A Randomized, Open-Label, Multiple-Dose, Parallel-Arm, Pivotal Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Aripiprazole 2-Month Long-Acting Injectable in Adults With Schizophrenia or Bipolar I Disorder

Abstract

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, registered on 23 July 2019).

Fig. 1

Study design. ^a Participants received overlapping oral antipsychotic treatment with the first study drug dose to ensure antipsychotic treatment continuity. No overlapping oral antipsychotic treatment was administered to participants stabilized on AOM 400; these participants could not be enrolled to the robust sampling schedule. AOM 400 aripiprazole once-monthly 400 mg, Ari 2MRTU 960 aripiprazole 2-month ready-to-use 960 mg, BP-I bipolar I disorder, ET early termination, R randomization

Fig. 2

Participant disposition. ^a Completed visit on Day 225. ^b Of the 104 participants receiving four doses of Ari 2MRTU 960, 2 participants were excluded from analysis due to dose administration outside of the permitted 2-day window, and 6 participants were excluded from analysis due to C₅₆ being outside of the collection window, or due to insufficient PK profile. ^c Of the 92 participants receiving the eighth dose of AOM 400, 1 participant was excluded from analysis due to having missed a dose, and 9 participants were excluded from analysis due to C₂₈ being outside of the collection window or due to insufficient PK profile. AE adverse event, AOM 400 aripiprazole once-monthly 400 mg, Ari 2MRTU 960 aripiprazole 2-month ready-to-use 960 mg, BP-I bipolar I disorder, C₂₈ plasma concentration of aripiprazole 28 days after AOM 400 administration, C₅₆ plasma concentration of aripiprazole 56 days after Ari 2MRTU 960 administration, PK pharmacokinetic

Fig. 3

Mean (SD) aripiprazole plasma concentrations after the fourth dose of Ari 2MRTU 960 versus the seventh and eighth doses of AOM 400 in adults with schizophrenia or BP-I. Ari 2MRTU 960 data are shown for 102 participants who received the fourth dose (sparse sampling schedule, n = 67; robust sampling schedule, n = 35). AOM 400 data are shown for 93 participants who received the seventh dose (sparse sampling schedule, n = 60; robust sampling schedule, n = 33), and for 91 participants who received the eighth dose (sparse sampling schedule, n = 58; robust sampling schedule, n = 33). Dotted line represents the estimated lower efficacy threshold of aripiprazole (95 ng/mL) [20]. AOM 400 aripiprazole once-monthly 400 mg, Ari 2MRTU 960 aripiprazole 2-month ready-to-use 960 mg, BP-I bipolar I disorder, SD standard deviation

Fig. 4

Aripiprazole concentrations following the administration of four doses of Ari 2MRTU 960 or eight doses of AOM 400 over the course of 32 weeks in adults with schizophrenia or BP-I. Data for the first dose are for participants enrolled to the robust sampling schedule only (Ari 2MRTU 960, n = 42 [Day 0–56]; AOM 400, n = 42 [Day 0–28]). Data for all other timepoints are for participants enrolled to the sparse (Ari 2MRTU 960, n = 90; AOM 400, n = 92) and robust (Ari 2MRTU 960, n = 42; AOM 400, n = 42) sampling schedules. Dotted line represents the estimated lower efficacy threshold of aripiprazole (95 ng/mL) [20]. AOM 400 aripiprazole once-monthly 400 mg, Ari 2MRTU 960 aripiprazole 2-month ready-to-use 960 mg, BP-I bipolar I disorder, SD standard deviation