Bio equivalence study of Clozapine tablets 100 mg vs CLOZARIL® (Clozapine) tablets 100 mg in adult schizophrenic patients.

Active, not recruiting

• Conditions: Schizophrenia, unspecified,

• Registration Number: CTRI/2017/03/008104
• Lead Sponsor: Lupin Somerset

Brief Summary

This is a randomized, multi center, open label, two-treatment, two period, two-sequence, multiple dose, crossover, steady state bioequivalence study of Clozapine tablets 100 mg Manufactured for Lupin Somerset., USA vs. CLOZARIL® (Clozapine) tablets 100mg Manufactured for Novartis Pharmaceuticals Corporation, East  07936  in adult schizophrenic  patients already receiving stable daily dose of Clozapine administered in equally divided doses at 12-hour intervals under fasting condition.

Treatments will be allocated to patient by carrying out randomization using statistical techniques. Patients who are on stable dose of Clozapine for atleast 3 months and who are receiving dose in multiple of 100 mg given every 12 hours will be eligible to participate in the study. Patients who are eligible to participate in the study would receive their own established dose twice daily (12 hours apart) for 20 days in a crossover design. In period-I (from day 1 to day 10), patients will receive either the Test product or the reference product every 12 hours for 10 days. In period-II (from day 11 to day 20), patients will be switched to the other product for a second period of 10 days. Blood samples will be collected over a dosing interval on day 10 & on day 20, following preliminary sampling on days 7, 8, and 9 in period I and on days 17, 18 & 19 in period II to confirm steady-state conditions. After the study is completed (after last PK sample collection on day 20), patients could be continued on their current dose of Clozapine using an approved Clozapine product as prescribed by their clinicians. The evening dose of Clozapine on day 10 & day 20 will be administered after last PK sample collection of 12 hours.

A total of 36 blood samples will be collected during the study for PK analysis. The pre-dose blood sample of 4.0 mL (00.00) will be scheduled to be collected within 5 minutes before dosing on days 7, 8, 9, 10 and days 17, 18, 19, 20 of the study. On day 10 & day 20, the post-dose blood samples of 4.0 mL each will be drawn at 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0 hrs following drug administration.

Detailed Description

Not available

Study Timeline

• Study Start: 2017-04-20
• Last Update Posted: 2021-12-10

Recruitment & Eligibility

• Status: Closed to Recruitment of Participants
• Sex: All
• Target Recruitment: 28

Inclusion Criteria

• 1 Men and women aged 18-65 years both inclusive having clinical diagnosis of schizophrenia DSM IV-TR. 2 Patients have a diagnosis of treatment-resistant schizophrenia.
• Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of atleast two different antipsychotic agents, including an atypical antipsychotic agent, prescribed for adequate duration. Atleast 15 days for each antipsychotic agent., or have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics. 3 Schizophrenic patients who are on stable dose of Clozapine for at least 3 months prior to randomization and receiving Clozapine in multiples of 100 mg every 12 hours. 4 Patients should be otherwise healthy as determined by physical examination, medical history, and routine hematologic and biochemical tests. 5 Willing and able to comply with housing, restrictions and other protocol requirements as indicated by signed written informed consent witnessed by a legally acceptable representative. 6 Willing to comply with the study requirements as per protocol and with the outpatient dosing schedule. 7 Females of childbearing potential who has not completed 1 year after menopause & have not gone through hysterectomy or bilateral tubal ligation must have a negative pregnancy test at screening, before randomization and before check-in to housing e.g. day 0 as well as must be non-lactating at screening and must agree to use an effective contraceptive method during study. 8 No participation in any clinical study within the past 90 days. 9 Adequate hepatic function at screening as defined by: Bilirubin <1.5 X ULN (upper limit of normal) AST/ ALT <1.5 X ULN Total Triglycerides <1.5 X ULN Total Cholesterol <1.5 X ULN 10 Adequate renal function at screening as defined by S.Creatinine <1.5 X ULN.

