CAMMS223
Alemtuzumab vs. Interferon Beta-1a in Early Multiple Sclerosis
Clinical Question
In previously untreated patients with early relapsing-remitting multiple sclerosis, is alemtuzumab more effective than subcutaneous interferon beta-1a in reducing disability accumulation and relapse rate?
Bottom Line
In patients with early, relapsing-remitting multiple sclerosis, alemtuzumab was significantly more effective than interferon beta-1a in reducing sustained disability accumulation and relapse rate and even improved existing disability, but was associated with significant autoimmune adverse events, most seriously immune thrombocytopenic purpura (including one death).
Major Points
- Alemtuzumab reduced the risk of sustained disability accumulation by 71% compared to interferon beta-1a (HR 0.29; P<0.001)
- Annualized relapse rate was 74% lower with alemtuzumab (0.10 vs 0.36; HR 0.26; P<0.001)
- Mean EDSS score improved by 0.39 point with alemtuzumab but worsened by 0.38 point with interferon beta-1a (net advantage 0.77 point; P<0.001)
- Alemtuzumab reduced T2 lesion burden (P=0.005) and increased brain volume from month 12-36 (P=0.02)
- No significant differences observed between the 12-mg and 24-mg alemtuzumab doses on any outcome or adverse event
- Autoimmunity was a major concern: thyroid disorders (23% vs 3%) and immune thrombocytopenic purpura (3% vs 1%), including one fatality that led to treatment suspension in September 2005
- Infections were more common with alemtuzumab (66% vs 47%)
- NNT to prevent one sustained disability event during 36 months was 5.8
Design
Study Type: Phase 2, randomized, rater-blinded, active-comparator controlled trial
Randomization: 1
Blinding: Rater-blinded (EDSS assessed by blinded neurologist; treating neurologist aware of assignment); 90-91% of raters remained unaware of assignment at end of study
Allocation: 1:1:1 randomization using Pocock and Simon minimization algorithm balancing for age (<30 or ≥30 years), sex, and baseline EDSS score (<2.0 or ≥2.0)
Enrollment Period: December 2002 to July 2004 (last patient started treatment September 2004)
Follow-up Duration: 36 months
Centers: 49
Countries: Europe (multiple countries), United States
Sample Size: 334
Analyzed: 333
Analysis: Modified intention-to-treat (1 patient excluded from efficacy analysis due to incorrect MS diagnosis - CADASIL); pooled alemtuzumab groups analysis not prespecified; Cox proportional-hazards model for time to sustained disability; Andersen-Gill model for relapse rate; Kaplan-Meier for cumulative estimates; Poisson regression for annualized relapse rate
Power Calculation: 285 patients needed for 75% power to detect treatment effect at 36 months, assuming 12% sustained disability in alemtuzumab vs 30% in interferon beta-1a group (two-sided test, alpha 2%, Bonferroni-adjusted)
Registration: ClinicalTrials.gov NCT00050778
Inclusion Criteria
- Diagnosis of relapsing-remitting multiple sclerosis based on McDonald criteria
- Symptom onset no more than 36 months before screening
- At least two clinical episodes during the previous 2 years
- EDSS score of 3.0 or less at baseline
- One or more enhancing lesions on at least one of up to four monthly cranial MRI scans
Exclusion Criteria
- Previous disease-modifying treatments for MS
- History of clinically significant autoimmunity
- Presence of serum antithyrotropin-receptor antibodies
Arms
| Field | Control | Alemtuzumab 12 mg | Alemtuzumab 24 mg |
|---|---|---|---|
| N | 111 | 113 | 110 |
| Intervention | Subcutaneous interferon beta-1a (Rebif) 44 μg three times weekly after dose escalation | Intravenous alemtuzumab 12 mg/day for 5 consecutive days at month 0, then 3 consecutive days at months 12 and 24 (third cycle at physician discretion if CD4+ T-cell count ≥100×10⁶/L) | Intravenous alemtuzumab 24 mg/day for 5 consecutive days at month 0, then 3 consecutive days at months 12 and 24 (third cycle at physician discretion if CD4+ T-cell count ≥100×10⁶/L) |
