Safety and efficacy of aripiprazole 2-month ready-to-use 960 mg: secondary analysis of outcomes in adult patients with bipolar I disorder in a randomized, open-label, parallel-arm, pivotal study

Abstract

Objective

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for administration every 2 months. A 32-week trial evaluated the safety, tolerability, and pharmacokinetics of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (BP-I) (per DSM-5 criteria). This secondary analysis evaluated the safety and efficacy of Ari 2MRTU 960 in the subpopulation of patients with BP-I.

Methods

Patients with BP-I were randomized to receive Ari 2MRTU 960 (n = 40) every 56 ± 2 days (4 injections scheduled) or aripiprazole once-monthly 400 mg (AOM 400; n = 41) every 28 ± 2 days (8 injections scheduled). Data were collected during August 2019–July 2020 across 16 US sites. Primary safety endpoints included reported adverse events (coded by the Medical Dictionary for Regulatory Activities preferred term), injection site reactions (assessments included a Visual Analog Scale [VAS] to evaluate patient-reported injection-site pain), and motoric symptoms. Secondary endpoints for efficacy included change from baseline at Week 32 in the Young Mania Rating Scale (YMRS), Montgomery–Åsberg Depression Rating Scale (MADRS), Clinical Global Impression – Bipolar Version (CGI-BP), and Subjective Well-being under Neuroleptic Treatment – Short Form (SWN-S) scores, and Clinical Global Impression – Improvement (CGI-I) at Week 32.

Results

The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (82.5% [33/40]) and AOM 400 (87.8% [36/41]; p = .5468). The most frequently reported TEAE was increased weight (Ari 2MRTU 960: 25.0% [10/40]; AOM 400: 26.8% [11/41]; p = 1). Injection-site pain was experienced by more patients in the Ari 2MRTU 960 group (25% [10/40]) versus the AOM 400 group (7.3% [3/41]; p = .0622). Mean (standard deviation [SD]) VAS scores for patient-reported injection-site pain following the last injection were 1.2 (2.07) for Ari 2MRTU 960 group and 1.3 (2.19) for AOM 400 (p = .9479) (VAS scale range 0–100 [no pain–extreme pain]). No notable improvement or decline from baseline was observed in motoric symptoms in either treatment group. Patients in both treatment groups remained clinically stable for the entire 32-week trial duration, with minimal difference between treatment groups in the least squares (LS) mean change from baseline at Week 32 in the YMRS Total (p = .8995), MADRS Total (p = .3185), and CGI-BP scores (p = .8485), and in mean CGI-I score (p = .7960). LS mean change from baseline in SWN-S score was greater for Ari 2MRTU 960 than for AOM 400 at Week 32 (p = .0169).

Conclusions

Ari 2MRTU 960 was well tolerated in patients with BP-I, with efficacy similar to AOM 400.

Trial registration

ClinicalTrials.gov identifier: NCT04030143.

Keywords:

• Long-acting injectable
• antipsychotic
• Young Mania Rating Scale
• Montgomery–Åsberg Depression Rating Scale
• Subjective Well-being under Neuroleptic Treatment – Short Form

Transparency

Declaration of funding

This work was sponsored by Otsuka Pharmaceutical Development & Commercialization Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark). The sponsors were involved in the design of the study, the collection, analysis and interpretation of data, the writing and reviewing of this article, and the decision to submit the article for publication.

Declaration of financial/other relationships

Roger S. McIntyre has received research grant support from the Canadian Institutes of Health Research, Global Alliance for Chronic Diseases, the Milken Institute and the National Natural Science Foundation of China, and speaker/consultation fees from AbbVie, Alkermes, Atai Life Sciences, Axsome Therapeutics, Bausch Health, Biogen, Boehringer Ingelheim, Eisai, Intra-Cellular Therapies, Janssen, Kris Pharma, Lundbeck, Mitsubishi Tanabe Pharma, Neumora Therapeutics, Neurocrine Biosciences, NewBridge Pharmaceuticals, Novo Nordisk, Otsuka Pharmaceutical, Pfizer, Purdue Pharma, Sage Therapeutics, Sanofi, Sunovion, Takeda Pharmaceutical Company, Viatris. Roger S. McIntyre is the CEO of Braxia Scientific Corp. Frank Larsen, Pedro Such, and Murat Yildirim are full-time employees of H. Lundbeck A/S. Jessica Madera-McDonough, Zhen Zhang, and Matthew Harlin are full-time employees of Otsuka Pharmaceutical Development & Commercialization Inc. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Matthew Harlin and Frank Larsen participated in trial conception and design. All authors were involved in data collection and/or analysis. All authors participated in the drafting or the critical review of the article; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Acknowledgements

Writing support was provided by Babette Jamieson, MSc, assisted by her colleagues at Cambridge – a Prime Global Agency (Knutsford, UK), and funded by Otsuka Pharmaceutical Development & Commercialization Inc. and H. Lundbeck A/S.

The authors would like to thank Calvin Liu for his programming support in data analysis, and Suzanne Watkin for her support in clinical management.

This is a secondary analysis of study drug safety and efficacy outcomes from study NCT04030143, in a subpopulation of patients with bipolar I disorder; results for the full study population, comprising patients with schizophrenia or bipolar I disorder, have been published in Harlin et al. CNS Drugs 2023. Data for the subpopulation of patients with schizophrenia will be reported elsewhere. Some of the data in this manuscript have previously been reported in a poster presented at the NEI Congress 2022, Colorado Springs, CO, USA, 3–6 November 2022; Poster 113.

D ata availability statement

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