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CTRI Number  CTRI/2014/04/004524 [Registered on: 04/04/2014] Trial Registered Prospectively
Last Modified On: 05/02/2015
Post Graduate Thesis  No 
Type of Trial  BA/BE 
Type of Study    
Study Design  Randomized, Crossover Trial 
Public Title of Study   Bioequivalence study of clozapine in schizophrenic patients 
Scientific Title of Study   A Randomized, Open Label, Multicentre, Two-Treatment, Two-Period, Two-Sequence, Steady State, Multiple Dose, Crossover, Comparative Bioequivalence Study of CLOZAREM (Clozapine) 100 mg Tablets of Remedica Ltd. with LEPONEX®/ CLOZARIL (Clozapine) 100 mg tablets, Manufactured by Novartis in Adult Patients Suffering from Schizophrenia under Fasting Conditions. 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
ARL/CT/13/004 version 00 dated 20 November, 2013  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Ashutosh Jani 
Designation  Head, Clinical Trials 
Affiliation  Accutest Research Laboratories (I) Pvt. Ltd. 
Address  Opposite The Grand Bhagwati Hotel,
Sarkhej-Gandhinagar Highway, Bodakdev
Ahmadabad
GUJARAT
380054
India 
Phone  091-79-40231612  
Fax  091-79-40239317  
Email  ashutosh.jani@accutestindia.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Agam Shah 
Designation  Senior Manager, Clinical Trials 
Affiliation  Accutest Research Laboratories (I) Pvt. Ltd. 
Address  Opposite The Grand Bhagwati Hotel,
Sarkhej-Gandhinagar Highway, Bodakdev
Ahmadabad
GUJARAT
380054
India 
Phone  091-79-40231612  
Fax  091-79-40239317  
Email  agam.shah@accutestindia.com  
 
Details of Contact Person
Public Query  
Name  Prasann Bavania 
Designation  Senior Research Associate 
Affiliation  Accutest Research Laboratories (I) Pvt. Ltd. 
Address  Opposite The Grand Bhagwati Hotel,
Sarkhej-Gandhinagar Highway, Bodakdev
Ahmadabad
GUJARAT
380054
India 
Phone  091-79-40231607  
Fax  091-79-40239317  
Email  prasann.bavania@accutestindia.com  
 
Source of Monetary or Material Support  
Remedica Ltd. P.O. Box 51706, CY-3508, Limassol, Cyprus (Europe) 
 
Primary Sponsor  
Name  Remedica Ltd 
Address  P.O. Box 51706, CY-3508, Limassol, Cyprus (Europe) 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 2  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Bakul Buch  Hatkesh Healthcare Foundation  Clinical Research Room, 2nd Floor, Hatkesh Trust Hospital, Opp. Bhutnath Temple, College Road
Junagadh
GUJARAT 		 091-285-2654652
091-285-2654652
bakulbuch@gmail.com 
Dr Vaishal Vora  Shivam Medical Hospital  C-4, Satyanarayan Society, Near Gor No Kuvo, Jashodanagar Cross Road, Maninagar East, Ahmedabad – 380008
Ahmadabad
GUJARAT 		 91-79-25835830

vnvora@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 2  
Name of Committee  Approval Status 
Hatkesh Healthcare Foundation Ethics Committee  Approved 
Shivam Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  Schizophrenia,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  CLOZAREM (Clozapine) 100 mg Tablets of Remedica Ltd.  Present study will enroll patients of Schizophrenia who are receiving a stable daily dose of clozapine 100 mg twice daily at 12-hour intervals and to evaluate their bio-equivalence. The same dose will be followed in both study periods of 10 days each. 
Comparator Agent  LEPONEX®/ CLOZARIL (Clozapine) 100 mg tablets, Manufactured by Novartis Pharma A.G., Switzerland (Marketing Authorization Holder: Novartis Pharmaceuticals UK Ltd.)  Present study will enroll patients of Schizophrenia who are receiving a stable daily dose of clozapine 100 mg twice daily at 12-hour intervals and to evaluate their bio-equivalence. The same dose will be followed in both study periods of 10 days each. 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  55.00 Year(s)
Gender  Both 
Details  The Patients who qualify for the study should meet the following inclusion criteria.
1. Either sex, aged 18 to 55 years (both inclusive) having clinical diagnosis of schizophrenia (DSM IV-TR)
2. Receiving clozapine treatment in divided doses at 12 hours interval for at least 3 months prior to randomization and on 100 mg twice daily dosage at the time of screening.
3. Willing and able to comply with study visit schedule and other protocol requirements as indicated by signed written informed consent witnessed by a legally acceptable representative.
4. 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. 
 
