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

Figures & data

Figure 1. Patient disposition. ^aIncludes patients with schizophrenia or BP-I. Data for the subpopulation of patients with schizophrenia will be reported elsewhere¹⁸. ^bCompleted visit on Day 225. Abbreviations. 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.

Table 1. Demographics and baseline disease characteristics in patients with BP-I.

Characteristic	Ari 2MRTU 960 (n = 40)	AOM 400 (n = 41)
Age, years	47.2 (11.8)	44.8 (11.3)
≥45 years, n (%)	26 (65.0)	25 (61.0)
Age at diagnosis, years	31.3 (13.6)	32.3 (13.3)
Female, n (%)	15 (37.5)	22 (53.7)
BMI, kg/m^2	28.1 (4.1)	27.2 (4.9)
Race, n (%)
White	18 (45.0)	21 (51.2)
Black or African American	19 (47.5)	18 (43.9)
Asian	3 (7.5)	2 (4.9)
Prior aripiprazole treatment, n (%)^a
Oral aripiprazole	17 (42.5)	13 (31.7)
AOM 400	1 (2.5)	0 (0.0)
Prior non-aripiprazole treatment, n (%)^a
Lurasidone hydrochloride	1 (2.5)	3 (7.3)
Olanzapine	3 (7.5)	4 (9.8)
Quetiapine	5 (12.5)	5 (12.2)
Quetiapine fumarate	11 (27.5)	13 (31.7)
Risperidone	9 (22.5)	5 (12.2)
Other	16 (40.0)	13 (31.7)
Mood stabilizers taken at baseline and during the treatment phase, n (%)^b
Valproate semisodium	8 (20.0)	6 (14.6)
Lamotrigine	1 (2.5)	3 (7.3)
Lithium	1 (2.5)	1 (2.4)
Lithium carbonate	1 (2.5)	1 (2.4)
Valproic acid	0 (0.0)	1 (2.4)
YMRS Total score	6.7 (7.3)	9.4 (8.2)
MADRS Total score	10.9 (9.4)	13.5 (9.7)
CGI-BP severity score (overall illness)	2.4 (1.1)	2.8 (1.2)
SWN-S Total score	92.1 (17.2)^c	88.6 (18.6)^d

Data are mean (SD), unless stated otherwise. p-values for between-group differences, calculated using a t-test (for continuous variables) or a Fisher’s exact test (for categorical variables), were >0.05 for all variables. The p-values are not reported here, since in a randomized trial, any between-group differences at baseline are necessarily due to chance, and significance tests evaluating differences between treatment groups at baseline do not assess whether any observed imbalance in variables between the groups or lack thereof might have affected the results of the trial²⁹.

Abbreviations. AOM 400, aripiprazole once-monthly 400 mg; Ari 2MRTU 960, aripiprazole 2-month ready-to-use 960 mg; BMI, body mass index; BP-I, bipolar I disorder; CGI-BP, Clinical Global Impression – Bipolar Version; MADRS, Montgomery–Åsberg Depression Rating Scale; SD, standard deviation; SWN-S, Subjective Well-being under Neuroleptic Treatment – Short Form; YMRS, Young Mania Rating Scale.

^aSome patients were receiving more than one antipsychotic medication prior to the start of the study.

^bContinued use of concomitant mood stabilizer and antidepressant treatment was allowed during the study.

^cn = 37.

^dn = 38.

Table 2. Summary of TEAEs in patients with BP-I.

