Assessing the Long-Term Effectiveness of Cladribine vs. Placebo in the Relapsing-Remitting Multiple Sclerosis CLARITY Randomized Controlled Trial and CLARITY Extension Using Treatment Switching Adjustment Methods.

Abstract

Treatment switching adjustment methods are often used to adjust for switching in oncology randomized controlled trials (RCTs). In this exploratory analysis, we apply these methods to adjust for treatment changes in the setting of an RCT followed by an extension study in relapsing-remitting multiple sclerosis. The CLARITY trial evaluated cladribine tablets versus placebo over 96weeks. In the 96-week CLARITY Extension, patients who received placebo in CLARITY received cladribine tablets; patients who received cladribine tablets in CLARITY were re-randomized to placebo or cladribine tablets. End points were time to first qualifying relapse (FQR) and time to 3- and 6-month confirmed disability progression (3mCDP, 6mCDP). We aimed to compare the effectiveness of cladribine tablets with placebo over CLARITY and the extension. The rank-preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE) were used to estimate what would have happened if patients had received placebo in CLARITY and the extension versus patients that received cladribine tablets and switched to placebo. To gauge whether treatment effect waned after the 96weeks of CLARITY, we compared hazard ratios (HRs) from the adjustment analysis with HRs from CLARITY. The RPSFTM resulted in an HR of 0.48 [95% confidence interval (CI) 0.36-0.62] for FQR, 0.62 (95% CI 0.46-0.84) for 3mCDP and 0.62 (95% CI 0.44-0.88) for 6mCDP. IPE algorithm results were similar. CLARITY HRs were 0.44 (95% CI 0.34-0.58), 0.60 (95% CI 0.41-0.87) and 0.58 (95% CI 0.40-0.83) for FQR, 3mCDP and 6mCDP, respectively. Treatment switching adjustment methods are applicable in non-oncology settings. Adjusted CLARITY plus CLARITY Extension HRs were similar to the CLARITY HRs, demonstrating significant treatment benefits associated with cladribine tablets versus placebo. EMD Serono, Inc. (a business of Merck KGaA, Darmstadt, Germany).