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CARE-MS II

Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial

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Year of Publication: 2012

Authors: Coles AJ, Twyman CL, Arnold DL, ..., for the CARE-MS II investigators

Journal: The Lancet

Citation: Lancet 2012; 380: 1829-39

Link: https://doi.org/10.1016/s0140-6736(12)61768-1

Clinical Question

In patients with relapsing-remitting MS who have relapsed on first-line therapy, does alemtuzumab reduce relapse rates and disability accumulation compared with interferon beta 1a?

Bottom Line

In patients with relapsing-remitting MS refractory to first-line therapy, alemtuzumab 12 mg significantly reduces relapse rates (by ~49%) and sustained disability accumulation (by ~42%) compared with interferon beta 1a, though with notable risks of infusion reactions, infections, and secondary autoimmunity (particularly thyroid disorders and immune thrombocytopenia) requiring risk management strategies.

Major Points

  • Alemtuzumab 12 mg reduced annualized relapse rate by 49.4% vs interferon beta 1a (rate ratio 0.51 [95% CI 0.39-0.65] from recurrent-event proportional means model; p<0.0001)
  • 65.4% (95% CI 60.7-69.7) of alemtuzumab patients were relapse-free at 2 years vs 46.7% (39.5-53.5) of interferon beta 1a patients; HR 0.53 (0.41-0.69); p<0.0001
  • Alemtuzumab reduced 6-month sustained accumulation of disability by 42% (HR 0.58 [0.38-0.87]; p=0.008)
  • Secondary MRI/clinical endpoints favored alemtuzumab: EDSS change -0.17 vs +0.24 (p<0.0001), MSFC +0.08 vs -0.04 (p=0.002 descriptive), fewer new/enlarging T2 lesions (46% vs 68%; p<0.0001) and Gd-enhancing lesions (9% vs 23%; p<0.0001); T2 lesion volume change did not differ (p=0.14)
  • Safety concerns with alemtuzumab (n=435): 90% infusion-associated reactions (393/435), 77% infections (334/435, mostly mild-moderate), 16% thyroid disorders (69/435), 1% immune thrombocytopenia (3/435)
  • Two-course dosing (5 days at baseline, 3 days at 12 months) demonstrated durable efficacy
  • Established alemtuzumab as an option for patients with breakthrough MS disease activity on first-line therapy

Design

Study Type: Randomized, rater-masked, phase 3 controlled trial

Randomization: 1

Blinding: Rater-masked (raters blinded to treatment assignment); open-label treatment due to differing routes of administration and adverse effect profiles precluding double-blinding

Allocation: 2:2:1 (alemtuzumab 12 mg : alemtuzumab 24 mg : interferon beta 1a) via interactive voice response system, stratified by site; alemtuzumab 24 mg arm discontinued December 2008 to accelerate recruitment, maintaining 2:1 randomization between alemtuzumab 12 mg and interferon beta 1a thereafter

Enrollment Period: October 20, 2007 to September 18, 2009

Follow-up Duration: 2 years

Centers: 194

Countries: 23

Sample Size: 840

Analyzed: 628

Analysis: Primary efficacy analysis included all patients who received at least one dose of study drug: 202 (87%) of 231 interferon beta 1a and 426 (98%) of 436 alemtuzumab 12 mg. Relapse rate analyzed with proportional means (recurrent-events) model; sustained disability with proportional hazards model with robust variance estimation, both including treatment group and geographical region as covariates. Hochberg procedure used to adjust for multiplicity of coprimary endpoints. Safety population for alemtuzumab 12 mg was n=435 (adds 9 patients originally allocated 24 mg who received 12 mg).

Power Calculation: 573 patients randomised 2:1 to alemtuzumab 12 mg vs interferon beta 1a provided ≥80% power to detect a 50% treatment effect on time to 6-month sustained accumulation of disability (two-sided α=0.05, assuming 10% discontinuation), and ≥95% power to detect a 40% treatment effect on relapse rate (assuming ≥20% of interferon beta 1a patients would meet the disability endpoint by 2 years).

Registration: ClinicalTrials.gov NCT00548405

Inclusion Criteria

  • Age 18-55 years
  • Relapsing-remitting multiple sclerosis fulfilling 2005 McDonald diagnostic criteria
  • Disease duration ≤10 years
  • At least 2 attacks in previous 2 years with at least 1 in previous year
  • At least 1 relapse while on interferon beta or glatiramer after at least 6 months of treatment
  • EDSS score ≤5.0
  • Cranial and spinal MRI lesions fulfilling protocol-defined criteria

Exclusion Criteria

  • Progressive forms of multiple sclerosis
  • Previous cytotoxic drug use or investigational therapy
  • Treatment within previous 6 months with natalizumab, methotrexate, azathioprine, or ciclosporin
  • History of clinically significant autoimmunity other than multiple sclerosis

