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CTRI Number  CTRI/2017/06/008857 [Registered on: 16/06/2017] Trial Registered Prospectively
Last Modified On: 21/08/2017
Post Graduate Thesis  No 
Type of Trial  BA/BE 
Type of Study    
Study Design  Other 
Public Title of Study   Bioequivalence study in adult schizophrenic patients already receiving stable daily dose of Clozapine 25 mg tablet twice daily under fasting conditions. 
Scientific Title of Study   A randomized, multi center,openlabel,two-treatment, wo-period, two-sequence, multiple dose,crossover,steadystatebioequivalence study of Clozapinetablets25 mg of Changzhou Pharmaceutical Factory,Chinavs.Clozaril@ 25mg Tablets, Distributed by:Novartis PharmaCorporation EastHanover,NJ 07936in adultschizophrenic patientsalreadyreceiving stable dailydoseof Clozapine 25mgtabletwicedailyunderfasting condition 
Trial Acronym   
Secondary IDs if Any
Modification(s)  
Secondary ID  Identifier 
16-VIN-0920 Ver 01 : 11 Jan 2017 Amd 01 : 26 Apr 2017  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Ashoka Kumar Singh 
Designation  Head Of the Department - Clinical Operations 
Affiliation  Veeda Clinical Research Pvt. Ltd.  
Address  Veeda Clinical Research Pvt. Ltd. Shivalik Plaza-A, Near IIM, Ambawadi, Ahmedabad. Ahmadabad GUJARAT 380015 India

Ahmadabad
GUJARAT
380015
India 
Phone  07930013000  
Fax    
Email  Ashoka.Singh@veedacr.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Yogesh Patel 
Designation  Medical Monitor- Senior Manager 
Affiliation  Veeda Clinical Research Pvt. Ltd 
Address  Veeda Clinical Research Pvt. Ltd. Shivalik Plaza-A, Near IIM, Ambawadi, Ahmedabad. Ahmadabad GUJARAT 380015 India

Ahmadabad
GUJARAT
380015
India 
Phone  07930013000  
Fax    
Email  yogesh.ap@veedacr.com  
 
Details of Contact Person
Public Query  
Name  Dr Ashoka Kumar Singh 
Designation  Head Of the Department - Clinical Operations 
Affiliation  Veeda Clinical Research Pvt. Ltd.  
Address  Veeda Clinical Research Pvt. Ltd. Shivalik Plaza-A, Near IIM, Ambawadi, Ahmedabad. Ahmadabad GUJARAT 380015 India

Ahmadabad
GUJARAT
380015
India 
Phone  07930013000  
Fax    
Email  Ashoka.Singh@veedacr.com  
 
Source of Monetary or Material Support  
Changzhou Pharmaceutical Factory No. 518 Laodong East Road, Changzhou, Jiangsu, China Post code: 213018 Tel. No.:86-519-88835505, 88813251-8212 Fax No. :86-519-88828412  
 
Primary Sponsor  
Name  Changzhou Pharmaceutical Factory 
Address  Changzhou Pharmaceutical Factory; No. 518 Laodong East Road, Changzhou, Jiangsu, China, Post code: 213018. Telephone: 86-519-88835505, 88813251-8212 Fax: 86-519-88828412 E Mail ID: wb@czpharma.com 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
Veeda Clinical Research Pvt Ltd  Veeda Clinical Research Pvt. Ltd. Shivalik Plaza-A, Near IIM, Ambawadi, Ahmedabad. Ahmadabad GUJARAT 380015 India Ahmadabad GUJARAT 380015 India  
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 2  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Rajendra Anand  Kanoria hospital & Research Centre  Airport Gandhinagar highway, Bhat, Gandhinagar 382428, Gujarat
Gandhinagar
GUJARAT 		 9824017400

drrajendraanand@yahoo.com 
Dr Vaishal Vora  Ratandeep Multispeciality Hospital  Nakshatra complex, Above HDFC bank, Maninagar cross road, Maninagar, Ahmedabad 380008, Gujarat
Ahmadabad
GUJARAT 		 9825440891

vnvora@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 2  
Name of Committee  Approval Status 
Kanoria Ethics Committee Kanoria Hospital and Research Centre  Approved 
Ratandeep Institutional Ethics Committee Ratandeep Multispeciality Hospital  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  Schizophrenia,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Clozaril® 25 mg Tablets, Manufactured by: Novartis Pharma Corporation Suffern   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 another product for a second period of 10 days.  
Intervention  of Clozapine tablets 25 mg of Changzhou Pharmaceutical Factory, China  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 another product for a second period of 10 days.  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  65.00 Year(s)
Gender  Both 
Details  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 an inadequate response to at least two antipsychotic drugs at the maximally tolerated dose within the recommended therapeutic range in treatment lasting six weeks or more. Termination of a medication due to adverse events before reaching the appropriate dose and duration should not be regarded as a failed treatment due to non response to the medication.
3. Schizophrenic patients who are on stable dose of Clozapine 25 mg for at least 3 months prior to randomization and receiving Clozapine 25 mg twice daily.
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. Females of childbearing potential (sexually active women who have not completed 1 year after menopause & have not gone through hysterectomy or bilateral tubal ligation) must have a negative pregnancy test (at screening and prior to check-in in Period I) as well as must be non-lactating at screening and must agree to use an effective contraceptive method during study.
7. No participation in any clinical study within the past 90 days.
 
