CARE‐MS I 2012.
| Methods | RCT | |
| Participants | Age: 18 to 50 years; definite RRMS; mean disease duration 2 years; mean EDSS 2.0; all participants were previously untreated patients | |
| Interventions | Alemtuzumab 12 mg per day intravenously on 5 consecutive days at month 0 and 3 consecutive days at month 12 (n = 386) Interferon beta‐1a (Rebif) 44 µg subcutaneous 3 times a week for 24 months (n = 195) Participants in both groups received 1 g per day of intravenous methylprednisolone on 3 consecutive days at baseline and at month 12. After a protocol amendment in January 2009, alemtuzumab patients received oral aciclovir 200 mg twice daily during alemtuzumab infusion and for 28 days thereafter as prophylaxis against herpes infection |
|
| Outcomes | Relapse at 12 and 24 months. Disability worsening at 24 months | |
| Notes | Funding: Genzyme (a Sanofi company) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "We randomly allocated patients in a 2:1 ratio" and "Randomisation was stratified by site" (Page 1820) |
| Allocation concealment (selection bias) | Low risk | "We randomly allocated patients using an interactive voice response system" (Page 1820) |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | "Because both study drugs have adverse effects that precluded masking of patients and treating clinicians to treatment assignment, and because subcutaneous interferon beta 1a was available only in proprietary prefilled syringes that could not effectively be duplicated for placebo..." (Page 1820) |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | "We secured clinical data integrity by stringent clinical and MRI rater masking, and adjudication of relapses by a committee comprising six independent and masked neurologists. In the absence of a masked rater, unmasked raters could submit EDSS assessments" (Page 1820). Moreover, it is not clear how and when the committee evaluated potential relapses |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Overall, 7.1% were lost to follow‐up (4.9% in alemtuzumab 12 mg and 11.3% in interferon beta‐1a), with some indication of the differences in reasons: adverse events of 2.6% in alemtuzumab and 0% in interferon beta‐1a |
| Selective reporting (reporting bias) | Low risk | The published report included all pre‐specified primary benefit outcomes |
| Other bias | High risk | "The study sponsor (Genzyme) was involved in the design and undertaking of the trial, data analysis and interpretation, writing of the manuscript, and the decision to submit the manuscript for publication. Bayer Schering Pharma participated in the design and oversight of the trial", "The sponsor did the statistical analyses" (Page 1822), and 4 co‐authors of the published paper were affiliated to the pharmaceutical company |