OBJECTIVES: Oral cladribine is a disease modifying treatment for multiple sclerosis. The CLARITY trial evaluated the efficacy of cladribine (LL) versus placebo (PP) over 96-weeks. After CLARITY, participants could enter a 96-week extension study, where placebo (PP) treated patients from CLARITY received cladribine (PPLL), and cladribine treated patients were randomised to placebo (LLPP) or continued cladribine. In the absence of a placebo arm across both 96-weeks (PPPP), we used statistical adjustment methods to compare 96-weeks low-dose cladribine to placebo alone over the combined CLARITY and extension periods for time to first qualifying relapse (FQR) and time to 3-month confirmed disability progression (3mCDP).

METHODS: Adjustment for treatment switching from placebo to low-dose cladribine was performed using the rank preserving structural failure time model (RPSFTM), and the Iterative Parameter Estimation (IPE) algorithm. Other methods including the two-stage approach and inverse probability of censoring weights were not considered as all placebo patients who entered the extension study switched to cladribine. To gauge whether the effect of cladribine appeared to wane over time, hazard ratios (HR) from the treatment switching analysis (LLPP vs PPPP) were compared with the HRs from CLARITY (LL vs PP).

RESULTS: Without adjustment, the HR for FQR was 0.44 (95% CI 0.34-0.58) (LL versus PP). The RPSFTM resulted in a HR of 0.48 (95% CI 0.36-0.62). The IPE resulted in a HR of 0.48 (95% CI 0.37-0.62). For 3mCDP, the HR was 0.60 (95%CI 0.41-0.87) (LL versus PP). RPSFTM resulted in a HR of 0.62 (95% CI 0.46-0.84) and IPE resulted in a HR of 0.62 (95% CI 0.45 to 0.83).

CONCLUSIONS: The RPSFTM and IPE (LLPP vs PPPP) HRs compared to the unadjusted (LL vs PP) HRs indicate that there is only slight waning of the cladribine treatment effect over the extension period.