| Duration | 36 months | 36 months | 36 months |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Coprimary: (1) Time to sustained accumulation of disability (increase of ≥1.5 points if baseline EDSS 0, or ≥1.0 point if baseline EDSS ≥1.0, confirmed twice over 6 months); (2) Annualized rate of relapse | Primary | Sustained disability: 26.2%; Annualized relapse rate: 0.36 | Sustained disability (pooled alemtuzumab): 9.0%; Annualized relapse rate (pooled alemtuzumab): 0.10 | 0.29 | <0.001 for both coprimary outcomes |
| Change in EDSS score from baseline at 36 months | Secondary | <0.001 | |||
| Odds ratio for worsening disability vs improved/stable disability (pooled alemtuzumab vs IFN-β1a) | Secondary | 0.37 | <0.001 | ||
| Sustained disability at 3 months (sensitivity analysis) | Secondary | 0.36 | <0.001 | ||
| T2-weighted MRI lesion burden change over 36 months | Secondary | 0.005 | |||
| Brain volume change on T1-weighted MRI from month 12 to 36 | Secondary | 0.02 | |||
| Sustained disability risk reduction by alemtuzumab dose | Secondary | 12 mg dose: 75% reduction (HR 0.25; 95% CI 0.11-0.57; P<0.001) · 24 mg dose: 67% reduction (HR 0.33; 95% CI 0.16-0.69; P=0.003) | |||
| Safety | Event: Autoimmune thyroid disorders · Alemtuzumab: 23% · Interferon beta-1a: 3% | ||||
| Safety | Event: Immune thrombocytopenic purpura (ITP) · Alemtuzumab: 3% (including 1 death; led to treatment suspension September 2005) · Interferon beta-1a: 1% (asymptomatic chronic ITP in 1 patient) | ||||
| Safety | Event: Infections · Alemtuzumab: 66% · Interferon beta-1a: 47% | ||||
| Safety | Event: Burkitt's lymphoma (not EBV-associated) · Note: One case reported (post-hoc adverse event) | ||||
| Safety | Event: Study completion rate · Alemtuzumab: 83% · Interferon beta-1a: 59% (higher discontinuation due to lack of efficacy and adverse events) | ||||
| Notable AEs | Adverse | Autoimmunity (thyroid, ITP), infections, infusion reactions | |||
| Serious AEs | Adverse | Three initial cases of immune thrombocytopenic purpura (one death) led to suspension of alemtuzumab dosing in September 2005; three additional ITP cases identified in December 2005, July 2006, September 2006; Burkitt's lymphoma (1 case) | |||
| Treatment suspension impact | Adverse | 155 patients (75%) precluded from receiving third cycle of alemtuzumab at month 24 due to safety suspension | |||
Subgroup Analysis
No significant differences between 12-mg and 24-mg alemtuzumab doses on any efficacy outcome or adverse event; pre-specified subgroup analyses balanced by age, sex, and baseline EDSS
Criticisms
- Phase 2 trial not powered to detect uncommon adverse events
- Only rater-blinded (treating neurologists were unblinded), introducing potential bias in safety assessment and patient management
- Treatment suspension in September 2005 meant 75% of patients could not receive the planned third cycle of alemtuzumab, complicating interpretation
- Higher discontinuation rate in the interferon beta-1a arm (41% did not complete study) may have introduced informative censoring bias favoring alemtuzumab
- Pooling of alemtuzumab dose groups was not prespecified in the statistical analysis plan
- Active comparator (rather than placebo) but different administration routes (IV vs SC) may have compromised blinding integrity
- Serious autoimmune adverse events including one death from ITP raise significant safety concerns
- Study conducted in early, active RRMS - findings may not generalize to more advanced disease or less active disease
Funding
Supported by Genzyme and Bayer Schering Pharma; Genzyme employees (Lake, Moran, Margolin, Norris, Tandon) participated in study operations and data analysis
Based on: CAMMS223 (New England Journal of Medicine, 2008)
Authors: The CAMMS223 Trial Investigators (writing group: Coles AJ, Compston DAS, Selmaj KW, ..., Tandon PK)
Citation: CAMMS223 Trial Investigators. Alemtuzumab vs. Interferon Beta-1a in Early Multiple Sclerosis. N Engl J Med 2008;359:1786-1801.
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