Baseline Characteristics

CharacteristicInterferon beta 1a (n=202)Alemtuzumab 12 mg (n=426)Alemtuzumab 24 mg (n=170)
Age (years, mean)35.8 (8.77)34.8 (8.36)35.1 (8.40)
Female131 (65%)281 (66%)120 (71%)
Race white187 (93%)385 (90%)142 (84%)
EDSS mean2.7 (1.21)2.7 (1.26)2.7 (1.17)
EDSS median2.5 (0.0-6.0)2.5 (0.0-6.5)2.5 (0.0-6.0)
Time since first clinical event (years, mean)4.7 (2.86)4.5 (2.68)4.3 (2.77)
Relapses in previous year (mean)1.5 (0.75)1.7 (0.86)1.6 (0.86)
Gd-enhancing lesions (mean)2.10 (4.95)2.28 (6.02)2.88 (8.47)
Patients with baseline lesions87/199 (44%)178/420 (42%)74/165 (45%)
T2-hyperintense lesion volume (cm³, mean)9.04 (10.42)9.94 (12.25)9.47 (9.66)
Brain parenchymal fraction (mean)0.817 (0.022)0.813 (0.023)0.816 (0.024)
Duration of previous MS drug use (months, mean)36 (23.7)35 (25.0)37 (23.9)
1 previous MS drug151 (75%)299 (70%)120 (71%)

Arms

FieldControlAlemtuzumab 12 mgAlemtuzumab 24 mg
N202426170
InterventionSubcutaneous interferon beta 1a 44 µg administered three times per week after dose titration. To control for steroid prophylaxis given to the alemtuzumab groups, patients in the interferon beta 1a group also received the same intravenous methylprednisolone 1 g/day regimen for 3 consecutive days at month 0 and month 12.Intravenous alemtuzumab 12 mg/day on 5 consecutive days at month 0 and 3 consecutive days at month 12; premedicated with IV methylprednisolone 1 g/day for 3 consecutive days at each course (antihistamines and antipyretics also permitted). Under a December 2008 protocol amendment, aciclovir 200 mg twice daily was added during infusion and for 28 days after each course as herpes simplex prophylaxis, but was received by only 188/435 (43%) at month 0 and 278/419 (66%) at month 12.Intravenous alemtuzumab 24 mg/day on 5 consecutive days at month 0 and 3 consecutive days at month 12 (arm discontinued December 2008 to accelerate recruitment; safety data only, safety population n=161)
Duration2 years2 years2 years