ExclusionCriteria 
Details  The Patients with any of the following criteria should be excluded:
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, Alcoholic and other toxic psychoses, severe tardive dyskinesia, or idiopathic Parkinson’s disease
3. History of toxic or idiosyncratic granulocytopenia/ agranulocytosis (with the exception of granulocytopenia/ agranulocytosis from previous chemotherapy), benign ethnic neutropenia, clozapine-induced agranulocytosis or myeloproliferative disorders
4. History of severe renal or cardiac disorders (e.g. myocarditis), 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.
5. History of multiple syncopal episodes or presence of significant orthostatic hypotension (Defined as a drop in supine systolic blood pressure of 30 mm Hg or more or a drop in supine diastolic blood pressure of 20 mm Hg or more on standing)
6. Current/ recent (within 3 months) history of uncontrolled epilepsy or risk for seizures
7. A medical or surgical condition that might interfere with the absorption, metabolism, or excretion of clozapine
8. Substance abuse or alcohol dependence during the 6-month period immediately prior to study entry (except dependence in full remission), as defined by DSM IV-TR criteria or chronic smoking (greater than or equal to 10 cigarettes or equivalent per day)
9. Any of the following laboratory abnormality:
• WBC count less than 3500 per microliter,
• Absolute Neutrophil Count less than 2000 per microliter,
• Absolute Eosinophil Count greater than 3000 per microliter or
• Platelet count less than 50,000 per microliter
• Serum creatinine greater than 1.5 mg per deciliter
• QTc greater than 500 milliseconds
• SGOT or SGPT greater than 3 times Upper Limit of Normal range (ULN)
• Bilirubin greater than 1.5 times ULN
• Reactive to antiHIV, HBsAg, antiHCV
10. 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
11. Participation in another clinical trial or use of other investigational product/ device within 4 weeks prior enrollment into this study.
12. Blood donation/ blood loss exceeding 200 ml within 90 days prior to enrollment in the study.
13. 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 OPD dosing or expected changes in concomitant medication that may interfere in study. 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Not Applicable 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
AUC0-tau and Cmax  dosing interval on day 10 
 
Secondary Outcome  
Outcome  TimePoints 
Cmin  dosing interval on day 10 
Tmax  dosing interval on day 10 
Cavg  dosing interval on day 10 
Degree of fluctuation  dosing interval on day 10 
 
Target Sample Size   Total Sample Size="24"
Sample Size from India="24" 
Final Enrollment numbers achieved (Total)= ""
Final Enrollment numbers achieved (India)="" 
Phase of Trial   N/A 
Date of First Enrollment (India)   07/04/2014 
Date of Study Completion (India) Date Missing 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="0"
Months="3"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Completed 
Publication Details   Nil 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary  

Clozapine, a dibenzodiazepine derivative, is an atypical antipsychotic drug with potent antipsychotic properties. Clozapine is indicated in treatment-resistant schizophrenic patients and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics.

Remedica Ltd., Cyprus, Europe (Remedica) has developed CLOZAREM (Clozapine) tablets. The present study aims to evaluate bioequivalence of Remedica’s test formulation against corresponding reference product LEPONEX®/ CLOZARIL (Clozapine) 100 mg tablets, Manufactured by Novartis in Adult Patients of Schizophrenia who are receiving a stable daily dose of clozapine 100 mg twice daily at 12-hour intervals.

Primary objective: To assess pharmacokinetics of CLOZAREM (Clozapine) 100 mg tablets of Remedica Ltd. (Test Product) vs. that of LEPONEX®/ CLOZARIL (Clozapine) 100 mg tablets, manufactured by Novartis (Reference Product), under fasting condition in adult patients of schizophrenia who are receiving a stable daily dose of clozapine administered in equally divided doses at 12-hour intervals and to evaluate their bioequivalence.

Secondary Objective: To monitor the safety and tolerability of clozapine 100 mg tablets in adult patients of schizophrenia who are receiving a stable daily dose of clozapine administered in equally divided doses at 12-hour intervals.
 
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