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CARE-MS I 5-Year

Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy

Year of Publication: 2017

Authors: Eva Havrdova, Douglas L. Arnold, Jeffrey A. Cohen, ..., Alasdair J. Coles

Journal: Neurology

Citation: Neurology 2017;89:1107-1116

Clinical Question

Does alemtuzumab provide durable efficacy through 5 years in treatment-naive RRMS patients in the absence of continuous treatment?

Bottom Line

Alemtuzumab provides durable efficacy through 5 years with most patients (68.5%) not receiving additional treatment courses, maintaining low relapse rates, stable disability, reduced brain volume loss, and high rates of NEDA.

        Major Points
        95.1% of CARE-MS I alemtuzumab completers enrolled in extension; 96% remained through year 5
68.5% received no alemtuzumab retreatment; 97.7% received no other DMT
ARR remained low and stable: 0.18 (years 0-2), 0.19 (year 3), 0.14 (year 4), 0.15 (year 5)
79.7% free of 6-month confirmed disability worsening over 5 years
33.4% achieved 6-month confirmed disability improvement
NEDA achieved by 61.7%, 60.2%, and 62.4% in years 3, 4, and 5 respectively
Median yearly BVL improved: -0.59% (year 1), -0.25% (year 2), -0.19% (year 3), -0.15% (year 4), -0.20% (year 5)
Thyroid AE incidence peaked at year 3 (15.3%) then declined (7.6% year 4, 3.5% year 5)
One death (sepsis with pancytopenia) judged treatment-related occurred in year 3

      

Design

Study Type: Open-label extension of Phase 3 RCT with as-needed retreatment

Randomization: 1

Blinding: Rater-blinded; EDSS assessors blinded to treatment history; MRI analyzed centrally by blinded specialists

Enrollment Period: Core study: September 2007 to April 2009; Extension ongoing

Follow-up Duration: 5 years from CARE-MS I enrollment

Centers: 101

Countries: 16 countries

Sample Size: 349

Analysis: Negative binomial regression for ARR; Kaplan-Meier for CDW and CDI; exposure-adjusted incidence rates for safety

Inclusion Criteria

Completion of CARE-MS I core study
Originally: treatment-naive adults aged 18-50 years
RRMS fulfilling 2005 McDonald criteria
Disease duration ≤5 years
≥2 relapses in previous 2 years and ≥1 in prior year
EDSS ≤3.0
Cranial MRI abnormalities attributable to MS

Exclusion Criteria

For retreatment: pregnancy
Diagnosis of ITP or other immune cytopenia
History of malignancy (except basal cell carcinoma)
History of anti-glomerular basement membrane disease

Arms

Field	Alemtuzumab
Intervention	12 mg/day IV on 5 consecutive days at baseline; 12 mg/day IV on 3 consecutive days at month 12; as-needed retreatment (12 mg/day on 3 consecutive days) for relapse or MRI activity
Duration	5 years

Outcomes

Outcome	Type	Intervention	P-value
Annualized relapse rate over 5 years	Primary		No significant difference between extension years and core study
Freedom from 6-month confirmed disability worsening (years 0-5)	Secondary	79.7%
6-month confirmed disability improvement (years 0-5)	Secondary	33.4%
NEDA (year 3)	Secondary	61.7%
NEDA (year 4)	Secondary	60.2%
NEDA (year 5)	Secondary	62.4%
Sustained NEDA (years 3-5)	Secondary	39.5%
Median yearly BVL (BPF change) - Year 1	Secondary	-0.59%
Median yearly BVL - Year 5	Secondary	-0.20%
Cumulative BPF change baseline to year 5	Secondary	-1.352%
Free of new T1 hypointense lesions (year 5)	Secondary	85.4%
Any AE (EAIR per 100 pt-years)	Adverse
Serious AE incidence (year 5)	Adverse	5.0%
Any infection (EAIR per 100 pt-years)	Adverse
Thyroid disorder incidence (year 3)	Adverse	16.7%
Thyroid disorder incidence (year 5)	Adverse	2.9%
ITP (5-year incidence)	Adverse	4 cases (0.2/100 pt-years)
Nephropathy	Adverse	1 case (membranous nephropathy)
Malignancy (5-year)	Adverse	6 cases (EAIR 0.3/100 pt-years)
Deaths	Adverse	2 (1 treatment-related: sepsis with pancytopenia)

Subgroup Analysis

Among 175 patients achieving NEDA in year 2 who received no retreatment or other DMT: 60.8% maintained sustained NEDA through years 2-5, demonstrating durable efficacy without additional treatment.