	Ari 2MRTU 960 (n = 40)	AOM 400 (n = 41)	p-value
Patients with TEAEs^a	33 (82.5)	36 (87.8)	.5468
Patients with serious TEAEs	1 (2.5)	3 (7.3)	.6156
Patients discontinuing due to TEAE	1 (2.5)	3 (7.3)	.6156
TEAEs occurring in ≥2% of patients in any treatment group
Blood and lymphatic system disorders (any)	0 (0.0)	1 (2.4)	1
Neutropenia	0 (0.0)	1 (2.4)	1
Eye disorders (any)	1 (2.5)	1 (2.4)	1
Vision blurred	1 (2.5)	1 (2.4)	1
Gastrointestinal disorders (any)	12 (30.0)	14 (34.1)	.8127
Toothache	2 (5.0)	6 (14.6)	.2640
Diarrhea	5 (12.5)	1 (2.4)	.1088
Constipation	4 (10.0)	3 (7.3)	.7123
Abdominal discomfort	2 (5.0)	2 (4.9)	1
Nausea	2 (5.0)	1 (2.4)	.6156
Dyspepsia	1 (2.5)	0 (0.0)	1
Vomiting	1 (2.5)	0 (0.0)	1
Dental discomfort	0 (0.0)	1 (2.4)	1
Flatulence	0 (0.0)	1 (2.4)	1
Gingival swelling	0 (0.0)	1 (2.4)	1
General disorders and administration site conditions (any)	12 (30.0)	5 (12.2)	.0600
Injection-site pain	10 (25.0)	3 (7.3)	.0622
Influenza like illness	1 (2.5)	2 (4.9)	1
Fatigue	1 (2.5)	0 (0.0)	1
Injection site mass	1 (2.5)	0 (0.0)	1
Edema peripheral	0 (0.0)	1 (2.4)	1
Infections and infestations (any)	7 (17.5)	5 (12.2)	.5468
Sinusitis	2 (5.0)	0 (0.0)	.6156
Nasopharyngitis	1 (2.5)	2 (4.9)	1
Upper respiratory tract infection	1 (2.5)	0 (0.0)	1
Bacterial vaginosis	1 (2.5)	0 (0.0)	1
Cellulitis	1 (2.5)	0 (0.0)	1
Infected bite	0 (0.0)	1 (2.4)	1
Influenza	1 (2.5)	0 (0.0)	1
Localized infection	0 (0.0)	1 (2.4)	1
Periodontitis	0 (0.0)	1 (2.4)	1
Injury, poisoning and procedural complications (any)	2 (5.0)	1 (2.4)	.6156
Hand fracture	1 (2.5)	0 (0.0)	1
Nail injury	1 (2.5)	0 (0.0)	1
Tooth fracture	1 (2.5)	0 (0.0)	1
Skin laceration	0 (0.0)	1 (2.4)	1
Investigations (any)	11 (27.5)	15 (36.6)	.4769
Weight increased	10 (25.0)	11 (26.8)	1
Weight decreased	0 (0.0)	2 (4.9)	1
Blood prolactin increased	1 (2.5)	0 (0.0)	1
Blood triglycerides increased	1 (2.5)	0 (0.0)	1
Liver function test increased	1 (2.5)	0 (0.0)	1
Alanine aminotransferase increased	0 (0.0)	1 (2.4)	1
Aspartate aminotransferase increased	0 (0.0)	1 (2.4)	1
Blood creatine phosphokinase increased	0 (0.0)	1 (2.4)	1
Hepatic enzyme increased	0 (0.0)	1 (2.4)	1
Metabolism and nutrition disorders (any)	4 (10.0)	3 (7.3)	.7123
Decreased appetite	0 (0.0)	1 (2.4)	1
Diabetes mellitus	1 (2.5)	0 (0.0)	1
Hypercalcemia	1 (2.5)	0 (0.0)	1
Hyperglycemia	1 (2.5)	0 (0.0)	1
Hyperuricemia	1 (2.5)	0 (0.0)	1
Increased appetite	0 (0.0)	2 (4.9)	1
Musculoskeletal and connective tissue disorders (any)	6 (15.0)	4 (9.8)	.5187
Back pain	2 (5.0)	1 (2.4)	.6156
Arthralgia	1 (2.5)	1 (2.4)	1
Neck pain	1 (2.5)	1 (2.4)	1
Fibromyalgia	1 (2.5)	0 (0.0)	1
Joint stiffness	1 (2.5)	0 (0.0)	1
Joint swelling	1 (2.5)	0 (0.0)	1
Muscle spasms	1 (2.5)	0 (0.0)	1
Musculoskeletal stiffness	1 (2.5)	0 (0.0)	1
Trismus	1 (2.5)	0 (0.0)	1
Pain in extremity	0 (0.0)	1 (2.4)	1
Nervous system disorders (any)	17 (42.5)	8 (19.5)	.0456
Akathisia	5 (12.5)	5 (12.2)	1
Headache	4 (10.0)	3 (7.3)	.7123
Dyskinesia	3 (7.5)	1 (2.4)	.3593
Somnolence	3 (7.5)	0 (0.0)	.3593
Dizziness	1 (2.5)	1 (2.4)	1
Extrapyramidal disorder	1 (2.5)	1 (2.4)	1
Tremor	1 (2.5)	1 (2.4)	1
Disturbance in attention	1 (2.5)	0 (0.0)	1
Hypoesthesia	1 (2.5)	0 (0.0)	1
Sciatica	1 (2.5)	0 (0.0)	1
Sedation	1 (2.5)	0 (0.0)	1
Tension headache	1 (2.5)	0 (0.0)	1
Psychiatric disorders (any)	13 (32.5)	11 (26.8)	.6319
Anxiety	5 (12.5)	5 (12.2)	1
Insomnia	2 (5.0)	3 (7.3)	1
Depressive symptom	2 (5.0)	2 (4.9)	1
Bipolar disorder	2 (5.0)	0 (0.0)	.6156
Depression	1 (2.5)	2 (4.9)	1
Agitation	1 (2.5)	0 (0.0)	1
Depressed mood	1 (2.5)	0 (0.0)	1
Hallucination, auditory	1 (2.5)	0 (0.0)	1
Psychotic disorder	1 (2.5)	0 (0.0)	1
Restlessness	1 (2.5)	0 (0.0)	1
Respiratory, thoracic and mediastinal disorders (any)	1 (2.5)	1 (2.4)	1
Chronic obstructive pulmonary disease	1 (2.5)	0 (0.0)	1
Oropharyngeal pain	0 (0.0)	1 (2.4)	1
Skin and subcutaneous tissue disorders (any)	0 (0.0)	2 (4.9)	1
Dermatitis contact	0 (0.0)	1 (2.4)	1
Erythema	0 (0.0)	1 (2.4)	1
Vascular disorders (any)	0 (0.0)	1 (2.4)	1
Hypertension	0 (0.0)	1 (2.4)	1

Data are n (%). Data are shown for the safety sample. p-values for between-group differences were calculated using Fisher’s exact test. Numbers of patients with TEAEs, numbers of patients with serious TEAEs, numbers of patients discontinuing due to TEAEs, and TEAEs occurring in ≥5% of patients with BP-I have previously been published by Harlin et al.¹⁷.

