaging at 24 and 36 months
Two trials reported the number of participants with new T2‐hyperintense lesions on MRI at 24 and 36 months (CARE‐MS I; CARE‐MS II). There was significant difference in developing new T2 lesions on MRI favouring alemtuzumab 12 mg at 24 months (RR 0.75, 95% CI 0.61 to 0.93) (Analysis 6.1). There was significant heterogeneity (I² = 73%), so we applied the random‐effects model).
Number of participants experiencing treatment discontinuation caused by adverse events
All three trials reported the number of participants experiencing treatment discontinuation caused by adverse events (CAMMS223 2008; CARE‐MS I; CARE‐MS II). In the alemtuzumab 12 mg comparison, there was a significant difference in favour of alemtuzumab at 24 and 36 months (RR 0.33, 95% CI 0.19 to 0.56). There was no significant heterogeneity (P = 0.50, I² = 0), so we applied the fixed‐effect model (Analysis 7.1). In the alemtuzumab 24 mg comparison, there was no significant difference in two groups (RR 0.34, 95% CI 0.10 to 1.16). There was significant heterogeneity (P = 0.14, I² = 55%), so we applied the random‐effect model (Analysis 7.2).
Discussion
Summary of main results
Alemtuzumab was more effective than IFN beta 1a for the treatment of RRMS. This systematic review compared the benetif, tolerability and safety of alemtuzumab versus IFN beta 1a in the treatment of people with RRMS. Three RCTs involving 1694 participants contributed to the final analysis. In CAMMS223 2008, participants received either subcutaneous IFN beta 1a 44 μg three times per week or annual intravenous cycles of alemtuzumab at 12 mg per day or 24 mg per day for 36 months. In CARE‐MS I and CARE‐MS II, participants received subcutaneous IFN beta 1a 44 μg three times per week or annual intravenous cycles of alemtuzumab 12 mg per day for 24 months. All three studies were at risk of performance bias and attrition bias, one study was 'unclear' risk in selection bias. In the alemtuzumab 12 mg comparison, the results showed statistically significant differences favouring alemtuzumab in reducing relapses, preventing disease progression and developing new T2 lesions on MRI after 24 and 36 months' follow‐up, but found no statistically significant difference in the changes of EDSS score. In the alemtuzumab 24 mg comparison, the results showed statistically significant differences favouring alemtuzumab in reducing relapses, preventing disease progression and the changes of EDSS score after 36 months' follow‐up. The rates of advese events were similarly high for both treatments, although the risk of discontinuations related to adverse effects was lower with alemtuzumab. However, considering that alemtuzumab is administered once per year, this could have an effect on the observation of adverse events.
Overall completeness and applicability of evidence
The review's aim was to compare the benefit, tolerability and safety of alemtuzumab versus interferon beta 1a in the treatment of people with RRMS to prevent disease activity. We included three studies involving 1694 participants. All three RCTs compared alemtuzumab versus subcutaneous interferon beta‐1a in participants with RRMS. alemtuzumab was given intravenously 12 mg per day or 24 mg per day on five consecutive days during the first month and on three consecutive days at months 12 and 24, while IFN beta 1a was given 44 μg subcutaneously three times weekly after dose titration. All three studies reported benefit as clinical relapses, disability worsening and changes of EDSS score. In addition, CARE‐MS I and CARE‐MS II reported participants with new T2‐hyperintense lesions on MRI. There is low‐ to moderate‐quality evidence that annual intravenous cycles of alemtuzumab at a dose of 12 mg per day or 24 mg per day probably reduces the proportion of participants who experience relapse, and may reduce disability worsening and development of new T2 lesions on MRI over 2 to 3 years in comparison with subcutaneous IFN beta‐1a 44 μg three times per week. An average reduction of 0.8 EDSS units with alemtuzumab compared with interferon beta‐1a was observed at a dose of 24 mg per day in one study. All three trials reported adverse events and serious adverse events. The rates of adverse events were similarly high for both treatments, although the risk of discontinuations related to adverse effects was lower with alemtuzumab. In our view, this review has reliably compared the benetif, tolerability and safety of alemtuzumab versus interferon beta 1a.
