Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial.

OBJECTIVE: To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0-2 (FREEDOMS) and years 2-4 (extension) in the extension ITT population. RESULTS: Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo-fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo-fingolimod patients. Within each placebo-fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo-fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported. CONCLUSION: Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS.

Efficacy and safety of valsartan in hypertensive children 6 months to 5 years of age.

OBJECTIVE: To evaluate a dose-dependent reduction in blood pressure (BP) and overall safety of valsartan in hypertensive children. METHOD: In a multicenter, randomized, double-blind, parallel-group study, 75 patients with a documented history of hypertension were randomized (2 : 1 : 2) to receive valsartan (0.25, 1 or 4  mg/kg per day) for 6 weeks, then rerandomized (1 : 1) to receive placebo or valsartan for 2 weeks. This followed the 18-week extension study in which all patients received open-label valsartan (1  mg/kg initial dose, titratable up to 4  mg/kg). The primary endpoint was the slope analysis of the dose-response curve for mean sitting SBP (MSSBP) derived through MSSBP reduction over the first 6 weeks. Safety was assessed in terms of adverse events and serious adverse events (SAEs). RESULTS: At Week 6, significant reductions in MSSBP (P < 0.05) from baseline were observed for all three valsartan doses. Greater reductions were observed with the medium and high doses, although the dose-response trend was not statistically significant (P = 0.099). At Week 8, a greater increase in BP was observed in patients who switched from valsartan to placebo; the difference was not significant. At the extension endpoint, MSSBP was comparable to that observed at Week 6 of the core study. Overall, valsartan was well tolerated with no dose-dependent increase in adverse events during the dose-ranging period (Week 0-6) and a comparable incidence of adverse events to placebo during the placebo withdrawal period (Week 7-8). CONCLUSION: Although a dose-response trend was observed, statistical significance was not achieved during the dose ranging (primary endpoint) or the placebo-withdrawal periods of the study. However, valsartan demonstrated significant reductions in BP compared with baseline and provided consistent reductions over 26 weeks.