The safety of agomelatine in standard medical practice in depressed patients: A 26-week international multicentre cohort study.

OBJECTIVE: The present observational cohort study documented the safety of agomelatine in current medical practice in out-patients suffering from major depressive disorder. METHOD: The 6-month evolution of agomelatine-treated patients was assessed with a focus on safety (emergent adverse events, liver acceptability), severity of depression using the Clinical Global Impression Severity (CGI-S) score, and functioning measured by the Sheehan Disability Scale (SDS). RESULTS: A total of 8453 depressed patients from 761 centres in 6 countries were analysed (female: 67.7%; mean age: 49.1 ± 14.8 years). Adverse events reported were in accordance with the known safety profile of agomelatine. Cutaneous events were reported in 1.7% of the patients and increased hepatic transaminases values were reported in 0.9 % of the patients. The incidence of events related to suicide/self-injury was 1.0%. Two completed suicides, not related to the study drug, were reported. CGI-S total scores and SDS sub-scores improved and numbers of days lost or underproductive decreased over the treatment period. CONCLUSIONS: In standard medical practice, agomelatine treatment was associated with a low incidence of side effects. No unexpected events were reported. A decrease in the severity of the depressive episode and improved functioning were observed. TRIAL REGISTRATION NAME: Observational cohort study to evaluate the safety of agomelatine in standard medical practice in depressed patients. A prospective, observational (non-interventional), international, multicentre cohort study. TRIAL REGISTRATION NUMBER: ISRCTN53570733.

Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke. METHODS: RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18-85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7-20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0-1 versus 2-6 and 0-2 versus 3-6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one dose of treatment. The study was registered at ClinicalTrials.gov, NCT02877615. FINDINGS: Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819 twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819 group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%) patients in the placebo group received at least one dose of treatment and had at least one mRS score taken after day 5, and were included in efficacy analyses. 195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients in the 300 mg S44819 group, and 193 (100%) patients in the placebo group received at least one dose of treatment, and were included in safety analyses. The primary endpoint of mRS at day 90 did not differ between each of the two S44819 groups and the placebo group (OR 0·91 [95% CI 0·64-1·31]; p=0·80 for 150 mg S44819 compared with placebo and OR 1·17 [95% CI 0·81-1·67]; p=0·80 for 300 mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90 (mRS 0-2 vs 3-6 or mRS 0-1 vs 2-6) did not differ between groups. Secondary endpoints did not reveal any significant group differences. The median NIHSS score at day 90 did not differ between groups (4 [IQR 2-8] in 150 mg S44819 group, 4 [2-7] in 300 mg S44819 group, and 4 [2-6] in placebo group), nor did the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156 in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%] of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55 [34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the median MoCA score (22·0 [IQR 17·0-26·0] in 150 mg S44819 group, 23·0 [19·0-26·5] in 300 mg S44819 group, and 22·0 [17·0-26·0] in placebo group), time needed to complete parts A (50 s [IQR 42-68] in 150 mg S44819 group, 49 s [36-63] in 300 mg S44819 group, and 50 s [38-68] in placebo group) and B (107 s [81-144] in 150 mg S44819 group, 121 s [76-159] in 300 mg S44819 group, and 130 s [86-175] in placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60-100] in 150 mg S44819 group, 90 [70-100] in 300 mg S44819 group, and 90 [70-100] in placebo group) were similar in all groups. Number and type of adverse events were similar between the three groups. There were no drug-related adverse events and no drug-related deaths. INTERPRETATION: There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans. FUNDING: Servier.

Agomelatine in Standard Medical Practice in Depressed Patients: Results of a 1-Year Multicentre Observational Study In France.

BACKGROUND AND OBJECTIVES: Non-interventional studies are a valuable source of evidence that is complementary to traditional randomised, blinded and controlled clinical trials, for evaluating antidepressants in a real-world setting. The aim of the present study was to document the use of agomelatine in current medical practice and evaluate its effectiveness and safety in outpatients prescribed agomelatine to treat their current depressive episode. METHODS: This 12-month observational French study included patients initiating agomelatine treatment. The intensity and severity of depression were assessed using the 17-item Hamilton Depression Rating Scale (HAM-D17) total score and the Clinical Global Impression-Severity of Illness (CGI-S) scale. Patients' quality of life and functioning were measured using the Quality of Life in Depression Scale and the Sheehan Disability Scale, respectively. The safety measures included emergent adverse events and biological samplings, with a focus on liver acceptability. RESULTS: A total of 1484 patients (70% of women; 49.6 ± 15.4 years of age) were enrolled in the study. Most patients (62.3%) were treated with agomelatine for at least 6 months and 28.8% were treated for at least 1 year. Mean HAM-D17 total score and mean CGI-S scores decreased by 13.6 ± 8.1 and 2.1 ± 1.5 points, respectively, from baseline to last visit on agomelatine. Rates of responders (i.e. with a decrease in HAM-D17 total score by at least 50%) and remitters (HAM-D total score < 7) at the last visit were 90.7% and 56.0%, respectively. The mean HAM-D total score decreased after agomelatine withdrawal (- 4.1 ± 6.7) until the last visit. The quality of life and daily functioning of patients improved, while the numbers of days lost and underproductive days decreased over the follow-up period. Safety findings were in accordance with the known information regarding agomelatine. CONCLUSION: In the current medical practice, this study confirms the effectiveness and good tolerability of agomelatine administered for a treatment period in agreement with guideline recommendations. TRIAL REGISTRATION NUMBER: ISRCTN53570733 on 27 August 2010.

Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event (RESTORE BRAIN study): a placebo controlled phase II study.

BACKGROUND: The GABAA-α5 receptor antagonist S44819 is a promising candidate to enhance functional recovery after acute ischemic stroke (IS). S44819 is currently evaluated in this indication; RESTORE brain study started in Dec 2016 and was completed in March 2019. METHODS/DESIGN: The study is a 3-month international, randomized, double-blind, parallel group, placebo-controlled phase II multicentre study. Patients in 14 countries who suffered an IS leading to a moderate or severe deficit defined by NIHSS score ranging from 7 to 20 and are aged between 18 to 85 years are included between 3 and 8 days after the stroke onset. Approximately 580 patients are to be included. The primary objective of the study is to demonstrate the superiority of at least one of the two doses of S44819 (150 or 300 mg bid) compared to placebo on top of usual care on functional recovery measured with the modified Rankin scale at 3 months. Comparisons between two doses of S44819 and placebo are assessed with ordinal logistic regression evaluating the odds of shifting from one category to the next in the direction of a better outcome at day 90. Secondary objectives include the evaluation of S44819 effects on neurological examination using the National Institute of Health Stroke Scale total score, activities of daily living using the Barthel Index total score, and cognitive performance using the Montreal Cognitive Assessment scale total score and Trail Making Test times. Safety and tolerability of the two doses of S44819 will also be analyzed. DISCUSSION: The RESTORE BRAIN study might represent the first proof of concept study of an innovative therapeutic approach that is primarily based on enhancing functional recovery after IS. TRIAL REGISTRATION: Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event, an international, multi-centre, randomized, double-blind placebo-controlled phase II study. ClinicalTrials.gov, NCT02877615; Eudract 2016-001005-16. Registered 24 August 2016.