Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study.

OBJECTIVE: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS). METHODS: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion. RESULTS: The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing. CONCLUSION: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.

Dose response of Gabapentin Enacarbil versus placebo in subjects with moderate-to-severe primary restless legs syndrome: an integrated analysis of three 12-week studies.

BACKGROUND: The efficacy and tolerability of gabapentin enacarbil (Horizant®; GlaxoSmithKline, Brentford, UK) has been demonstrated in several restless legs syndrome (RLS) phase II and phase III clinical studies at various doses from 600 mg to 2400 mg. OBJECTIVE: The objective of this study was to evaluate key efficacy and safety outcomes in subjects with RLS treated with once-daily gabapentin enacarbil 600 mg, 1200 mg, 1800 mg and 2400 mg, providing supportive evidence of the efficacy of gabapentin enacarbil 600 mg compared with higher doses and placebo. STUDY DESIGN: Integrated post hoc analysis of three 12-week, randomized, double-blind, placebo-controlled trials in subjects with RLS. SETTING: The three studies were carried out at multiple centres in the US. PATIENTS: In total, 760 subjects were included in the pooled analysis (placebo, n = 245; gabapentin enacarbil 600 mg, n = 163; gabapentin enacarbil 1200 mg, n = 269; gabapentin enacarbil 1800 mg, n = 38; gabapentin enacarbil 2400 mg, n = 45). INTERVENTION: In all studies, gabapentin enacarbil or placebo was administered once daily at approximately 5 p.m. with food. Gabapentin enacarbil was initiated at a dose of 600 mg with subsequent titration in 600 mg increments every 3 days up to the randomized dose. MAIN OUTCOME MEASURE: The efficacy endpoints analysed for the purpose of this integrated analysis were change from baseline in International Restless Legs Scale (IRLS) total score and the proportion of responders (subjects rated as 'much' or 'very much' improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale. Safety endpoints assessed were the incidence of treatment-emergent adverse events (AEs) and serious AEs. RESULTS: Gabapentin enacarbil 600 mg significantly improved IRLS total score compared with placebo (adjusted mean [standard error] change in IRLS total score from baseline to week 12 last observation carried forward: -13.6 [0.71] vs -9.3 [0.55]; adjusted mean treatment difference: -4.3; 95% CI -6.01, -2.52; p < 0.0001). A significantly higher proportion of subjects was rated as responders on the investigator-rated CGI-I scale with gabapentin enacarbil 600 mg compared with placebo (70.2% vs 42.2%; adjusted odds ratio 3.1; 95% CI 1.96, 4.89; p < 0.0001). Similar treatment benefits were seen with both efficacy endpoints for the three higher doses. The AEs reported most frequently were somnolence and dizziness; there was a dose-response relationship to these AEs. No new or unexpected safety issues were identified by this integrated analysis. CONCLUSION: The lowest dose of gabapentin enacarbil evaluated (600 mg) significantly improved RLS symptoms compared with placebo. The safety profile was consistent with that described previously in the literature.

Extended-release bupropion for patients with major depressive disorder presenting with symptoms of reduced energy, pleasure, and interest: findings from a randomized, double-blind, placebo-controlled study.

OBJECTIVE: This multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of extended-release bupropion (bupropion XL) in the treatment of major depressive disorder (MDD) with prominent symptoms of decreased energy, pleasure, and interest. METHOD: Eligible adult outpatients meeting DSM-IV criteria for MDD were randomly assigned to bupropion XL 300 to 450 mg/day (N = 135) or placebo (N = 139) for 8 weeks. The primary efficacy measure, change from baseline on the 30-item Inventory of Depressive Symptomatology-Self Report (IDS-IVR-30) total score, was obtained using interactive voice response (IVR) technology. Secondary measures included change from baseline on the 30-item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C-30) total score and change in domain subset scores for energy, pleasure, and interest; for insomnia; and for anxiety. Response and remission rates were also calculated. Safety was assessed by withdrawal rates, adverse events (AEs), body weight, and vital signs. The study was conducted from June 24, 2003, to June 30, 2004. RESULTS: Bupropion XL was superior to placebo at endpoint in reducing the IDS-IVR-30 total score (p = .018) and the energy, pleasure, and interest domain (p = .007) and the insomnia domain (p = .023) scores. IDS-C-30 outcomes were also significant (p < .001; p < .001, and p = .008, respectively). Clinician-rated remission rates were significantly higher with bupropion XL than placebo (32% vs. 18%, IDS-C-30; 41% vs. 27%, IDS-IVR-30), as were response rates (50% vs. 35%, IDS-C-30; 53% vs. 38%, Clinical Global Impressions-Improvement of Illness). Most AEs were mild or moderate. The incidence of a >or= 7% body weight loss was 3.7% with bupropion XL and 1.4% with placebo. CONCLUSION: Bupropion XL was effective and well tolerated in MDD patients with decreased energy, pleasure, and interest.