Apremilast for Behcet's Syndrome - A Phase 2, Placebo-Controlled Study

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Hatemi G, et al. "Apremilast for Behçet's syndrome--a phase 2, placebo-controlled study". The New England Journal of Medicine. 2015. 372(16):1510-1518.
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Clinical Question

In patients with Behcet's Syndrome, is apremilast (a phosphodiesterase-4 inhibitor with immunomodulatory properties) safe and effective in decreasing the number of, and pain from, oral and genital ulcers?

Bottom Line

Major Points

Guidelines

Design

  • Phase 2, Double-blind, multicenter, placebo-controlled, parallel-group study
  • Randomly assigned @ 1:1 ratio (stratified by sex in blocks of 4) to:
  • N = 111 (recruitment stopped early due to slow accrual; initial N planned as 156 for 90% power)
    • 55 assigned to apremilast
    • 56 assigned to placebo
  • Setting: 6 University Hospitals (3 in Turkey, 3 in US)
  • Enrollment: 10/2009-10/2011
  • Mean follow-up:
  • Analysis: Intention-to-treat; Last-observation-carried-forward used for any patients discontinuing early

Population

Inclusion Criteria

  • Meet international study group definition for Behcet's Disease
  • At least 18 years old
  • At least 1 oral or genital ulcer within 28 days before screening
  • At least 2 oral ulcers at time of randomization

Exclusion Criteria

  • Patients with active involvement of a major organ during 12 months prior to enrollment
  • Pregnant or breastfeeding females
  • Patients with active infection
  • Patients with history of recurrent or chronic infections
  • Patients with latent TB

Baseline Characteristics

Interventions

  • Apremilast 30 mg BID or placebo BID for 12 weeks
  • After 12 weeks, all participants changed to apremilast for 12 weeks
  • All then enter 4 week followup phase
  • Randomized to Apremilast: |-------Apremilast x 12 weeks-------||-----Apremilast x 12 weeks-----||---4 week followup phase---|
  • Randomized to Placebo: |-------Placebo x 12 weeks----------||-----Apremilast x 12 weeks-----||---4 week followup phase---|
  • Apremilast dosed as 10 mg BID x2 days --> 20 mg BID x3 days --> 30 mg BID for remainder; placebo matched to this dose. Single dose reduction was allowed.

Outcomes

Comparisons are placebo group vs apremilast group

Primary Outcomes

  • Number of oral ulcers at week 12

Secondary Outcomes

  • Change in disease activity from baseline to week 12 based on Behcet's Disease Current Activity Form and Behcet's Syndrome Activity Score
  • Change in pain from oral and genital ulcers from baseline to week 12 (visual analogue scale)
  • Number of genital ulcers at week 12
  • Proportion of patietns with a complete response (no oral ulcers) with respect to oral ulcers
  • Proportion of patients with partial (>50% reduction in # of oral ulcers) with respect to oral ulcers
  • Number of oral ulcers, pain levels from oral ulcers, Number of genital ulcers, pain from genital ulcers, disease activity at week 24
  • Safety endpoints - type/frequency/severity of adverse events

Subgroup Analysis

Adverse Events

Criticisms

Funding

  • Celgene (study drug manufacturer) - involved in processing, management, stat analysis, and data interpretation

Further Reading