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CLARITY Extension

Safety and efficacy of cladribine tablets in patients with relapsing–remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study

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Year of Publication: 2018

Authors: Gavin Giovannoni, Per Soelberg Sorensen, Stuart Cook, ..., Patrick Vermersch

Journal: Multiple Sclerosis Journal

Citation: Mult Scler J. 2018;24(12):1594–1604

Clinical Question

What are the long-term safety and efficacy outcomes of cladribine tablets treatment in patients who completed the CLARITY study, including assessment of treatment duration and durability of clinical benefits?

Bottom Line

Cladribine tablets treatment for 2 years followed by 2 years of placebo produced durable clinical benefits similar to 4 years of continuous cladribine treatment with acceptable safety profile. No additional clinical benefit was apparent from extending cladribine treatment beyond the initial 2-year period.

Major Points

  • Extension study of CLARITY trial with 806 patients across 5 treatment groups over 2 years
  • Patients who received cladribine in CLARITY maintained clinical benefits during 2-year placebo extension period
  • 75% of patients who received cladribine 3.5mg/kg in CLARITY remained relapse-free during placebo extension
  • No significant incremental benefit from additional 2 years of cladribine treatment beyond initial 2-year course
  • Lymphopenia was dose-dependent with higher rates in continuous cladribine groups (40.9-53.2% Grade ≥3)
  • No cases of progressive multifocal leukoencephalopathy (PML) occurred during extension study

Design

Study Type: Randomized, double-blind, placebo-controlled extension study

Randomization: 1

Blinding: Double-blind with maintained blinding from CLARITY study

Enrollment Period: January 16, 2008 to July 20, 2009

Follow-up Duration: 96 weeks plus 24-week supplemental follow-up

Centers: 133 sites (22 fewer than original CLARITY)

Countries: Multiple countries - not specifically detailed

Sample Size: 806

Analysis: Intention-to-treat for efficacy, safety population for safety outcomes, exploratory analyses with nominal p≤0.025 considered significant

Inclusion Criteria

  • Completed the 2-year CLARITY study period
  • Normal lymphocyte count within 28 days of first planned dose
  • Normal hematological results within 28 days
  • If received interferon beta or glatiramer acetate during gap period, must discontinue ≥3 months before Extension

Exclusion Criteria

  • Abnormal lymphocyte or hematological parameters
  • Use of disease-modifying drugs within 3 months of Extension start (except as specified)
  • Other standard exclusion criteria detailed in Supplementary Materials

Arms

FieldCP 3.5mg/kgCP 5.25mg/kgCC 7mg/kgCC 8.75mg/kgControl
InterventionCladribine 3.5mg/kg in CLARITY followed by placebo in ExtensionCladribine 5.25mg/kg in CLARITY followed by placebo in ExtensionCladribine 3.5mg/kg in CLARITY followed by cladribine 3.5mg/kg in Extension (total 7mg/kg)Cladribine 5.25mg/kg in CLARITY followed by cladribine 3.5mg/kg in Extension (total 8.75mg/kg)Placebo in CLARITY followed by cladribine 3.5mg/kg in Extension
Duration96 weeks Extension plus 24-week follow-up96 weeks Extension plus 24-week follow-up96 weeks Extension plus 24-week follow-up96 weeks Extension plus 24-week follow-up96 weeks Extension plus 24-week follow-up

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Annualized relapse rate during Extension periodPrimaryPC 3.5mg/kg: 0.10 (95% CI 0.07-0.13)CP 3.5mg/kg: 0.15 (95% CI 0.09-0.21), CP 5.25mg/kg: 0.13 (95% CI 0.08-0.19), CC 7mg/kg: 0.10 (95% CI 0.06-0.13), CC 8.75mg/kg: 0.12 (95% CI 0.08-0.16)All comparisons >0.05
Proportion relapse-free during ExtensionSecondaryPC 3.5mg/kg: 79.6%CP 3.5mg/kg: 75.6%, CP 5.25mg/kg: 75.3%, CC 7mg/kg: 81.2%, CC 8.75mg/kg: 76.7%No significant differences>0.05 for all comparisons
3-month confirmed EDSS progression-freeSecondaryPC 3.5mg/kg: 75.8%CP 3.5mg/kg: 72.4%, CP 5.25mg/kg: 78.3%, CC 7mg/kg: 77.4%, CC 8.75mg/kg: 76.3%No significant differences>0.05 for all comparisons
Grade ≥3 lymphopenia incidenceSecondaryPC 3.5mg/kg: 25.0%CP 3.5mg/kg: 5.1%, CP 5.25mg/kg: 6.5%, CC 7mg/kg: 40.9%, CC 8.75mg/kg: 53.2%Dose-dependent increaseNot formally tested
Any adverse eventAdversePC 3.5mg/kg: 79.5%CP 3.5mg/kg: 75.5%, CP 5.25mg/kg: 77.2%, CC 7mg/kg: 80.1%, CC 8.75mg/kg: 80.1%Similar across groups
Serious adverse eventsAdversePC 3.5mg/kg: 9.0%CP 3.5mg/kg: 16.3%, CP 5.25mg/kg: 8.7%, CC 7mg/kg: 13.4%, CC 8.75mg/kg: 12.4%Not specified
Treatment discontinuation due to AEsAdversePC 3.5mg/kg: 10.7%CP 3.5mg/kg: 3.1%, CP 5.25mg/kg: 4.3%, CC 7mg/kg: 14.0%, CC 8.75mg/kg: 16.1%Higher in continuous treatment groupsNot specified

Subgroup Analysis

Analysis showed 60.7% relative reduction in ARR when PC 3.5mg/kg group switched from placebo (ARR 0.26) to cladribine (ARR 0.10) treatment, comparable to original CLARITY results

Criticisms

  • Not powered for efficacy analyses due to limited patient numbers from CLARITY enrollment
  • Variable gap period between CLARITY and Extension (median 40.3 weeks) could confound results
  • Treating physicians potentially functionally unblinded due to laboratory parameters, though evaluating physicians remained blinded
  • Extension was not pre-planned, creating potential selection bias
  • Limited by exploring multiple treatment comparisons without formal hypothesis testing
  • High cumulative doses in continuous treatment groups led to prolonged lymphopenia recovery times
  • No formal analysis of infection risk relationship to lymphopenia severity due to confounding factors

Funding

Sponsored by EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany (United States), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (rest of world)

Based on: CLARITY Extension (Multiple Sclerosis Journal, 2018)

Authors: Gavin Giovannoni, Per Soelberg Sorensen, Stuart Cook, ..., Patrick Vermersch

Citation: Mult Scler J. 2018;24(12):1594–1604

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