Steady-state Bioequivalence Study of Aripiprazole for Injection in Patients With Schizophrenia.

A Randomized, Open-label, Two-period, Crossover, Steady-state Bioequivalence Study of Aripiprazole for Injection Following Multiple Dosing in Patients With Schizophrenia

The primary objective of this study is to evaluate the bioequivalence of aripiprazole for injection (Test product, 400 mg) compared with Abilify Maintena® (Reference product, 400 mg) at steady state in patients with schizophrenia.his is a multi-center, randomized, open-label, two-period, crossover study. Approximately 116 clinically stable patients will be enrolled and randomly assigned to one of two treatment sequences: Sequence A (Test-Reference) or Sequence B (Reference-Test). In each 141-day study period, participants will receive five injections of either the test or reference product at 28-day intervals to achieve steady-state plasma concentrations. Bioequivalence, safety and tolerability of the study drug will be assessed in this study.

Purpose: The primary objective of this study is to evaluate the steady-state bioequivalence between Aripiprazole for Injection (400 mg) manufactured by CSPC Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd. (Test product) and Abilify Maintena® (400 mg) manufactured by Otsuka Pharmaceutical (Reference product) in Chinese patients with stable schizophrenia.

Methods: This is a multicenter, randomized, open-label, two-period, crossover, multiple-dose,steady-state bioequivalence study. Approximately 116 eligible patients with stable schizophrenia will be randomly assigned to one of two treatment sequences (Test-Reference or Reference-Test). In each period, subjects will receive five intramuscular injections of either the Test or Reference product (400 mg) at 28-day intervals to ensure that steady-state blood concentrations are achieved by the fourth dose.

Primary Endpoints: Pharmacokinetic (PK) samples will be collected to determine the steady-state maximum plasma concentration (Cmax,ss) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCτ,ss).

Safety: The safety and tolerability of both formulations will also be monitored and compared throughout the trial.

Inclusion Criteria:

• 1. Aged 18 to 65 years (inclusive), male or female.
• 2. Patients diagnosed with schizophrenia according to ICD-10 criteria, with a Positive and Negative Syndrome Scale (PANSS) total score ≤ 70, judged as clinically stable for at least 28 days prior to screening (no medication changes or hospitalization due to condition changes).
• 3. Receiving treatment with ≤ 2 other oral antipsychotic medications, which must have been at a stable dose for ≥ 14 days before the first study injection (excluding prohibited medications).
• 4. Body weight ≥ 45 kg for females and ≥ 50 kg for males; Body Mass Index (BMI) between 18.5 and 35.0 kg/m² (inclusive).
• 5. Subject or partner has no pregnancy plan and agrees to use effective non-drug contraception during the study and for six months after the last dose.
• 6. Subjects and their legal guardians voluntarily sign the Informed Consent Form (ICF) and are able to comply with all study requirements.

Exclusion Criteria:

• 1.Diagnosis of any psychiatric disorder other than schizophrenia according to ICD-10 criteria.
• 2.History or presence of clinically significant cardiovascular, hepatic, renal, gastrointestinal, psychiatric, or neurological diseases that, in the investigator's judgment, would affect participation in the study.
• 3.Patients with Parkinson's disease, Lewy body dementia, or dementia-related psychosis.
• 4.History or presence of Neuroleptic Malignant Syndrome (NMS).
• 5.History or presence of epilepsy or convulsive disorders (except childhood febrile seizures), or a history of stroke or transient ischemic attack (TIA) within one year before signing the Informed Consent Form (ICF).
• 6.Concurrent tardive dyskinesia (or history) or severe akathisia.
• 7.Esophageal motility dysfunction or dysphagia with a potential risk of aspiration pneumonia.
• 8.Cardiovascular Risks: Congenital long QT syndrome; presence of uncontrolled or significant cardiovascular disease, including NYHA Class II or higher heart failure, unstable angina, myocardial infarction, or significant arrhythmia/frequent ventricular premature beats within 6 months before the first dose; QTcF > 450 ms in males or > 470 ms in females; presence of risk factors for Torsades de Pointes or sudden death (such as bradycardia, clinically significant hypokalemia, or current use of QTc-prolonging medications; excluding bradycardia judged by the investigator to be risk-controllable and stable after treatment, corrected hypokalemia, or instances where QTc-prolonging medications are discontinued or evaluated as acceptable for stable use) or other clinically significant ECG abnormalities judged by the investigator as potentially affecting subject safety or interfering with study participation.
• 9.Blood Pressure Abnormalities: Poorly controlled hypertension (SBP > 160 mmHg and/or DBP > 100 mmHg after stable antihypertensive treatment); symptomatic hypotension; or orthostatic hypotension (SBP drop ≥ 20 mmHg or DBP drop ≥ 10 mmHg within 3 minutes of standing during screening or baseline).
• 10.Glycosylated hemoglobin (HbA1c) level ≥ 7% at screening or baseline.
• 11.Laboratory Abnormalities: 1) TBiL > 1.5 × ULN, or AST/ALT > 2 × ULN; 2) CLcr < 90 mL/min; 3) WBC < 3 × 10⁹/L, Neutrophils < 1.5 × 10⁹/L, Platelets < 75 × 10⁹/L, RBC < 3.0 × 10¹²/L, or Hemoglobin < 100 g/L.
• 12.Positive results for HBsAg, HCV-Ab, HIV-Ab, or Syphilis-Ab that, in the investigator's judgment, affect study participation.
• 13.Severe Suicide Risk: 1) Positive response to item 4 or 5 of "suicidal ideation" on C-SSRS within the past 6 months; 2) History of suicidal behavior within the past 6 months; or 3) Judged by the investigator to have a severe suicide risk.
• 14.Received electroconvulsive therapy (ECT) or invasive psychiatric treatment within 28 days before signing the ICF.
• 15.History of Blood Loss: Blood loss ≥ 400 mL within 3 months or ≥ 200 mL within 1 month before signing the ICF.
• 16.Major surgery within 3 months before signing the ICF, or planned surgery during the study or within one month after study completion.
• 17.Other Clinical Studies: Participation in any other drug clinical study within one month before the first dose (except for aripiprazole BE studies).
• 18.Long-acting Injectable (LAI) History: Prior treatment with non-aripiprazole LAIs where the interval since the last dose is shorter than the labeled dosing interval of that LAI; or a requirement for other LAIs during the study.
• 19.Medication Contraindications: Use of Chlorpromazine or Thioridazine within 28 days before the first dose; or use of strong/moderate CYP3A4 or CYP2D6 inhibitors or inducers within 14 days or five half-lives (whichever is longer).
• 20.Consumption of foods or beverages rich in xanthines, grapefruit, or caffeine within 48 hours before the first dose, or other special diets that could affect drug pharmacokinetics.
• 21.History of drug abuse, drug usage, or positive drug screening within one year before signing the ICF.
• 22.Chronic Alcohol Consumption: Males > 14 units/week, females > 7 units/week (1 unit ≈ 10g pure alcohol).
• 23.History of needle phobia or blood phobia judged by the investigator to be clinically significant.
• 24.Known or suspected hypersensitivity to the study drug or any of its components.
• 25.Female Status: Women who are pregnant, breastfeeding, or planning to become pregnant (excludes those postmenopausal for ≥ 1 year or surgically sterilized).
• 26.Other conditions that the investigator deems unsuitable for participation in the study.