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CAMMS223

Alemtuzumab vs. Interferon Beta-1a in Early Multiple Sclerosis

Year of Publication: 2008

Authors: The CAMMS223 Trial Investigators (writing group: Coles AJ, Compston DAS, Selmaj KW, ..., Tandon PK)

Journal: New England Journal of Medicine

Citation: CAMMS223 Trial Investigators. Alemtuzumab vs. Interferon Beta-1a in Early Multiple Sclerosis. N Engl J Med 2008;359:1786-1801.

Link: https://doi.org/10.1056/nejmoa0802670

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

Baseline Characteristics

Characteristic	Interferon beta-1a (n=111)	Alemtuzumab 12 mg (n=112)	Alemtuzumab 24 mg (n=110)
Age (years, mean±SD)	32.8±8.8	31.9±8.0	32.2±8.8
Female %	64.0%	64.3%	64.5%
White race %	90.1%	91.1%	89.1%
Baseline EDSS (mean±SD)	1.9±0.83	1.9±0.74	2.0±0.73
Median time since first relapse (years)	1.4	1.3	1.2
Total relapses	293	301	290
Relapses in previous 2 years - 2 relapses (%)	65.8%	51.8%	50.9%
Relapses in previous 2 years - ≥3 relapses (%)	27.0%	41.1%	36.4%

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.

Content summarized and formatted by NeuroTrials.ai.

CAMMS223

(2008)

Objective

To compare the efficacy and safety of alemtuzumab versus subcutaneous interferon beta-1a in previously untreated patients with early, relapsing-remitting multiple sclerosis.

Study Summary

• Alemtuzumab reduced the risk of sustained accumulation of disability by 71% vs interferon beta-1a (9.0% vs 26.2%; HR 0.29; 95% CI 0.16-0.54; P<0.001)
• Annualized relapse rate was significantly lower with alemtuzumab (0.10 vs 0.36; HR 0.26; 95% CI 0.16-0.41; P<0.001)
• Mean EDSS disability score improved by 0.39 point with alemtuzumab vs worsened by 0.38 point with interferon beta-1a (P<0.001)
• T2 lesion burden was reduced and brain volume increased with alemtuzumab (P=0.005 and P=0.02 respectively)
• Alemtuzumab was associated with autoimmunity (thyroid disorders 23% vs 3%; immune thrombocytopenic purpura 3% vs 1%, one death) and more infections (66% vs 47%)

Intervention

Annual intravenous cycles of alemtuzumab (12 mg or 24 mg per day) vs subcutaneous interferon beta-1a 44 μg three times weekly for 36 months

Inclusion Criteria

Previously untreated, early relapsing-remitting MS (McDonald criteria); symptom onset ≤36 months before screening; ≥2 clinical episodes in previous 2 years; EDSS score ≤3.0; ≥1 enhancing lesion on MRI

Study Design

Arms: Alemtuzumab 12 mg/day (n=113) vs Alemtuzumab 24 mg/day (n=110) vs Interferon beta-1a 44 μg SC 3x/week (n=111)

Patients per Arm: 12-mg alemtuzumab: 113; 24-mg alemtuzumab: 110; Interferon beta-1a: 111

Outcome

• Sustained accumulation of disability: 9.0% (alemtuzumab pooled) vs 26.2% (interferon beta-1a); HR 0.29 (95% CI 0.16-0.54); P<0.001
• Annualized relapse rate: 0.10 vs 0.36; HR 0.26 (95% CI 0.16-0.41); P<0.001
• EDSS change from baseline: improved 0.39 point vs worsened 0.38 point (net advantage 0.77 point; P<0.001)
• NNT to prevent one sustained disability event: 5.8
• Adverse events: autoimmune thyroid disorders (23% vs 3%), immune thrombocytopenic purpura (3% vs 1%, including one death), infections (66% vs 47%)
• No significant differences between 12-mg and 24-mg alemtuzumab doses

Bottom Line

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

Study Design

Study Type: Phase 2, randomized, rater-blinded, active-comparator controlled trial
Randomization: Yes
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
Sample Size: 334
Follow-up: 36 months
Centers: 49
Countries: Europe (multiple countries), United States

Primary Outcome

Definition: 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

Control	Intervention	HR/OR	P-value
Sustained disability: 26.2%; Annualized relapse rate: 0.36	Sustained disability (pooled alemtuzumab): 9.0%; Annualized relapse rate (pooled alemtuzumab): 0.10	0.29 (Sustained disability HR: 0.16-0.54; Relapse HR: 0.16-0.41)	<0.001 for both coprimary outcomes

Limitations & 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

Citation

CAMMS223 Trial Investigators. Alemtuzumab vs. Interferon Beta-1a in Early Multiple Sclerosis. N Engl J Med 2008;359:1786-1801.

View Original Publication →

CAMMS223

Alemtuzumab vs. Interferon Beta-1a in Early Multiple Sclerosis

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about CAMMS223