Exclusion Criteria

• 1 A history of allergic reactions to Clozapine or other chemically related psychotropic drugs 2 Concurrent primary psychiatric or neurological diagnosis,including organic mental disorder, severe tardive dyskinesia, or idiopathic Parkinson’s disease.
• 3 History of severe renal or cardiac disorders e.g. myocarditis, cardiomyopathy, bradycardia, paralytic ileus, prostatic enlargement, narrow-angle glaucoma, colonic disease or lower abdominal surgery, active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure.
• 4 A history of granulocytopenia/ agranulocytosis or myeloproliferative disorders drug-induced or idiopathic.
• 5 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.
• 6 Concurrent use of anti hypertensive medication or any medication that might predispose to orthostatic hypotension.
• 7 A medical or surgical condition that might interfere with the absorption, metabolism, or excretion of Clozapine.
• 8 A history of epilepsy or risk for seizures.
• 9 Any of the following investigational abnormality in screening Total white blood cell count < 4000/c.mm Absolute neutrophil count < 2000/c.mm Absolute eosinophil count > 700 / c.mm Platelet count < 50,000 /c.mm HbA1c > 9% QTc > 500 milliseconds 10 Concurrent use of other drugs known to suppress bone marrow function.
• 11 Expected changes in concomitant medications during the period of study.
• 12 Positive tests for drug or alcohol abuse at screening or baseline.
• 13 A history of alcohol or drug dependence by Diagnostic and Statistical Manual of Mental Disorders IV -DSM-IV criteria during the 6-month period immediately prior to study entry.
• 14 History of multiple syncopal episodes.
• 15 Patients have a history of narrow-angle glaucoma.
• 16 Use of any of the following in the 14 days preceding enrolment including but not limited to: Drugs significantly influencing CYP1A2 activity.
• Drugs significantly inhibiting CYP2D6 activity.
• Medications known to prolong the QTc interval Substances known to have a substantial potential for causing agranulocytosis.
• Phenytoin, lithium highly protein bound substances Antihypertensive and other drugs known to cause postural hypotension.
• Alcohol, MAOIs, CNS depressants including narcotics and benzodiazepines Antimuscarinic 17 Patient had major surgery within 4 weeks prior to study entry, or who have not recovered from prior major surgery.
• 18 Patients with known positivity for human immunodeficiency virus HIV, HBsAg or HCV.
• 19 Chronic Smokers who smokes greater than or equal to 10 cigarettes or equivalent per day.
• 20 History of difficulty with donating blood or difficulty in accessibility of veins.
• 21 Compliance with outpatient medication schedule not expected as per Principal investigator’s opinion.
• 22 Donation of blood (1 unit or 350 ml) within 90 days prior to receiving the first dose of investigational medicinal product for the current study.
• 23 An unusual or abnormal diet, for whatever reason planned e.g. religious fasting during the course of the study.
• 24 Any condition/ Abnormal baseline findings that in the investigators’ judgment might increase the risk to the patient or decrease the chance of obtaining satisfactory data needed to obtain the objective of the study e.g. low expectation of compliance to dosing or expected changes in concomitant medication that may interfere in study.

Study & Design

• Study Type: BA/BE
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To demonstrate the bioequivalence at steady state of Clozapine tablets 100 mg Manufactured for Lupin Somerset., USA vs. CLOZARIL®(Clozapine) tablets 100 mg Manufactured for Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 in adult schizophrenic patients already receiving stable daily dose of Clozapine administered in equally divided doses at 12-hour intervals under fasting conditions.	The pre-dose blood sample of 4.0 mL (00.00) will be scheduled to be collected within 5 minutes before dosing on days 7, 8, 9, 10 and days 17, 18, 19, 20 of the study. On day 10 & day 20, the post-dose blood samples of 4.0 mL each will be | drawn at 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0 hrs following drug administration.

Secondary Outcome Measures

Name	Time	Method
To monitor the safety and tolerability profile of the study formulations.	NA

Trial Locations

Locations (6)

Divyam Hospital,; 🇮🇳 Surat, GUJARAT, India

Hatkesh Healthcare Foundation; 🇮🇳 Junagadh, GUJARAT, India

Kanoria Hospital & Research Centre; 🇮🇳 Gandhinagar, GUJARAT, India

Malpani Multispeciality Hospital; 🇮🇳 Jaipur, RAJASTHAN, India

Ratandeep Multispeciality Hospital; 🇮🇳 Ahmadabad, GUJARAT, India

Sanjivani Superspeciality Hospital; 🇮🇳 Ahmadabad, GUJARAT, India

Divyam Hospital,

🇮🇳Surat, GUJARAT, India

Dr Timir Shah

Principal investigator

9825137443

divyamhospital@gmail.com