Background Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for gluteal administration every 2 months, currently being investigated for the treatment of schizophrenia and bipolar I disorder (BP-I). The objectives of this trial were to evaluate the safety and tolerability of Ari 2MRTU 960, and the similarity of aripiprazole plasma concentrations following administration of Ari 2MRTU 960 or aripiprazole once-monthly 400 mg (AOM 400), in adults with schizophrenia or BP-I. Methods This was a 32-week open-label study. Eligible participants were randomized 1:1 to receive Ari 2MRTU 960 every 56 ± 2 days (four injections scheduled) or AOM 400 every 28 ± 2 days (eight injections scheduled). Participants received overlapping oral antipsychotic treatment with the first administration of study drug (there was no oral overlap for participants stabilized on AOM 400). Safety, tolerability, and pharmacokinetics (PK) were evaluated throughout the study. Primary safety endpoints included reported adverse events, injection site reactions, and extrapyramidal symptoms. Primary PK endpoints were plasma concentration of aripiprazole 56 days after the fourth dose of Ari 2MRTU 960 and 28 days after the eighth dose of AOM 400, and area under the concentration–time curve (AUC) from Day 0 to 56 postdose after the fourth dose of Ari 2MRTU 960, or AUC from Day 0 to 28 after the seventh and eighth doses of AOM 400. Results Of the 266 participants enrolled (schizophrenia, n = 185; BP-I, n = 81), 132 were randomized to receive Ari 2MRTU 960 and 134 were randomized to receive AOM 400. The majority (66.2%) of participants were male; 72.9% were Black or African American, and mean age was 47.3 years; demographic characteristics and baseline disease characteristics were generally well balanced between groups. Study completion rate was 77.3% in the Ari 2MRTU 960 group and 68.7% in the AOM 400 group. The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (71.2%) and AOM 400 (70.9%). The most frequently reported TEAEs were increased weight (Ari 2MRTU 960: 22.7%; AOM 400: 20.9%) and injection-site pain (Ari 2MRTU 960: 18.2%; AOM 400: 9.0%). The geometric means ratio (GMR) of aripiprazole plasma concentrations on the last day following the final dosing for Ari 2MRTU 960 versus AOM 400 was 1.011 (90% confidence interval [CI] 0.893–1.145), and the GMR of aripiprazole plasma exposure (area under the concentration–time curve) over the fourth Ari 2MRTU 960 dosing interval versus the seventh and eighth AOM 400 dosing intervals was 1.006 (90% CI 0.851–1.190). Conclusions Ari 2MRTU 960 was generally well tolerated in adults with schizophrenia or BP-I, with a safety profile comparable with that of AOM 400, and aripiprazole exposure equivalent to that with AOM 400 (ClinicalTrials.gov identifier: NCT04030143...

Purpose/Background: Centanafadine is an inhibitor of norepinephrine, dopamine, and serotonin reuptake transporters under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD).Methods/Procedures: Two phase 3 randomized, double-blind, placebocontrolled, parallel-group studies of 200 mg/d or 400 mg/d centanafadine sustained-release tablets versus placebo included adults (18-55 years of age) with a diagnosis of ADHD. The primary and key secondary efficacy endpoints were the change from baseline at day 42 in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score and the Clinical Global Impression-Severity of Illness Scale, respectively. Findings/Results: Subjects randomized in study 1 (centanafadine 200 mg/d, n = 149; centanafadine 400 mg/d, n = 149; placebo, n = 148) and study 2 (centanafadine 200 mg/d, n = 145; centanafadine 400 mg/d, n = 143; placebo, n = 142) had moderate to severe ADHD (mean AISRS total score, 38.7 [SD, 6.8] across both studies). At day 42, statistically significant leastsquares mean differences in AISRS total score were observed in favor of centanafadine versus placebo in study 1 (200 mg/d: −3.16, P = 0.019; 400 mg/d: −2.74, P = 0.039) and study 2 (200 mg/d: −4.01, P = 0.002; 400 mg/d: −4.47, P = 0.001). Effect sizes versus placebo were −0.28 for 200 mg/d and −0.24 for 400 mg/d in study 1 and −0.37 for 200 mg/d and −0.40 for 400 mg/d in study 2. The overall rate of treatment-emergent adverse events (TEAEs) was low, but there was a small increase in TEAE occurrence with increasing dose. Incidences of serious TEAEs and abuse potential-related AEs were low. Implications/Conclusions: These are the first large-scale studies to demonstrate the efficacy and safety profiles of 200 mg/d and 400 mg/d centanafadine in adults with ADHD.

IntroductionAripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months, intended for the treatment of schizophrenia and maintenance monotherapy treatment of bipolar I disorder (BP-I). This 32-week trial evaluated the safety, tolerability, and pharmacokinetic profile of multiple-dose administration of Ari 2MRTU 960 in clinically stable adult patients with a diagnosis of schizophrenia or BP-I, versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the treatment of schizophrenia and maintenance monotherapy treatment of BP-I).MethodsThis was an open-label, multiple-dose, randomized, parallel-arm trial conducted at 16 sites in the US. Patients were randomized to receive Ari 2MRTU 960 every 56±2 days (n=132) or AOM 400 every 28±2 days (n=134). The primary objective was to establish the similarity of aripiprazole concentrations on the last day of the dosing interval, as well as exposure during the dosing interval (area under the concentration-time curve [AUC]), between Ari 2MRTU 960 and AOM 400 following multiple doses. It was pre-specified that the lower bound of the 90% confidence interval (CI) of the geometric means ratio (GMR) for these parameters must be >0.8.ResultsIn the Ari 2MRTU 960 group, 102 patients (77.3%) completed the study; in the AOM 400 group, 92 patients (68.7%) completed the study. The GMR of C56 for Ari 2MRTU 960 to C28 for AOM 400 was 1.011 (90% CI: 0.893, 1.145). The GMR (90% CI) of AUC0–56 for Ari 2MRTU 960 to AUC0–28 for AOM 400 was 1.006 (90% CI: 0.851, 1.190). Mean (standard deviation) maximum aripiprazole plasma concentration was 342 (157) ng/ml after the fourth Ari 2MRTU 960 dose and 344 (212) ng/ml after the eighth AOM 400 dose.ConclusionPharmacokinetic parameters were similar between Ari 2MRTU 960 and AOM 400.FundingOtsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).

BackgroundAripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months. This 32-week trial evaluated the safety, pharmacokinetics, and efficacy of multiple-dose administration of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (BP-I), versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole [indication varies by country]). Safety and efficacy outcomes in the subpopulation of patients with schizophrenia are reported here.MethodsPatients with schizophrenia were randomized to receive Ari 2MRTU 960 every 56±2 days or AOM 400 every 28±2 days. Safety and tolerability assessments included adverse event (AE) reporting, Visual Analogue Scale [VAS] scores (scale range: 0–100) for patient-reported injection site pain, and extrapyramidal symptom (EPS) monitoring. Efficacy was evaluated at Week 32 using mean (standard deviation [SD]) Clinical Global Impression – Improvement (CGI-I) score, and mean (SD) change from baseline in Clinical Global Impression – Severity (CGI-S) score, Subjective Well-being under Neuroleptic Treatment – Short Form [SWN-S] Total score, and Positive and Negative Syndrome Scale (PANSS) Total score.ResultsStudy completion rate was 79.3% (73/92 patients) in the Ari 2MRTU 960 group and 67.7% (63/93 patients) in the AOM 400 group. Demographics and disease characteristics were well balanced between groups at baseline (mean [SD] PANSS Total score: Ari 2MRTU 960, 62.0 [13.5]; AOM 400, 61.8 [13.5]; mean (SD) CGI-S score: Ari 2MRTU 960, 3.3 [0.9]; AOM 400, 3.1 [0.9]). Treatment-emergent AE (TEAE) incidence was 66.3% with Ari 2MRTU 960 and 63.4% with AOM 400. The most frequent TEAEs were increased