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Coprimary endpoints: (1) relapse rate (analyzed with proportional means / recurrent-event model, yielding a rate ratio — not a risk ratio), and (2) time to 6-month sustained accumulation of disability (analyzed with proportional hazards model), comparing alemtuzumab 12 mg vs interferon beta 1a in patients who received at least one dose of study drugPrimaryRelapse: 104/202 (51%) patients relapsed (201 events); Disability: 40/202 (20%) had sustained accumulation of disability [21.13% (95% CI 15.95-27.68) by Kaplan-Meier]Relapse: 147/426 (35%) patients relapsed (236 events); Disability: 54/426 (13%) had sustained accumulation of disability [12.71% (95% CI 9.89-16.27) by Kaplan-Meier]0.58Relapse p<0.0001; Disability p=0.008 (0.0084)
Proportion relapse-free at 2 years (Kaplan-Meier estimate)Secondary46.7% (95% CI 39.5-53.5)65.4% (95% CI 60.7-69.7)0.53 (95% CI 0.41-0.69)<0.0001
Change in EDSS score from baseline (mean, mixed model for repeated measures)Secondary+0.24 (95% CI 0.07 to 0.41)-0.17 (95% CI -0.29 to -0.05)<0.0001 (net benefit 0.41 EDSS points favoring alemtuzumab)
Sustained reduction in disability confirmed for 6 months (Kaplan-Meier)Secondary18/202 (9%); 12.93% (95% CI 8.34-19.77)92/426 (22%); 28.82% (95% CI 24.18-34.13)2.57 (95% CI 1.57-4.20)0.0002
Change in MSFC z-score from baseline (mean, mixed model)Secondary-0.04 (95% CI -0.10 to 0.02)+0.08 (95% CI 0.04 to 0.12)0.002 (descriptive only — formal sequential testing had stopped when EDSS p-value exceeded 0.05 threshold in prior step; note: MSFC actually met the hierarchical criterion here — reported descriptively per protocol plan)
Median change in T2-hyperintense lesion volume (%)Secondary-1.23% (IQR -11.13 to 11.39)-1.27% (IQR -12.70 to 7.78)0.14 (not significant)
Patients with new or enlarging T2-hyperintense lesions over 2 yearsSecondary127/187 (68%)186/403 (46%)<0.0001
Patients with gadolinium-enhancing lesions at 24 months (tertiary)Secondary44/190 (23%)38/410 (9%)<0.0001
Median change in brain parenchymal fraction (%, tertiary)Secondary-0.810% (IQR -1.539 to 0.203)-0.615% (IQR -1.299 to 0.006)0.01
Patients clinically disease-free at 2 years (tertiary)Secondary83/202 (41%)254/426 (60%)2.14 (95% CI 1.52-3.01)<0.0001
Patients MRI and clinically disease-free at 2 years (tertiary)Secondary25/184 (14%)127/396 (32%)3.03 (95% CI 1.89-4.86)<0.0001
Any adverse event (safety population)SafetyControl (interferon beta 1a, n=202): 191/202 (95%) · Intervention (alemtuzumab 12 mg, n=435): 428/435 (98%)
Infusion-associated reactions (alemtuzumab 12 mg only)Safety393/435 (90%); 12/435 (3%) had serious infusion-associated events; no anaphylaxis
Any infectionSafetyControl (interferon beta 1a, n=202): 134/202 (66%) · Intervention (alemtuzumab 12 mg, n=435): 334/435 (77%), mostly mild-moderate, none fatal
Herpes viral infectionsSafetyControl (interferon beta 1a, n=202): 8/202 (4%) · Intervention (alemtuzumab 12 mg, n=435): 68/435 (16%) — herpes simplex 42/435 (10%), herpes zoster 26/435 (6%)
Thyroid disorders (any)SafetyControl (interferon beta 1a, n=202): 10/202 (5%) · Intervention (alemtuzumab 12 mg, n=435): 69/435 (16%) — hyperthyroidism 22/435 (5%), hypothyroidism 19/435 (4%), thyroiditis 7/435 (2%), goitre 16/435 (4%)
Autoimmune thrombocytopenia (immune thrombocytopenic purpura)SafetyControl (interferon beta 1a, n=202): 0/202 · Intervention (alemtuzumab 12 mg, n=435): 3/435 (1%) — all reported as serious
Serious adverse events (excluding MS relapses)SafetyControl (interferon beta 1a, n=202): 26/202 (13%) · Intervention (alemtuzumab 12 mg, n=435): 58/435 (13%)
Study drug discontinuation because of adverse eventSafetyControl (interferon beta 1a, n=202): 15/202 (7%) · Intervention (alemtuzumab 12 mg, n=435): 14/435 (3%)
DeathsSafetyControl (interferon beta 1a, n=202): 0/202 · Intervention (alemtuzumab 12 mg, n=435): 2/435 (<1%) — one motor vehicle accident, one aspiration pneumonia after prior brainstem relapse (on-study)
Malignant disease (any)SafetyControl (interferon beta 1a, n=202): 2/202 (1%) — basal cell carcinoma, acute myeloid leukaemia · Intervention (alemtuzumab 12 mg, n=435): 2/435 (<1%) — basal cell carcinoma, thyroid cancer
Alemtuzumab 12 mg (safety population n=435)AdverseAny adverse event: 428/435 (98%) · Infusion-associated reactions: 393/435 (90%); serious in 12/435 (3%) · Any infection: 334/435 (77%) — mostly mild-moderate, none fatal · Herpes viral infections: 68/435 (16%) · Thyroid disorders: 69/435 (16%) · Immune thrombocytopenia: 3/435 (1%) · Serious adverse events (excluding MS relapses): 58/435 (13%) · Deaths: 2/435 (<1%)
Interferon beta 1a (safety population n=202)AdverseAny adverse event: 191/202 (95%) · Any infection: 134/202 (66%) · Herpes viral infections: 8/202 (4%) · Thyroid disorders: 10/202 (5%) · Immune thrombocytopenia: 0/202 · Serious adverse events (excluding MS relapses): 26/202 (13%) · Deaths: 0/202
Alemtuzumab 24 mg (safety population n=161)AdverseAny adverse event: 159/161 (99%) · Infusion-associated reactions: 156/161 (97%) · Any infection: 134/161 (83%) · Thyroid disorders: 31/161 (19%) · Autoimmune thrombocytopenia: 2/161 (1%)

Subgroup Analysis

Alemtuzumab's superior efficacy on both relapse rate and disability was seen in all subgroups defined by previous therapy (interferon vs glatiramer, or those specifically failing subcutaneous interferon beta 1a) and by presence/absence of anti-interferon antibodies at baseline or month 24 (appendix).

Criticisms

  • Open-label treatment due to inability to double-blind (only rater-masked); mitigated by independent relapse adjudication and steroid-regimen matching in the IFN arm
  • Alemtuzumab 24 mg arm discontinued mid-trial (December 2008), reducing statistical power for higher-dose comparison
  • Interferon beta 1a comparator may not represent best available first-line therapy at the time of publication
  • Aciclovir prophylaxis was added by protocol amendment and inconsistently applied (43% at month 0, 66% at month 12), likely explaining elevated herpes rates
  • Notable safety concerns including secondary autoimmunity (thyroid, ITP) requiring long-term monitoring
  • MSFC secondary endpoint reported descriptively because prior hierarchical step (T2 volume) did not meet significance threshold

Funding

Genzyme (Sanofi) and Bayer Schering Pharma

Based on: CARE-MS II (The Lancet, 2012)

Authors: Coles AJ, Twyman CL, Arnold DL, ..., for the CARE-MS II investigators

Citation: Lancet 2012; 380: 1829-39

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