Quality of the evidence
As presented in summary of findings Table for the main comparison and summary of findings Table 2, the quality of the body of evidence obtained for each outcome ranged from very low to moderate. All three studies were at high risk of performance bias and attrition bias, one study was 'unclear' risk in selection bias. There were a low number of events and a high heterogeneity in some outcomes.
Potential biases in the review process
An extensive and comprehensive search was undertaken to limit bias in the review process, however a low number of studies were retrieved.
There were no potential biases from the review authors in the review process. In the development of this review, three review authors independently read and screened trials retrieved for inclusion, independently completed data extraction and assessed the quality of included trials to minimize potential biases. No conflict of interests were found in relation to the review authors of this review.
The limitations of this review include:
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no assessment of publication bias through funnel plot analysis because there were only 3 studies.
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the lack of some outcome data in the included RCTs, for example, the data for benefit outcomes of alemtuzumab at a dose of 24 mg per day were not provided.
Agreements and disagreements with other studies or reviews
One systematic review included three studies in a qualitative synthesis and evaluated the effectiveness of alemtuzumab in the treatment of MS (Riera 2016). The same studies were eligible for meta‐analyses in our current systematic review. There are subtle distinctions between the two reviews in the methods of meta‐analysis, but overall, our review achieved similar conclusions.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Number of participants experiencing at least one relapse at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.
Comparison 1 Number of participants experiencing at least one relapse at 24 and 36 months, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.
Comparison 2 Number of participants whose disease progressed at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.
Comparison 2 Number of participants whose disease progressed at 24 and 36 months, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.
Comparison 3 Number of participants with at least one adverse event at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.
Comparison 3 Number of participants with at least one adverse event at 24 and 36 months, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.
Comparison 4 Number of participants with severe adverse events at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.
Comparison 4 Number of participants with severe adverse events at 24 and 36 months, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.
Comparison 5 Mean Expanded Disability Status Scale score change from baseline at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.
Comparison 5 Mean Expanded Disability Status Scale score change from baseline at 24 and 36 months, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.
Comparison 6 Number of participants with new T2‐hyperintense lesions on magnetic resonance imaging at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.
Comparison 7 Number of participants experiencing treatment discontinuation caused by adverse events, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.
Comparison 7 Number of participants experiencing treatment discontinuation caused by adverse events, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.
| alemtuzumab12 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis | ||||||
| Patient or population: patients with relapsing‐remitting multiple sclerosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Interferon beta 1a | alemtuzumab12 mg | |||||
| Number of participants experiencing at least one relapse | 448 per 1000 | 269 per 1000 | RR 0.6 | 1414 | ⊕⊕⊕⊝ | |
| Number of participants whose disability worsened | 168 per 1000 | 101 per 1000 | RR 0.6 | 1414 | ⊕⊕⊝⊝ | |
| Number of participants with at least one adverse event | 948 per 1000 | 976 per 1000 | RR 1.03 | 1415 | ⊕⊕⊝⊝ | |
| Number of participants with serious adverse events | 192 per 1000 | 197 per 1000 | RR 1.03 | 1415 | ⊕⊕⊕⊝ | |
| Mean Expanded Disability Status Scale score change from baseline | The mean EDSS score in the control groups ranged from ‐0.14 to 0.38 | Mean EDSS score in the intervention groups was 0.35 lower (0.73 lower to 0.03 higher) | 1414 | ⊕⊕⊝⊝ | ||
| Number of participants with new T2‐hyperintense lesions on magnetic resonance imaging | 630 per 1000 | 472 per 1000 | RR 0.75 | 1125 | ⊕⊕⊝⊝ | |
| Number of participants experiencing treatment discontinuation caused by adverse events | 76 per 1000 | 25 per 1000 | RR 0.33 | 1414 | ⊕⊕⊝⊝ | |
| *The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is the median control group risk across studies. CI: Confidence interval; RR: Risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to study limitation (blinding of participants and personnel could not be well performed). 2 Downgraded for one level due to inconsistency (I2 = 66%) | ||||||
| alemtuzumab24 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis | ||||||