Criticisms

Open-label extension without active comparator limits definitive efficacy conclusions
Selection bias: patients completing core study and entering extension may represent better responders
Lack of long-term direct comparison with IFN-β-1a
Autoimmune adverse events require long-term monitoring (4 years post-last dose)
Retreatment eligibility criteria may have led to earlier retreatment than clinically necessary

Funding

Supported by Sanofi and Bayer HealthCare Pharmaceuticals

Based on: CARE-MS I 5-Year (Neurology, 2017)

Authors: Eva Havrdova, Douglas L. Arnold, Jeffrey A. Cohen, ..., Alasdair J. Coles

Citation: Neurology 2017;89:1107-1116

Content summarized and formatted by NeuroTrials.ai.

CARE-MS I 5-Year

(2017)

Objective

To evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting MS

Study Summary

• 68.5% of patients received no alemtuzumab retreatment over 5 years
• ARR remained low through years 3-5 (0.14-0.19)
• 79.7% free of 6-month confirmed disability worsening; 33.4% achieved confirmed disability improvement

Intervention

Alemtuzumab 12 mg IV on 5 consecutive days at baseline and 3 consecutive days at month 12; as-needed retreatment in extension

Inclusion Criteria

Treatment-naive adults aged 18-50 with active RRMS, ≥2 relapses in previous 2 years with ≥1 in prior year, EDSS ≤3.0, disease duration ≤5 years

Study Design

Arms: Alemtuzumab 12 mg with optional retreatment vs SC IFN-β-1a 44 μg TIW (core study comparator)

Patients per Arm: 349 alemtuzumab patients entered extension (95.1% of completers); 335 completed year 5

Outcome

• ARR years 3-5: 0.19, 0.14, 0.15
• 60-62% achieved NEDA annually in years 3-5
• Median yearly BVL stabilized at -0.15% to -0.20% in years 3-5

Bottom Line

Major Points

95.1% of CARE-MS I alemtuzumab completers enrolled in extension; 96% remained through year 5
68.5% received no alemtuzumab retreatment; 97.7% received no other DMT
ARR remained low and stable: 0.18 (years 0-2), 0.19 (year 3), 0.14 (year 4), 0.15 (year 5)
79.7% free of 6-month confirmed disability worsening over 5 years
33.4% achieved 6-month confirmed disability improvement
NEDA achieved by 61.7%, 60.2%, and 62.4% in years 3, 4, and 5 respectively
Median yearly BVL improved: -0.59% (year 1), -0.25% (year 2), -0.19% (year 3), -0.15% (year 4), -0.20% (year 5)
Thyroid AE incidence peaked at year 3 (15.3%) then declined (7.6% year 4, 3.5% year 5)
One death (sepsis with pancytopenia) judged treatment-related occurred in year 3

Study Design

Study Type: Open-label extension of Phase 3 RCT with as-needed retreatment
Randomization: Yes
Blinding: Rater-blinded; EDSS assessors blinded to treatment history; MRI analyzed centrally by blinded specialists
Sample Size: 349
Follow-up: 5 years from CARE-MS I enrollment
Centers: 101
Countries: 16 countries

Primary Outcome

Definition: Annualized relapse rate over 5 years

Control	Intervention	HR/OR	P-value
-	-	- (See yearly rates)	No significant difference between extension years and core study

Limitations & Criticisms

Open-label extension without active comparator limits definitive efficacy conclusions
Selection bias: patients completing core study and entering extension may represent better responders
Lack of long-term direct comparison with IFN-β-1a
Autoimmune adverse events require long-term monitoring (4 years post-last dose)
Retreatment eligibility criteria may have led to earlier retreatment than clinically necessary

Citation

Neurology 2017;89:1107-1116

View Original Publication →

CARE-MS I 5-Year

Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about CARE-MS I 5-Year