Abstract
Background
Alemtuzumab is a humanised monoclonal antibody that alters the circulating lymphocyte pool, causing prolonged lymphopenia, thus remoulding the immune repertoire that accompanies homeostatic lymphocyte reconstitution. It has been proved more effective than interferon (IFN) 1a for the treatment of relapsing-remitting multiple sclerosis (RRMS).
Objectives
To compare the efficacy, tolerability and safety of alemtuzumab versus interferon beta 1a in the treatment of people with RRMS to prevent disease activity.
Search methods
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register (1 February 2017) which, among other sources, contains records from CENTRAL, MEDLINE, Embase, CINAHL, LILACS, PEDRO and the trial registry databases Clinical Trials.gov and WHO International Clinical Trials Registry Platform for all prospectively registered and ongoing trials.
Selection criteria
All double-blind, randomised, controlled trials comparing 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) versus subcutaneous IFN beta 1a (22 μg or 44 μg three times per week (Rebif) or intramuscular injection 30 μg once a week (Avonex)) in people of any gender and age with RRMS.
Data collection and analysis
We used standard methodological procedures expected by Cochrane.
Main results
We included three trials involving 1694 participants. All trials compared alemtuzumab 12 mg per day or 24 mg per day versus IFN beta 1a for treating RRMS. In CAMMS223, participants received either subcutaneous IFN beta 1a 44 μg three times per week or annual intravenous cycles of alemtuzumab (at a dose of 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. The methodological quality was good for all three studies.
In the alemtuzumab 12 mg per day group, the results showed statistically significant difference in reducing relapses (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.52 to 0.70), preventing disease progression (RR 0.60, 95% CI 0.45 to 0.79) and developing new T2 lesions on magnetic resonance imaging (RR 0.75, 95% CI 0.61 to 0.93) after 24 and 36 months’ follow-up, but found no statistically significant difference in the changes of Expanded Disability Status Scale (EDSS) score (mean difference (MD) -0.35, 95% CI -0.73 to 0.03). In the alemtuzumab 24 mg per day group, the results showed statistically significant differences in reducing relapses (RR 0.38, 95% CI 0.23 to 0.62), preventing disease progression (RR 0.42, 95% CI 0.21 to 0.84) and the changes of EDSS score (MD -0.83, 95% CI -1.17 to -0.49) after 36 months’ follow-up.
All three trials reported adverse events and serious adverse events. There was no statistically significant difference in the number of participants with at least one adverse event (RR 1.03, 95% CI 0.97 to 1.08) and the number of participants who experienced serious adverse events (RR 1.03, 95% CI 0.83 to 4.54).
Authors’ conclusions
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 reduces the proportion of participants with relapses, disease progression, change of EDSS score and developing new T2 lesions on MRI over 24 to 36 months in comparison with subcutaneous IFN beta-1a 44 μg three times per week.
Alemtuzumab appeared to be relatively well tolerated. The most frequently reported adverse events were infusion-associated reactions, infections and autoimmune events. The use of alemtuzumab requires careful monitoring so that potentially serious adverse effects can be treated early and effectively.
Plain language summary
Alemtuzumab, a humanised monoclonal antibody, as possible alternative therapy to interferon beta 1a in people with RRMS
Background
Multiple sclerosis is a progressive disease of the central nervous system where the person’s own body destroys the coating that protects nerves. The disease may go into remission (where the symptoms reduce or stop) and then relapse (where the symptoms return). This is called relapsing-remitting multiple sclerosis (RRMS). Medicines called monoclonal antibodies (such as alemtuzumab) could be a possible alternative immunotherapy (treatment to stimulate the immune system) to interferon beta treatment (one of the usual treatments) in people with RRMS. In this review, we aimed to compare the effectiveness, side effects and safety of alemtuzumab versus interferon beta 1a in the treatment of people with RRMS.
Study characteristics
We searched medical databases and found three studies involving 1694 participants (CAMMS223, CARE-MS I and CARE-MS II). CAMMS223 involved people with previously untreated, early RRMS. Participants received either subcutaneous (under the skin) interferon beta 1a (at a dose of 44 μg) three times per week or annual intravenous (into a vein) courses of alemtuzumab (at a dose of 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 courses of alemtuzumab 12 mg per day or subcutaneous interferon 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 interferon beta or glatiramer (another medicine that alters the immune response) treatment. Participants received subcutaneous interferon beta 1a 44 μg three times per week, annual intravenous courses of alemtuzumab 12 mg per day or annual intravenous courses of alemtuzumab 24 mg per day. The evidence is current to 1 February 2017.
Key results
In the alemtuzumab 12 mg per day group, the results showed that alemtuzumab was better than interferon beta 1a in reducing relapses, preventing disease progression and developing new lesions in nerve coatings after 24 and 36 months of assessment, but found no difference in the changes of Expanded Disability Status Scale (EDSS; a measurement of disability) score. In the alemtuzumab 24 mg per day group, alemtuzumab was better than interferon beta 1a in reducing relapses, preventing disease progression and the changes of EDSS score after 36 months of assessment.
All three trials reported side effects and serious side effects. Alemtuzumab did not increase the total risk of having side effects compared with interferon beta 1a.
Quality of the evidence
We considered all three studies to be of high quality. But the overall quality of the evidence was low to moderate, which was limited by the low number of included studies.
