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ATAMS

Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial

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Year of Publication: 2014

Authors: Ludwig Kappos, Hans-Peter Hartung, Mark S Freedman, ..., for the ATAMS Study Group

Journal: Lancet Neurology

Citation: Lancet Neurol 2014; 13: 353-63

Link: https://doi.org/10.1016/S1474-4422(14)70028-6

Clinical Question

Does atacicept, a B-cell suppressing recombinant fusion protein, reduce disease activity in patients with relapsing multiple sclerosis?

Bottom Line

Atacicept unexpectedly INCREASED clinical disease activity (annualised relapse rate) in patients with relapsing multiple sclerosis compared to placebo, leading to early trial termination. This demonstrates that the role of B cells and humoral immunity in MS is more complex than a simple pathogenic role, and that rigorous monitoring for negative effects is essential when exploring immunomodulation in MS.

Major Points

  • Trial was TERMINATED EARLY by the independent data and safety monitoring board due to increased relapse rates in atacicept groups
  • Annualised relapse rates were higher in ALL atacicept doses vs placebo (25mg: 0.86, 75mg: 0.79, 150mg: 0.98 vs placebo: 0.38)
  • Despite increased clinical activity, mean gadolinium-enhancing T1 lesions per scan were SIMILAR across groups (atacicept arms trended slightly lower)
  • Demonstrates clinical-radiological dissociation: MRI lesion burden did not predict clinical outcome
  • During safety follow-up, immunoglobulin concentrations, B-cell counts, and relapse rates returned toward placebo values after treatment discontinuation
  • Findings suggest the role of B cells and humoral immunity in MS is complex; not all B-cell directed therapies are beneficial
  • Highlights need for rigorous monitoring for negative effects in MS immunomodulation trials

Design

Study Type: Randomized, placebo-controlled, double-blind, phase 2 multicenter trial

Randomization: 1

Blinding: Double-blind (patients and study personnel masked); atacicept and placebo supplied in 1 mL prefilled glass syringes with non-transparent labels

Allocation: 1:1:1:1 ratio, stratified by geographical region, via interactive voice-response system (S-Clinica, Brussels, Belgium)

Enrollment Period: April 23, 2008 to September 11, 2009 (early termination)

Follow-up Duration: 36-week treatment period with 60-week safety follow-up added by protocol amendment; ATAMS EXT extension planned for up to 5 years

Centers: 47

Countries: Australia, Canada, USA, and 14 European countries

Sample Size: 255

Analyzed: 255

Analysis: Intention-to-treat for efficacy endpoints; safety population (all patients receiving ≥1 dose) for safety endpoints; negative binomial regression model corrected for overdispersion for primary endpoint and annualised relapse rates

Power Calculation: 73 patients per group would provide 80% power to detect differences in mean gadolinium-enhancing T1 lesions (assumed placebo: 2.0; 25mg: 1.4; 75mg: 1.3; 150mg: 1.2 — reductions of 30%, 35%, 40%), assuming 10% withdrawal and 5% type I error

Registration: NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT)

Inclusion Criteria

  • Aged 18-60 years
  • Diagnosis of relapsing multiple sclerosis per 2005 McDonald criteria
  • At least one of the following: ≥2 documented relapses within 2 years, ≥1 documented relapse within 1 year, or ≥1 gadolinium-enhancing lesion on T1-weighted MRI at screening

Exclusion Criteria

  • Primary or secondary progressive multiple sclerosis without superimposed relapses
  • Previous B-cell suppressive, immunosuppressive, myelosuppressive, or cytotoxic treatment
  • Active clinically significant acute or chronic infection
  • Major episode of infection requiring hospital admission within 4 weeks
  • Previous treatment with cytokine or anticytokine drugs within 6 months
  • Intravenous immunoglobulin or plasmapheresis within 6 months
  • Immunomodulatory drugs within 3 months
  • Investigational drugs within 2 months
  • Corticosteroids within 1 month
  • Live vaccines within 1 month
  • Parenteral anti-infective drugs within 1 month

Arms

FieldControlAtacicept 25 mgAtacicept 75 mgAtacicept 150 mg
N63636465
InterventionMatching placebo subcutaneous injection: twice weekly for 4 weeks (loading), then once weekly for 32 weeks (maintenance)Atacicept 25 mg subcutaneous: twice weekly for 4 weeks (loading), then once weekly for 32 weeks (maintenance)Atacicept 75 mg subcutaneous: twice weekly for 4 weeks (loading), then once weekly for 32 weeks (maintenance)Atacicept 150 mg subcutaneous: twice weekly for 4 weeks (loading), then once weekly for 32 weeks (maintenance)
Duration36 weeks36 weeks36 weeks36 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Mean number of gadolinium-enhancing T1 lesions per patient per scan (originally weeks 12-36; redefined as full double-blind period weeks 0-36 due to early termination)PrimaryPlacebo: 3.07 (95% CI 1.40-6.77)Atacicept 25 mg: 2.26 (0.97-5.27); 75 mg: 2.30 (1.08-4.92); 150 mg: 2.49 (1.18-5.27)Mean gadolinium-enhancing T1 lesions per scan similar across all groups; no statistically significant reduction
Annualised relapse rate during double-blind period (initially tertiary endpoint, became key safety signal)SecondaryPlacebo: 0.38 (95% CI 0.17-0.87)Atacicept 25 mg: 0.86 (0.43-1.74); 75 mg: 0.79 (0.40-1.58); 150 mg: 0.98 (0.52-1.81)Annualised relapse rates were HIGHER in all atacicept groups vs placebo — opposite of hypothesized effect
Mean number of gadolinium-enhancing T1 lesions per patient per scan from weeks 24 to 36 (secondary endpoint)SecondaryNot specified in available textNot specified in available text
Number of new T1 hypointense lesions (black holes) per patientSecondaryNot specified in available textNot specified in available text
Proportion of patients free from relapse during the 36-week treatment periodSecondaryNot specified in available textNot specified in available text
Discontinuation due to adverse eventsSafety7 patients discontinued treatment due to adverse events (1 placebo, 6 atacicept)
MortalitySafety1 death occurred in the placebo group; no deaths in atacicept groups
Immunoglobulin concentrations and B-cell countsSafetyReturned toward predose values during the 60-week safety follow-up after treatment discontinuation
Annualised relapse rates after treatment discontinuationSafetyDecreased during safety follow-up until similar to placebo group

Subgroup Analysis

Post-hoc analysis investigated whether BLyS mRNA status at baseline affected disease exacerbation (relapse) — full results truncated in available text

Criticisms

  • Trial was terminated early, limiting follow-up duration and potentially affecting power for primary endpoint
  • Clinical-radiological dissociation observed (MRI lesions similar but clinical relapses worse with atacicept) — mechanism not fully explained
  • Primary endpoint was changed from original (weeks 12-36) to full double-blind period (weeks 0-36) due to early termination — could be viewed as post-hoc analytical change
  • Annualised relapse rate was originally only a tertiary endpoint but became the key safety signal driving trial termination
  • Multiple sclerosis relapses were not documented as adverse events, which may complicate safety event reporting

Funding

Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA)

Based on: ATAMS (Lancet Neurology, 2014)

Authors: Ludwig Kappos, Hans-Peter Hartung, Mark S Freedman, ..., for the ATAMS Study Group

Citation: Lancet Neurol 2014; 13: 353-63

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