Abbreviations. AOM 400, aripiprazole once-monthly 400 mg; Ari 2MRTU 960, aripiprazole 2-month ready-to-use 960 mg; BP-I, bipolar I disorder; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event.

^aMultiple occurrences of a TEAE were counted once per MedDRA preferred term.

Figure 2. Efficacy outcomes at Week 32. Data shown are from the efficacy analysis sample (MMRM analysis). Mean (SD) YMRS Total score at baseline was 6.6 (7.4) in the Ari 2MRTU 960 group and 9.4 (8.3) in the AOM 400 group. Mean (SD) MADRS Total score at baseline was 11.0 (9.5) in the Ari 2MRTU 960 group and 13.0 (9.3) in the AOM 400 group. Mean (SD) CGI-BP score at baseline was 2.3 (1.2) in the Ari 2MRTU 960 group and 2.8 (1.2) in the AOM 400 group. Mean (SD) SWN-S score at baseline was 91.9 (17.3) in the Ari 2MRTU 960 group and 89.2 (18.5) in the AOM 400 group. ^ap-values for between-group comparison were derived from an MMRM analysis with fixed effects of treatment, pharmacokinetic sampling schedule for determining the concentration of aripiprazole in patients’ plasma, week, treatment-by-week interaction, and baseline-by-week interaction as covariate. Abbreviations. AOM 400, aripiprazole once-monthly 400 mg; Ari 2MRTU 960, aripiprazole 2-month ready-to-use 960 mg; CGI-BP, Clinical Global Impression – Bipolar Version; LS, least squares; MADRS, Montgomery–Åsberg Depression Rating Scale; MMRM, mixed model for repeated measures; SD, standard deviation; SE, standard error; SWN-S, Subjective Well-being under Neuroleptic Treatment – Short Form; YMRS, Young Mania Rating Scale.

Table 3. Efficacy outcomes at Week 32 in patients with BP-I.

Measure	Ari 2MRTU 960		AOM 400		p value
	n	Score	n	Score
YMRS Total score
Baseline, mean (SD)	39	6.6 (7.4)	40	9.4 (8.3)	–
Week 32, mean (SD)	29	2.8 (3.4)	30	4.4 (4.2)	–
Change from baseline at Week 32,  LS mean (SE)	29	−4.8 (0.7)	30	−5.0 (0.7)	.8995
MADRS Total score
Baseline, mean (SD)	39	11.0 (9.5)	40	13.0 (9.3)	–
Week 32, mean (SD)	29	6.2 (7.8)	30	9.0 (9.4)	–
Change from baseline at Week 32,  LS mean (SE)	29	−5.7 (1.5)	30	−3.6 (1.5)	.3185
CGI-BP score
Baseline, mean (SD)	39	2.3 (1.2)	40	2.8 (1.2)	–
Week 32, mean (SD)	29	1.9 (1.0)	30	2.3 (1.1)	–
Change from baseline at Week 32,  LS mean (SE)	29	−0.5 (0.2)	30	−0.5 (0.2)	.8485
SWN-S Total score
Baseline, mean (SD)	36	91.9 (17.3)	37	89.2 (18.5)	–
Week 32, mean (SD)	27	102.2 (16.1)	30	94.2 (14.5)	–
Change from baseline at Week 32,  LS mean (SE)	27	12.1 (2.8)	30	2.9 (2.8)	.0169
CGI-I score at Week 32, mean (SD)	35	3.1 (1.2)	35	3.2 (1.5)	.7960

Baseline data, data at Week 32 and data for the change from baseline at Week 32 for YMRS Total score, MADRS Total score, CGI-BP score, and SWN-S Total score are from the MMRM analysis (efficacy sample). Data for the CGI-I score at Week 32 are from the LOCF analysis (efficacy sample) and have previously been published by Harlin et al.¹⁷

Abbreviations. AOM 400, aripiprazole once-monthly 400 mg; Ari 2MRTU 960, aripiprazole 2-month ready-to-use 960 mg; BP-I, bipolar I disorder; CGI-BP, Clinical Global Impression – Bipolar Version; CGI-I, Clinical Global Impression – Improvement; LOCF, last observation carried forward; LS, least squares; MADRS, Montgomery–Åsberg Depression Rating Scale; MMRM, mixed model for repeated measures; SD, standard deviation; SE, standard error; SWN-S, Subjective Well-being under Neuroleptic Treatment – Short Form; YMRS, Young Mania Rating Scale.

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