Clinical trials in MS - Developments and challengesFriday, October 12, 2007, 14:50 - 15:00
Preliminary CHOICE results: a phase 2, randomised, double-blind, placebo-controlled multicentre study of subcutaneous daclizumab in patients with active, relapsing forms of multiple sclerosis on interferon betaX. Montalban, D. Wynn, M. Kaufman, M. Wang, A. Fong (Barcelona, E; Northbrook, Charlotte, Fremont, USA)
Background: Open-label studies of daclizumab (DAC) given to patients with relapsing forms of MS suggested that DAC reduces the number of new MRI lesions in patients refractory to interferon-beta therapies.
Objectives: To evaluate the efficacy and safety of DAC in a controlled MS trial.
Methods: Patients (pts) with confirmed MS diagnosis, EDSS <=5 at screening, stable interferon-beta for >=6 months, and >=1 relapse or qualifying MRI within 12 months of screening were included. A total of 230 pts were equally randomized to 1 of 3 treatments: 2mg/kg DAC every 2 weeks (high dose), 1mg/kg DAC every 4 weeks (low dose) or placebo. Study drug was given for 24 weeks with 48 weeks followup. The primary efficacy endpoint was the total number of new or enlarged gadolinium contrast enhancing lesions (Gd-CELs) on monthly brain MRIs collected from Week 8 to Week 24. A secondary efficacy endpoint was the relapse rate between Weeks 8 to 24. Pharmacokinetics, pharmacodynamics, immunogenicity and changes in EDSS and MSFC-3 were also assessed. The study is currently ongoing and pts will be monitored to Week 72.
Results: Primary efficacy analysis on intention-to-treat (ITT) pts showed the mean number of new or enlarged Gd-CELs was significantly reduced by 72% in the 2mg/kg group (n=75) compared with the placebo group (n=77) (p=0.004). The 1mg/kg group (n=78) showed a 25% reduction compared with placebo but did not achieve statistical significance.
Based on data up to Week 24, the relapse rate analysis on the ITT population indicates that both DAC regimens reduced the annualized relapse rate by approximately 35 % compared to placebo, but did not reach statistical significance. The study was not powered for the relapse rate endpoint.
Preliminary safety data showed a similar overall infection rate across all treatment groups; the overall incidence of serious infections was higher in the 2mg/kg group. Urinary tract infections were slightly higher with the 2mg/kg dose (17% vs 13% placebo). The incidence of cutaneous events was higher in the combined DAC groups (34% DAC vs 27% placebo) and often appeared during the washout phase. The nature of the cutaneous events varied but improved with standard treatment.
Conclusions: The addition of DAC 2mg/kg q2 weeks to beta interferon was associated with a statistically significant reduction of Gd-CELs and a favourable trend in reducing relapse rates. In general, DAC was safe and well tolerated in this beta interferon treated MS population.