 
ExclusionCriteria 
Details  1. A history of allergic reactions to Clozapine / any of the component of study drug or other chemically related psychotropic drugs
2. Concurrent primary psychiatric disorder other than schizophrenia or neurological diagnosis, including organic mental disorder, neuroleptic malignant syndrome, severe tardive dyskinesia, or idiopathic Parkinson’s disease and dementia related psychosis, a history of epilepsy or other predisposing risk factors for seizures, history of multiple syncopal attacks or any other clinically significant CNS disorder.
3. Patients with the following cardiac conditions:
• Recent myocardial infarction (<12 months)
• QTc prolongation (screening electrocardiogram with QTc >450 msec for men, QTc >470 msec for women)
• History of QTc prolongation or using concomitant medications which prolong QTc interval.
• Sustained cardiac arrhythmia or history of sustained cardiac arrhythmia
• Uncompensated congestive heart failure, myocarditis, cardiomyopathy
• Complete left bundle branch block
• First-degree heart block with PR interval > 0.22 seconds
4. Patients with significant renal or hepatic impairment in which dose reduction is necessary as per the clinical evaluation of the patient by the Investigator.
5. Patients with narrow-angle glaucoma, concomitant anticholinergic medications, prostatic hypertrophy, or other conditions in which anticholinergic medications are required for the treatment, paralytic ileus, intestinal obstruction etc.
6. Patients with known history of CYP2D6 poor metabolizers.
7. A history of granulocytopenia/ agranulocytosis or myeloproliferative disorders (drug-induced or idiopathic)
8. Patient with the history or presence of 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) at the time of screening.
9. Concurrent use of antihypertensive medication or any medication that might pre¬dispose to orthostatic hypotension
10. A medical or surgical condition that might interfere with the absorption, metabolism, or excretion of Clozapine
11. Any of the following hematological abnormality at screening
• Total white blood cell count < 4000/c.mm
• Absolute neutrophil count < 2000/c.mm
• Absolute eosinophil count > 700 / c.mm
• Patients with poor glycemic control as defined by HbA1c ≥7% and/or fasting blood glucose >160 mg/dL at screening
• Patients with total cholesterol >300 mg/dL and triglycerides level > 300 mg/dL at screening
12. Concurrent use of other drugs known to suppress bone marrow function
13. Expected changes in concomitant medications during the period of study.
14. Positive tests for drug or alcohol abuse at screening or baseline.
15. 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.
16. History of multiple syncopal episodes.
17. Patients have a history of narrow-angle glaucoma
18. Use of any of the following medications within14 days or at least five half lives have not been passed between last dose of the previous medication and first dose of the study medication, preceding enrolment including but not limited to:
• Strong CYP1A2 Inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin etc.).
• CYP2D6 and CYP3A4 Inhibitors(e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline etc).
• CYP1A2 and CYP3A4 Inducers (e.g. carbamazepine, phenytoin, St. John’s wort, and rifampin etc)
• Medications known to prolong the QTc interval (e.g. specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class IIIantiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus)
• Substances known to have a substantial potential for causing agranulocytosis and lowering the seizure threshold
• Lithium
• Anticholinergic drugs
Note: Any drug which induces or inhibits CYP 1A2, 2D6 or 3A4 should be restricted medication. This list is as per the drugs which affect the metabolism of the test product and may affect the primary objective of the trial. This is not an exhaustive list but guidance.
If other drug therapy is required prior to or during the study, decisions shall be taken by the Investigator to continue or discontinue the patient based on the following:
a) The pharmacology and pharmacokinetic of the non-study medication.
b) The likelihood of a drug–drug interaction, thereby affecting the pharmacokinetic comparison of study medicine. Prescribing Information of Clozaril® should be referred to assess the possibility of such interactions.
c) The time and duration of administration of the non-study medicine
19. Patient had major surgery within 4 weeks prior to study entry, or who have not recovered from prior major surgery.
20. Patients with known positivity for human immunodeficiency virus (HIV), HBsAg or HCV.
21. Chronic Smokers who smokes greater than or equal to 10 cigarettes or equivalent per day.
22. History of difficulty with donating blood or difficulty in accessibility of veins.
23. Compliance with outpatient medication schedule not expected as per Principal investigator’s opinion.
24. 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.
25. An unusual or abnormal diet, for whatever reason planned e.g. religious fasting during the course of the study.
26. 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.
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Other 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
To demonstrate the bioequivalence at steady state of Clozapine tablets 25 mg of Changzhou Pharmaceutical Factory, China vs. Clozaril® 25 mg Tablets, distributed by: Novartis Pharma Corporation East Hanover, NJ 07936 in adult schizophrenic patients already receiving stable daily dose of Clozapine 25 mg tablet twice daily under fasting conditions.   A total of 34 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 morning dosing on days 8, 9, 10 and days 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 morning drug administration.  
 
Secondary Outcome  
Outcome  TimePoints 
NIL  NA 
 
Target Sample Size   Total Sample Size="12"
Sample Size from India="12" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   N/A 
Date of First Enrollment (India)   26/06/2017 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="0"
Months="2"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Closed to Recruitment of Participants 
Publication Details   NIL 
Individual Participant Data (IPD) Sharing Statement

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

Brief Summary   The therapeutic efficasy of clozapine in Schizophrenia is modified through antagonism of the dopamine type 2 (D2) and the serotonin type 2A (5-HT2A) receptors. Clozapine also acts as an antagonist at adreneric,cholinergic,histaminergi and other dopaminergic and serotonergic receptors. The study will carried out on adult Schizophrenic patients already receiving stable daily dose of clozapine 25 mg tablet twice daily under fasting conditions. 
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