Bioequivalence Study of Long-Acting Paliperidone Palmitate in Patients With Schizophrenia

A Multicenter, Randomized, Open-Label, Parallel-Group, Multiple-Dose Bioequivalence Study of Paliperidone Palmitate Injection in Chinese Patients With Schizophrenia

This multicenter, randomized, open-label, parallel-group, multiple-dose study is designed to evaluate the bioequivalence, at pharmacokinetic steady state, of a paliperidone palmitate injection manufactured by CSPC Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd. (Test Group) and a paliperidone palmitate injection manufactured by Janssen Pharmaceutica N.V. (Reference Group) in patients with schizophrenia in China. Bioequivalence will be assessed based on steady-state pharmacokinetic parameters after repeated intramuscular administration (e.g., Cmax,ss and AUCτ). The safety and tolerability of the test and reference products will also be evaluated.

Purpose: This trial was conducted to evaluate the bioequivalence of a test (T) and a reference (R) formulation of once-monthly paliperidone palmitate (PP1M) in patients with schizophrenia.

Patients and methods: In this randomized, open-label, parallel-group, steady-state bioequivalence study, patients with stabilized schizophrenia were randomized 1:1 to receive T or R formulation. The regimen was 150 mg deltoid on Day 1, then 100 mg deltoid on Day 8, followed by five subsequent 100 mg gluteal injections every 28 days. The primary objective was to demonstrate steady-state bioequivalence. The primary endpoints were key pharmacokinetic parameters of paliperidone, including steady-state maximum concentration (Cmax,ss) and the area under the concentration-time curve over a dosing interval at steady state (AUCτ,ss). Bioequivalence was shown if the 90% confidence interval (CI) for the ratio of the geometric least squares means of the pharmacokinetic parameters (AUCτ,ss and Cmax,ss) fell within 80%-125%.

Inclusion Criteria:

1. Age 18 to 65 years inclusive at the time of consent.
2. Diagnosis of schizophrenia (ICD-10 criteria) prior to screening.
3. PANSS total score ≤70 at screening and at baseline.
4. CGI-S score ≤4 at screening and at baseline.
5. Body weight at screening: ≥50.0 kg (male) or ≥45.0 kg (female); body mass index (BMI) 19.0 to 35.0 kg/m2 (inclusive).
6. The participant and/or partner have no plans for pregnancy during the study and for 6 months after the last dose, and agree to use effective contraception (oral contraceptives are not allowed).
7. Signed informed consent and willingness and ability to comply with all study requirements.

Exclusion Criteria:

1. Known or suspected hypersensitivity to the study drug (paliperidone palmitate) or any of its components.
2. Diagnosis per ICD-10 or DSM-5 of any psychiatric disorder other than schizophrenia.
3. Clinically significant diseases or abnormalities, as judged by the investigator, in the respiratory, cardiovascular, gastrointestinal, genitourinary, reproductive, nervous, endocrine, or immune systems that may affect participant safety or interfere with study participation.
4. Laboratory abnormalities at screening or baseline meeting any of the following: (1) total bilirubin >1.5 × ULN, or AST or ALT >2 × ULN; (2) creatinine clearance (CLcr) <90 mL/min; (3) white blood cell count <3 × 10^9/L, or absolute neutrophil count <1.5 × 10^9/L, or platelets <80 × 10^9/L.
5. History of orthostatic hypotension or syncope due to orthostatic hypotension (except if stable for >6 months); or at screening/baseline, a decrease in systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg within 3 minutes after changing from supine to standing.
6. Congenital long QT syndrome; uncontrolled or significant cardiovascular disease, including congestive heart failure of NYHA class II or higher, unstable angina, or myocardial infarction within 6 months prior to first study dose; significant arrhythmias (including frequent premature ventricular contractions), or clinically significant arrhythmias requiring treatment at screening; QTc >450 ms (male) or >460 ms (female) at screening or baseline; risk factors for torsades de pointes or sudden death (e.g., bradycardia, clinically significant hypokalemia or hypomagnesemia, current use of medications that prolong QTc); or other clinically significant ECG abnormalities as judged by the investigator.
7. Past or current neuroleptic malignant syndrome.
8. Parkinson's disease, Lewy body dementia, or dementia-related psychosis.
9. Past or current seizure or convulsive disorders (except childhood febrile seizures), or stroke or transient ischemic attack within 1 year prior to consent.
10. History of tardive dyskinesia induced by risperidone, paliperidone, or other antipsychotics.
11. Uncontrolled diabetes mellitus, or HbA1c ≥7% at screening or baseline.
12. Electroconvulsive therapy within 28 days prior to consent.
13. Blood loss ≥400 mL within 3 months prior to consent, or ≥200 mL within 1 month prior to consent due to donation, surgery, or other causes.
14. Esophageal motility disorders, dysphagia, or other conditions that confer risk of aspiration pneumonia.
15. Positive tests for hepatitis B surface antigen, hepatitis C antibody, HIV antibody, or treponemal (syphilis) antibody.
16. Harmful alcohol use: >14 units per week (1 unit = 360 mL beer, or 150 mL wine, or 45 mL spirits).
17. Use of any investigational drug within 1 month prior to first study dose (excluding paliperidone palmitate or placebo), or prior participation in a gene therapy or cell therapy clinical trial such that, in the investigator's judgment, the participant is not suitable for this study.
18. Major surgery within 3 months prior to consent, or planned surgery within 1 month after study completion.
19. High suicide risk: C-SSRS suicidal ideation items 4 or 5 answered "Yes" within the past 6 months at screening/baseline; or suicidal behavior within the past 6 months; or, in the investigator's judgment, a serious risk of suicide.
20. Prohibited medications/treatments: (1) ziprasidone or thioridazine within 4 weeks prior to consent; (2) any other long-acting injectable antipsychotic received within one labeled dosing interval prior to consent (except risperidone microspheres), or receipt of risperidone microspheres (e.g., Hengde®) within 6 weeks prior to consent; (3) non-selective or irreversible monoamine oxidase inhibitors within 1 month prior to first dose; (4) strong or moderate inhibitors or inducers of CYP3A4, CYP2D6, or P-gp within 2 weeks prior to consent.
21. Pregnant, breastfeeding, or planning pregnancy; except for women who are postmenopausal for ≥1 year or surgically sterile (e.g., bilateral tubal ligation with non-recanalized tubes, bilateral oophorectomy, or hysterectomy).
22. Drug abuse history, illicit drug use, or positive drug abuse screening within 1 year prior to consent.
23. Clinically significant history of syncope related to needles or blood draws. Any other condition that, in the investigator's opinion, makes the participant unsuitable for the study.