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Summary Background Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine. Methods We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9–12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638. Findings Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9–12. The change from the observation period in mean number of migraine days per month during weeks 9–12 was −4·3 days (95% CI –4·8 to –3·9) with rimegepant and −3·5 days (–4·0 to –3·0) with placebo (least squares mean difference −0·8 days, 95% CI −1·46 to −0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died. Interpretation Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted. Funding Biohaven Pharmaceuticals.

Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment.In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered.A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P0.001). The most common adverse events were nausea and urinary tract infection.Treatment of a migraine attack with the oral calcitonin gene-related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).

Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine.In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual.Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p0·0001; risk difference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3 × the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2 × the upper limit of normal were reported. Treated participants reported no serious adverse events.In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns.Biohaven Pharmaceuticals.

Objective BETA was designed to evaluate the overall effectiveness of aripiprazole in patients with schizophrenia or schizoaffective disorder treated in a general psychiatry outpatient practice setting. Methods In this 8-week, multicenter, open-label study, 1599 outpatients with schizophrenia or schizoaffective disorder were randomly assigned to receive either aripiprazole (n = 1295) or another antipsychotic medication (safety control [SC] group; n = 304). Aripiprazole was initiated at 15 mg/d with the option to adjust between 10–30 mg/d. The SC medication was specifically selected for each patient by the clinician and dosed according to prescribing guidelines for that medication. The primary effectiveness measure was the Clinical Global Impression–Improvement (CGI–I) score of the aripiprazole group at study end point. Secondary measures included response rates and preference of medicine (POM) ratings by patients and caregivers. Results Sixty-five percent of aripiprazole patients completed the study. The mean aripiprazole dose at end point was 19.9 mg/d, with approximately 39% of patients starting and remaining at 15 mg/d. At end point, the mean CGI–I score of 2.77 demonstrated that aripiprazole was minimally to moderately effective; the mean CGI–I score for the SC group was 3.59 indicating minimally effective to no change. Fifty-three percent of aripiprazole patients responded to treatment (CGI–I score of 1 or 2; last-observation-carried-forward [LOCF]), and approximately 71% of patients and caregivers rated aripiprazole as better than the prestudy medication on the POM (LOCF). Incidence and severity of adverse events (AEs) were similar to those reported in double-blind, randomized, placebo-controlled aripiprazole clinical trials. The most frequent AE in the aripiprazole group was insomnia (24%). Conclusions Aripiprazole was effective for the treatment of schizophrenia and schizoaffective disorder in a general psychiatry outpatient practice setting. Overall, aripiprazole was found to be effective by the treating clinician and well accepted by patients and caregivers over the 8-week treatment course.

BackgroundDespite several treatment options, adherence to therapy is poor in patients with bipolar disorder.AimsA double-blind, controlled comparison of aripiprazole and haloperidol in patients with bipolar I disorder experiencing acute manic or mixed episodes.MethodPatients (n=347) were randomised to receive aripiprazole or haloperidol in this 12-week, multicentre study. The primary outcome measure was the number of patients in response (550% improvement from baseline in Young Mania Rating Scale score) and receiving therapy at week 12.ResultsAt week 12, significantly more patients taking aripiprazole (49. 7%) were in response and receiving therapy compared with those taking haloperidol (28. 4%; Pv. 24. 0%).ConclusionsAripiprazole showed superior levels of response and tolerability to haloperidol in the treatment of an acute manic episode for up to 12 weeks.

Background: Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). Method: This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. Results: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P

To investigate the efficacy and safety of intramuscular (IM) aripiprazole for the treatment of agitation in patients with bipolar I disorder, manic or mixed episodes. In total, 301 patients experiencing acute agitation were randomized to IM aripiprazole 9.75 mg per injection (n = 78), IM aripiprazole 15 mg per injection (n = 78), IM lorazepam 2 mg per injection (n = 70), or IM placebo (n = 75) in this double-blind multicenter study. Patients could receive up to 3 injections over 24 hours. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component score from baseline at 2 hours after first injection. Mean improvements in Positive and Negative Syndrome Scale Excited Component score at 2 hours were significantly greater with IM aripiprazole (9.75 mg, -8.7; 15 mg, -8.7) and IM lorazepam (-9.6) versus IM placebo (-5.8; P

A sub-population analysis of 325 patients with agitation (Positive and Negative Syndrome Scale Excited Component [PEC] scoreor = 15 andor = 32; score ofor = 4 onor = 2 items) associated with schizophrenia in a randomized, double-blind study investigating the efficacy and tolerability of intramuscular (IM) aripiprazole 9.75 mg, IM haloperidol 6.5 mg, or IM placebo and the transition to oral therapy.Over 24 h, patients could receive up to three IM injections; the second and third administeredor = 2 andor = 4 h, respectively, after the first, if deemed clinically necessary. Following IM treatment, oral aripiprazole or haloperidol was administered for 4 days. The primary efficacy measure was the mean change in PEC score from baseline at 2 h.At 2 h, mean improvements in PEC scores with IM aripiprazole (-8.0) were significantly greater versus IM placebo (-5.7; por = 0.01), and similar versus IM haloperidol (-8.3). Secondary efficacy measures also significantly improved with active IM treatment versus IM placebo. Continuation with oral treatment provided continued efficacy with both active treatments. The safety profiles of IM and oral aripiprazole were similar. The incidence of extrapyramidal symptom-related adverse events was 0% with IM aripiprazole, 1.6% with IM placebo and 16.5% with IM haloperidol.Intramuscular aripiprazole is effective in patients with acute agitation associated with schizophrenia, comparable to IM haloperidol, and enables convenient transfer to oral aripiprazole therapy.