weight (Ari 2MRTU 960, 21.7%; AOM 400, 18.3%) and injection site pain (Ari 2MRTU 960, 15.2%; AOM 400, 9.7%). Mean (SD) VAS score for pain after last injection was 1.5 (4.58) with Ari 2MRTU 960 and 1.3 (2.79) with AOM 400. Minimal change was seen in EPS in either group. At Week 32, mean (SD) CGI-I score was similar between groups (Ari 2MRTU 960, 3.5 [1.0]; AOM 400, 3.6 [0.9]). Minimal change from baseline was seen at Week 32 in CGI-S score and SWN-S Total score. There was no clinically meaningful difference between the groups for PANSS Total score (difference of least squares mean change from baseline [95% confidence interval]: -0.9 [-3.5, 1.8]; p=0.5154).ConclusionsIn patients with schizophrenia, administration of Ari 2MRTU 960, as compared with AOM 400, was generally well tolerated, and clinical stability was maintained during the study.FundingOtsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).

BackgroundAripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months. This 32-week trial evaluated the safety, pharmacokinetics, and efficacy of multiple-dose administration of Ari 2MRTU 960 in clinically stable adults with schizophrenia or BP-I, versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole and maintenance monotherapy treatment of BP-I [indication varies by country]). Safety and efficacy outcomes in the subpopulation of patients with BP-I are reported here.MethodsPatients with BP-I were randomized to receive Ari 2MRTU 960 every 56±2 days or AOM 400 every 28±2 days. Safety and tolerability assessments included adverse event (AE) reporting, Visual Analogue Scale (VAS) scores (scale range: 0–100) for patient-reported injection site pain, and extrapyramidal symptom (EPS) monitoring. Efficacy was assessed at Week 32 by Clinical Global Impression – Improvement (CGI-I), Clinical Global Impression – Bipolar Version (CGI-BP), Subjective Well-being under Neuroleptic Treatment – Short Form (SWN-S), Montgomery–Åsberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS).ResultsStudy completion rate was 72.5% (29/40 patients) in the Ari 2MRTU 960 group and 70.7% (29/41 patients) in the AOM 400 group. Demographics and baseline disease characteristics were generally well balanced between treatment groups. Treatment-emergent AE (TEAE) incidence was 82.5% with Ari 2MRTU 960 and 87.8% with AOM 400. The most frequent TEAEs were increased weight (Ari 2MRTU 960, 25.0%; AOM 400, 26.8%) and injection site pain (Ari 2MRTU 960, 25.0%; AOM 400, 7.3%). Mean (standard deviation [SD]) VAS score for pain after last injection was 1.2 (2.07) with Ari 2MRTU 960 and 1.3 (2.19) with AOM 400. Minimal change was seen in EPS in either group. At Week 32, mean (SD) CGI-I score was 3.1 [1.2] with Ari 2MRTU 960 and 3.2 [1.5] with AOM 400, and there was minimal mean (SD) change from baseline in CGI-BP score (Ari 2MRTU 960, -0.2 [1.0]; AOM 400, -0.6 [1.2]). Mean (SD) change from baseline in SWN-S Total score was 10.3 (16.1) with Ari 2MRTU 960 and 3.4 (21.4) with AOM 400. There was no clinically meaningful difference between the groups in MADRS Total score or YMRS Total score (difference of least squares mean change from baseline [95% confidence interval]: MADRS Total score -2.1 [-6.3, 2.1], p=0.3185; YMRS Total score 0.1 [-1.8, 2.1], p=0.8995).ConclusionsIn patients with BP-I, Ari 2MRTU 960 was generally well tolerated, and clinical stability was maintained during the study.FundingOtsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).