| Patient or population: patients with relapsing‐remitting multiple sclerosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Interferon beta 1a | alemtuzumab24 mg | |||||
| Number of participants experiencing at least one relapse | 405 per 1000 | 154 per 1000 | RR 0.38 | 221 | ⊕⊕⊝⊝ | Single study estimate |
| Number of participants whose disability worsened | 216 per 1000 | 91 per 1000 | RR 0.42 | 221 | ⊕⊕⊝⊝ | Single study estimate |
| Number of participants with at least one adverse event | 964 per 1000 | 984 per 1000 | RR 1.02 | 578 | ⊕⊕⊝⊝ | |
| Number of participants with serious adverse events | 220 per 1000 | 209 per 1000 | RR 0.95 | 578 | ⊕⊕⊕⊝ | |
| Mean Expanded Disability Status Scale score change from baseline | Mean EDSS score in the control group was 0.38 higher | Mean EDSS score in the intervention group was 0.45 lower | 221 | ⊕⊝⊝⊝ | Single study estimate | |
| Number of participants experiencing treatment discontinuation caused by adverse events | 89 per 1000 | 30 per 1000 | RR 0.34 (0.10 to 1.16) | 593 | ⊕⊝⊝⊝ | |
| *The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is the median control group risk across studies. CI: Confidence interval; RR: Risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to study limitation (blinding of participants and personnel could not be well performed). 2 Downgraded one level due to imprecision (low number of events). 4 Imprecision (‐2): In view of the low number of participants and the wide confidence intervals, we downgraded by two points. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot | 3 | 1414 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.52, 0.70] |
| 1.1 At 24 months | 2 | 1191 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.53, 0.72] |
| 1.2 At 36 months | 1 | 223 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.53 [0.35, 0.80] |
| 2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot | 1 | 221 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.23, 0.62] |
| 2.1 At 36 months | 1 | 221 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.23, 0.62] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot | 3 | 1414 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.45, 0.79] |
| 1.1 At 24 months | 2 | 1191 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.50, 0.92] |
| 1.2 At 36 months | 1 | 223 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.16, 0.70] |
| 2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot | 1 | 221 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.42 [0.21, 0.84] |
| 2.1 At 36 months | 1 | 221 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.42 [0.21, 0.84] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot | 3 | 1415 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.98, 1.08] |
| 1.1 At 24 months | 2 | 1200 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [1.01, 1.07] |
| 1.2 At 36 months | 1 | 215 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.98, 1.02] |
| 2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot | 2 | 578 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.96, 1.08] |
| 2.1 At 24 months | 1 | 363 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [1.01, 1.08] |
| 2.2 At 36 months | 1 | 215 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.97, 1.02] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot | 3 | 1415 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.82, 1.29] |
| 1.1 At 24 months | 2 | 1200 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.81, 1.34] |
| 1.2 At 36 months | 1 | 215 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.60, 1.63] |
| 2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot | 2 | 578 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.70, 1.31] |
| 2.1 At 24 months | 1 | 363 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.56, 1.30] |
| 2.2 At 36 months | 1 | 215 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.69, 1.80] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot | 3 | 1414 | Mean Difference (IV, Random, 95% CI) | ‐0.35 [‐0.73, 0.03] |
| 1.1 At 24 months | 2 | 1191 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.60, 0.20] |
| 1.2 At 36 months | 1 | 223 | Mean Difference (IV, Random, 95% CI) | ‐0.7 [‐1.04, ‐0.36] |
| 2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot | 1 | 221 | Mean Difference (IV, Random, 95% CI) | ‐0.83 [‐1.17, ‐0.49] |
| 2.1 At 36 months | 1 | 221 | Mean Difference (IV, Random, 95% CI) | ‐0.83 [‐1.17, ‐0.49] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot | 2 | 1125 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.61, 0.93] |
| 1.1 At 24 months | 2 | 1125 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.61, 0.93] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot | 3 | 1414 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.19, 0.56] |
| 1.1 At 24 months | 2 | 1191 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.37 [0.20, 0.66] |
| 1.2 At 36 months | 1 | 223 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.23 [0.07, 0.78] |
| 2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot | 2 | 593 | Risk Ratio (M‐H, Random, 95% CI) | 0.34 [0.10, 1.16] |
| 2.1 At 24 months | 1 | 372 | Risk Ratio (M‐H, Random, 95% CI) | 0.55 [0.23, 1.33] |
| 2.2 At 36 months | 1 | 221 | Risk Ratio (M‐H, Random, 95% CI) | 0.16 [0.04, 0.67] |