This double-blind, placebo-controlled study investigated the efficacy and safety of intramuscular (IM) aripiprazole and IM haloperidol for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder. Four-hundred and forty-eight patients were randomized (2:2:1 ratio) to IM aripiprazole 9.75 mg, IM haloperidol 6.5 mg, or IM placebo. Patients could receive up to three injections over the first 24 h, with second and third injections administered ≥2 and ≥4 h, respectively, after the first if deemed clinically necessary. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component (PEC) score from baseline to 2 h. Mean improvement in PEC at 2 h was significantly greater for IM aripiprazole (−7.27) vs placebo (−4.78; p

BACKGROUND Aripiprazole is a novel antipsychotic for the management of schizophrenia. This study investigated the efficacy, safety, and tolerability of aripiprazole in preventing relapse in adult chronic schizophrenia patients experiencing ongoing stable symptomatology. METHOD In this 26-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center study, 310 patients with DSM-IV schizophrenia (mean Positive and Negative Syndrome Scale [PANSS] total score = 82) were randomly assigned to receive a once-daily fixed dose of aripiprazole, 15 mg, or placebo. The primary outcome measure was time to relapse following randomization. Secondary objectives were to assess the efficacy, safety, and tolerability of aripiprazole, 15 mg, compared with placebo, in the study population. The study was conducted between Dec. 21, 2000, and Aug. 20, 2001. RESULTS The time to relapse following randomization was significantly (p < .001) longer for aripiprazole compared with placebo. More patients relapsed with placebo (N = 85; 57%) than aripiprazole (N = 50; 34%); the relative risk of relapse for the aripiprazole group was 0.59 (p < .001). Aripiprazole was significantly superior to placebo from baseline to endpoint in PANSS total, PANSS positive, PANSS-derived Brief Psychiatric Rating Scale, and Clinical Global Impressions-Severity of Illness scale (CGI-S) scores and demonstrated significantly better mean Clinical Global Impressions-Global Improvement scale scores (p < or = .01 for all comparisons except CGI-S: .01 < p < or = .05). Aripiprazole was well tolerated, with no evidence of marked sedation and no evidence of hyperprolactinemia or prolonged heart rate-corrected QT interval (QTc). Extrapyramidal symptoms were comparable in the aripiprazole and placebo groups. Modest mean weight loss at endpoint was evident in both groups. CONCLUSION Aripiprazole, 15 mg once daily, is an effective, well-tolerated treatment for prevention of relapse in patients with chronic, stable schizophrenia.

Aripiprazole is a novel antipsychotic with a unique mechanism of action. Presented here is a pooled analysis of safety and tolerability data from all completed short-term, placebo-controlled trials in schizophrenia from the aripiprazole clinical development program. Data were analyzed from five 4- to 6-week double-blind multicenter studies of patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder randomized to aripiprazole (n=932), placebo (n=416), or haloperidol (n=201). Daily aripiprazole doses ranged from 2 to 30 mg. Safety assessments included adverse event (AE) reports, EPS scales, ECGs, weight, and prolactin, glucose and cholesterol levels. Aripiprazole was well tolerated, with similar AE incidence rates to placebo, and lower rates than haloperidol for akathisia, extrapyramidal syndrome and somnolence. Objective EPS assessments demonstrated no significant differences between aripiprazole and placebo on Simpson-Angus Scale (SAS) scores, no dose-dependent effects on Barnes Akathisia scores, and significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores from baseline vs. placebo (p

Background: Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. This multicenter trial examined the efficacy, safety, and tolerability of aripiprazole in patients with acute exacerbation of schizophrenia or schizoaffective disorder. Methods: In this 4-week double-blind study, 404 patients were randomized to 20 mg/d (n=101) or 30 mg/d (n=101)ofaripiprazole,placebo(n=103),or6mg/dofrisperidone (n=99). Efficacy assessments included Positive and Negative Syndrome Scale (PANSS) scores and ClinicalGlobalImpressionscores.Safetyandtolerabilityevaluations included extrapyramidal symptoms and effects on weight, prolactin, and corrected QT (QTc) interval. Results: Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/d) were significantly better than placebo on all efficacy measures. Separation from placebo occurred at week 1 for PANSS total and positive scores with aripiprazole and risperidone and for PANSS negative scores with aripiprazole. There were no significant differences between aripiprazole and placebo in mean change from baseline in the extrapyramidal symptom rating scales. Meanprolactinlevelsdecreasedwitharipiprazolebutsignificantlyincreased5-foldwithrisperidone.Meanchange in QTc interval did not differ significantly from placebo with any active treatment group. Aripiprazole and risperidone groups showed a similar lowincidence of clinically significant weight gain. Conclusions: Aripiprazole is effective, safe, and well toleratedforthepositiveandnegativesymptomsinschizophreniaandschizoaffectivedisorder.Itisthefirstnon-D2receptorantagonistwithclearantipsychoticeffectsandrepresents a novel treatment development for psychotic disorders. Arch Gen Psychiatry. 2003;60:681-690