A Multicentric, Open-label, Randomized, Two-treatment, Two-sequence, Two-period, Crossover, Steady-state Clinical Bioequivalence Study of ZIPROC-100 (Clozapine) 100 mg Tablets of Torrent Pharma Philippines Inc., Philippines (Test) with LEPONEX®(Clozapine) 100 mg tablets of Novartis Healthcare Philippines, Inc., Philippines (Reference) in Schizophrenic Patients who are Receiving Stable Daily Dose of Clozapine 100 mg BID under Fasting Conditions
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 56
- 试验地点
- 6
- 主要终点
- •AUC0-tau ss: Area under the plasma concentration – time curve over the steady state dosing interval
研究概览
简要总结
This study is a multi-centric, open-label, randomized, two-treatment, two-sequence, two-period, crossover, steady-state clinical bioequivalence study of ZIPROC-100 (Clozapine) 100 mg tablets of Torrent Pharma Philippines Inc., Philippines (Test) with LEPONEX® (Clozapine)100 mg tablets of Novartis Healthcare Philippines, Inc., Philippines (Reference) in schizophrenic patients who are receiving stable daily dose of Clozapine 100 mg BID under fasting conditions. Patients will be randomized in 1:1 ratio to either Test or Reference (as per the randomization schedule) and 100 mg tablets will be administered twice daily orally for 10 days (each period) followed by crossover without washout period under fasting conditions. Plasma concentration of clozapine will be quantified using a validated liquid chromatography-mass spectrometry (LC-MC/MS) analytical method.
Statistical analyses will be performed on individual PK parameters (AUC0-tau ss, Cmax ss, Cmin ss, Cavg ss,Tmax ss, percentage fluctuation, swing, and Cpd) of Clozapine obtained for different time points for ZIPROC-100 versus LEPONEX® using the SAS® package (SAS® Institute Inc., USA, Version 9.2or higher).
Arithmetic means, standard deviations and coefficients of variation will be calculated for all the PK parameters. Additionally, geometric means will be calculated AUC0-tau ss, Cmax ss, Cmin ss, Cavg ss, Tmax ss, percentage fluctuation, swing, and Cpd. ANOVA, ratio analysis, 90 % confidence interval (CI), inter- and intra-subject variability, and power will be calculated for the primary PK parameters(AUC0-tau ss, Cmax ss) using the SAS® package (SAS® Institute Inc., USA, Version 9.2 or higher).
研究设计
- 研究类型
- Interventional
- 分配方式
- Other
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 55.00 Year(s)（—）
- 性别
- All
入选标准
- •â€¢Patients of either sex, aged 18 to 55 years (both inclusive) having clinical diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria (DSM-V TR) •Patients with body mass index between 18 and 25 kg/m2 •Patients who are appropriate candidates for Clozapine therapy (as stated in ZIPROC-100 and LEPONEX® package inserts) and have been taking a stable dose of Clozapine 100 mg twice daily for at least three months before enrolment in the study •Patients who are healthy as determined by physical examination, medical history, and no significant abnormality in any of the laboratory parameters, including electrocardiogram and Chest x-ray •Ability to comprehend the full nature and purpose of the study, including possible risks and adverse events (AEs); ability to co-operate with the investigator and study team and to comply with the requirements of the entire study •Patients/legally acceptable representative has given written consent after being advised of the nature and risks of the study •Patients must have adequate hematologic reserve: Hemoglobin (Hb) ≥ 11 gm/dL White blood cells (WBC) ≥ 4000 /mm3 or /μL Platelets ≥ 100,000 mm3 or /μL Absolute neutrophil count (ANC) ≥ 2000 /mm3 or /μL •Adequate and stable hepatic function at screening as defined by: Bilirubin ≤ 1.5 × ULN (upper limit of normal) Aspartate aminotransferase/alanine aminotransferase (AST/ ALT) ≤ 1.5 × ULN Total triglycerides ≤ 1.5 × ULN Total cholesterol ≤ 1.5 × ULN •Adequate renal function at screening as defined by: Creatinine ≤ ULN for the clinical laboratory Serum potassium ≤ ULN Serum magnesium ≤ ULN •Female patients of childbearing potential must have a negative urine pregnancy test at screening and check-in.
排除标准
- •â€¢History of suicidal tendencies (e.g. suicidal attempts) within the past 3 months prior to screening or immediate risk of harm to self or other at the time of screening, as judged by the investigator •Elderly patients with diagnosed dementia related psychosis •Patients with medical or surgical condition that might interfere with the absorption, metabolism, or excretion of Clozapine or other study medications •Patients with history of granulocytopenia or myeloproliferative disorder, either drug-induced or idiopathic •Patients with history of clinically significant cardiovascular, renal, hepatic, respiratory, endocrine (except noninsulin-dependent diabetes mellitus), or gastrointestinal disease •Patient’s positive for HIV, HBs Ag or HCV •Patients with history of epilepsy or seizures or are comatose or experiencing severe central nervous system depression •Patients who are unable to communicate with the investigator and study team •Patients with a history of allergic reactions to Clozapine or chemically related psychotropic drugs •Patients having concurrent primary psychiatric or neurological diagnosis, including organic mental disorder (DSM-V criteria), mental retardation, severe tardive dyskinesia, or idiopathic Parkinson’s disease •Patients who had undergone electroconvulsive therapy within the past 1 month •Patients have demonstrated clinically significant homicidal behaviour within the past 12 months •Patients have received any investigational drug within the past 90 days •Patients having a history of narrow-angle glaucoma •Patients requiring treatment with drugs that are known to interact with Clozapine (e.g., agents having a well-known potential to suppress bone- marrow functioning, drugs that are highly protein-bound, cimetidine, or phenytoin).
- •Clozapine may also potentiate the effects of antihypertensive and anticholinergics; therefore, caution should be taken if patients receiving these drugs are enrolled in the study •Patients with known history of phenylketonuria •Significant orthostatic hypotension (i.e., a drop in systolic blood pressure of 30 mm Hg or more and / or a drop in diastolic blood pressure of 20 mm Hg or more on standing) •Concurrent use of antihypertensive medication or any medication that might pre-dispose to orthostatic hypotension • Positive tests for drug or alcohol abuse at screening and before check-in •A history of alcohol or drug dependence by DSM-V criteria during the 6-month period immediately prior to study entry •History of multiple syncopal episodes •Patients who smoke more than 10 cigarettes / day or unable to abstain from smoking during the study •Expected changes in concomitant medication during the period of study.
结局指标
主要结局
•AUC0-tau ss: Area under the plasma concentration – time curve over the steady state dosing interval
时间窗: On Day 10 and Day 20
•Cmax ss: Maximum concentration over the steady state dosing interval
时间窗: On Day 10 and Day 20
次要结局
- •Cmin ss: Minimum concentration over the steady state dosing interval(•Cavg ss: Average concentration over the steady state dosing interval)