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Background: Ofatumumab is approved for the treatment of relapsing multiple sclerosis (RMS). Ongoing safety reporting is crucial to understand its long-term benefit–risk profile. Objective: Report the safety and tolerability of ofatumumab in RMS after extended treatment up to 3.5 years. Methods: Patients completing ASCLEPIOS I/II (phase 3), APLIOS, or APOLITOS (phase 2) trials could enter ALITHIOS, a phase 3b, open-label, long-term safety study. We analyzed cumulative data of continuous ofatumumab treatment and of patients newly switched from teriflunomide. Results: The safety population had 1969 patients: 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched (median time-at-risk 18.3 months, 986 patient-years). A total of 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events. No opportunistic infections or progressive multifocal leukoencephalopathy events were identified; the risk of malignancies was low. Mean serum immunoglobulin (Ig) G levels remained stable. Mean IgM levels decreased but remained above the lower limit of normal in most. Serious infection incidence was low; decreased Ig levels were not associated with serious infections. Conclusion: In patients with up to 3.5 years’ exposure, ofatumumab was well tolerated, with no new safety risks identified. These findings, with its established effectiveness, support a favorable benefit–risk profile of ofatumumab in RMS.

SummaryObjectives To evaluate dose–response relationship of BGG492 as add-on therapy to 1–3 antiepileptic drugs in patients with partial-onset seizures and to investigate safety and tolerability of BGG492. Methods This was a 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study (core study) with a 30-week, flexible-dose, open-label extension. In the core study, patients were randomized (1:2) to placebo or BGG492 100 mg t.i.d. in cohort 1, and in cohort 2 patients were randomized (1:4) to placebo or BGG492 150 mg t.i.d. On completion of the core study, eligible patients entered the extension study. Primary outcome measures were total partial seizure frequency per 28 days (core study) and safety and tolerability (extension study). Results Overall, 93 patients were randomized (150 mg [n = 44]; 100 mg [n = 24]; placebo [n = 25]), and 81 (87.1%) completed the core study. Fifty-one patients entered and 43 (84.3%) completed the extension study. In the core study, no statistically significant dose–response trend among the BGG492 treatment groups (100 and 150 mg) was observed at the 4-week double-blind maintenance period (weeks 7–10); however, there was higher percent reduction in total partial seizure frequency in the BGG492 150 mg over placebo groups (37.32%; 95% confidence interval [CI] −18.90, 66.95). Dizziness, somnolence, and fatigue were the most common adverse events (AEs), higher in the BGG492 150 mg group than in the 100 mg and placebo groups (dizziness: 14 [31.8%] vs. 3 [12.5%] and 1 [4.0%]; somnolence: 7 [15.9%] vs. 1 [4.2%] and 1 [4.0%]; fatigue: 5 [11.4%] vs. 1 [4.2%] and 1 [4.0%]). During the open-label extension study, 39 (76.5%) patients on BGG492 had AEs, and the most commonly experienced AEs were dizziness (14 [27.5%]) and somnolence (9 [17.6%]). Significance There was no significant dose–response trend in the BGG492 treatment groups (100 and 150 mg); however, higher percent reduction over placebo was observed in the BGG492 150 mg group. Safety and tolerability data were consistent with the known safety profile for BGG492, and no new safety risks were identified.

Summary Objective To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. Methods The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0·5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. Findings Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17·3% of patients on rivastigmine and 21·4% on placebo progressed to AD (hazard ratio 0·85 [95% CI 0·64–1·12]; p=0·225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (−0·10 [95% CI −0·63 to 0·44], p=0·726). Serious adverse events were reported by 141 (27·9%) rivastigmine-treated patients and 155 (30·5%) patients on placebo; adverse events of all types were reported by 483 (95·6%) rivastigmine-treated patients and 472 (92·7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. Interpretation There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.

The authors investigated neuropsychiatric symptoms in mild cognitive impairment (MCI) from baseline data of the Investigation in the Delay to Diagnosis of AD with Exelon (InDDEx) study (n = 1,010). Neuropsychiatric symptoms were reported in 59% of subjects (Neuropsychiatric Inventory [NPI]). NPI+ subjects had significantly greater impairment on global, cognitive, and functional scores than NPI− subjects. The presence of neuropsychiatric symptoms appears to be a marker of MCI severity.

Background The purpose of this study was to evaluate the safety and effectiveness of iloperidone for the prevention of relapse in schizophrenia. Methods Study subjects were adults with schizophrenia who started on oral open-label iloperidone titrated to an initial target dose of 12 mg/day (6 mg twice daily) and then stabilized on a flexible-dose iloperidone regimen (range 8–24 mg/day) for up to 24 weeks. Subjects meeting stabilization criteria then entered the relapse-prevention phase and were randomized 1:1 in a double-blind fashion to continue with iloperidone or placebo withdrawal for up to 26 weeks or until meeting relapse or other withdrawal criteria. Results A total of 303 subjects were randomized to the relapse-prevention phase; 153 continued to receive iloperidone, and 150 were withdrawn to placebo. The modal total daily dose for iloperidone in all phases of the study was 12 mg/day. The pre-defined unblinded interim analysis upon reaching 68 relapse events confirmed the hypothesis that iloperidone (n = 97) was more effective than placebo (n = 96) in preventing relapse events, and the trial was stopped early. The estimated relapse rates were 63.4 % (Kaplan–Meier [KM] estimate) for placebo compared with 20.4 % (KM estimate) for those continuing to receive iloperidone (log rank test: p