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CTRI Number  CTRI/2013/06/003745 [Registered on: 12/06/2013] Trial Registered Prospectively
Last Modified On: 18/09/2015
Post Graduate Thesis  No 
Type of Trial  BA/BE 
Type of Study    
Study Design  Randomized, Crossover Trial 
Public Title of Study   A Clinical Trial to study the clinical bioequivalence of Clozapine 100 mg tablet of Aurobindo in comparison to Clozaril® (Clozapine) 100 mg tablet of Novartis in patients suffering from Schizophrenia 
Scientific Title of Study   A multicenter, open-label, randomized, two-treatment, two- sequence, two-period, cross-over, steady-state clinical Bio-equivalence study of Clozapine 100 mg tablet of Aurobindo (test) with Clozaril® (Clozapine) 100 mg tablet of Novartis (reference) in schizophrenic patients already receiving/ stabilized with Clozapine under fasting conditions.  
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
CR002/12  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Subhra Lahiri 
Designation  Associate Vice President 
Affiliation  AXIS Clinicals Ltd 
Address  AXIS Clinicals Ltd., 1-121/1, Miyapur

Hyderabad
ANDHRA PRADESH
500049
India 
Phone  914040408064  
Fax  04040408060  
Email  subhra.l@axisclinicals.com  
 
Details of Contact Person
Scientific Query
Modification(s)  
Name  Dr Subhra Lahiri 
Designation  Associate Vice President 
Affiliation  AXIS Clinicals Ltd 
Address  1-121/1, Miyapur

Hyderabad
ANDHRA PRADESH
500049
India 
Phone  914040408064  
Fax  04040408060  
Email  subhra.l@axisclinicals.com  
 
Details of Contact Person
Public Query  
Name  Monika Sharma 
Designation  Team Lead-Clinical Rsearch 
Affiliation  AXIS Clinicals Ltd 
Address  1-121/1, Miyapur

Hyderabad
ANDHRA PRADESH
500049
India 
Phone  914040408270  
Fax  04040408060  
Email  monika.s@axisclinicals.com  
 
Source of Monetary or Material Support  
Aurobindo Pharma Limited 
 
Primary Sponsor  
Name  Aurobindo Pharma Limited 
Address  APL Research centre, Aurobindo Pharma Limited, Clinical Pharmacology Department, Survey No. 313, Bachupally Village, Quthubullapur Mandal, Hyderabad- 500090 Andhra Pradesh , India Telephone: 91-40-23040261/ 62  
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
Axis Clinical Ltd  1-121/1, Miyapur, Hyderabad-500049 Andhra Pradesh, 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 G Prasad Rao  Asha Hospital  298 Road No. 14, Banjara Hills, Hyderabad – 500034 Andhra Pradesh India
Hyderabad
ANDHRA PRADESH 		 914027568979
914066759658
prasad40@gmail.com 
Dr Vaishal N Vora  SNEH Clinic  301-2-3, Nakshatra Complex, Above HDFC Bank, Maninagar X Roads, Maninagar, Ahmedabad- 380008 Gujarat, India
Ahmadabad
GUJARAT 		 917925463963
917930020656
vnvora@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 2  
Name of Committee  Approval Status 
Anubhav Independent Ethics committee  Approved 
Ethics Committee Asha 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 
Intervention  Clozapine  100 mg, twice daily for 10 days  
Comparator Agent  Clozaril  100 mg, twice daily for 10 days  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  60.00 Year(s)
Gender  Both 
Details  1) Patients have a diagnosis of a) treatment-resistant schizophrenia or; b)schizophrenia, chronic (all types) and in a residual phase or in remission, or schizoaffective disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria
2) Body mass index between 18 and 35kg/m2 aged between 18 and 60 years
3) Patients should be appropriate candidates for Clozapine therapy (as stated in product labeling) and have been taking a stable dose of Clozapine for at least three months.
4) Patients who are already receiving/ stabilized on Clozapine daily dose of 100mg twice daily (100 mg Q12h).
5) Patients should be otherwise healthy as determined by physical examination, medical history, and no significant abnormality in any of the laboratory parameters including ECG and Chest X-ray.
6) Ability to comprehend the full nature and purpose of the study, including possible risks and adverse events; ability to co-operate with the Investigator and to comply with the requirements of the entire study.
7) Patients/Legal Representative has given written consent after being advised of the nature and risks of the study.
8) Patients must have adequate hematologic reserve
I. Hemoglobin ≥10gm/dL
II. WBC (white blood cells) >4000/mm3
III. Platelets ≥100,000/mm3
IV. ANC (absolute neutrophils count) >2000/mm3
9) Adequate and stable hepatic function at screening as defined by:
I. Bilirubin <1.5 X ULN (upper limit of normal)
II. AST/ ALT <1.5 X ULN
III. Total Triglycerides <1.5 X ULN
IV. Total Cholesterol <1.5 X ULN
10) Adequate renal function at screening as defined by:
I. Creatinine <1.5 X ULN for the clinical laboratory
11) Female subjects of childbearing potential must have a negative serum pregnancy test at enrolment
 
 
ExclusionCriteria 
Details  1) 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.
2) Absolute neutrophil count ≤ 2000/mm3 and WBC count ≤ 4000/mm3.
3) Elderly patients with diagonosed dementia related psychosis.
4) Patients have a medical or surgical condition that might interfere with the absorption, metabolism, or excretion of Clozapine or other study medications.
5) Patients have a history of granulocytopenia or myeloproliferative disorder, either drug-induced or idiopathic.
6) Patients have a history of clinically significant cardiovascular, renal, hepatic,respiratory, endocrine (except noninsulin-dependent diabetes mellitus), or gastrointestinal disease.
7) Patients have a known history of human immunodeficiency virus infection.
8) Patients have a history of epilepsy or seizures or are comatose or experiencing severe central nervous system depression.
9) Patients are unable to communicate with the investigator.
10) Patients have a history of allergic reactions to Clozapine or chemically related psychotropic drugs.
11) Patients have a concurrent primary psychiatric or neurological diagnosis, including organic mental disorder (DSM-IV criteria), mental retardation, severe tardive dyskinesia, or idiopathic Parkinson’s disease.
12) Patients have had electroconvulsive therapy within the past one month.
13) Patients have demonstrated clinically significant homicidal behavior within the past 12 months.
14) Patients have received an investigational drug within the past 90 days.
15) Patients have a history of narrow-angle glaucoma.
16) Patients require 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.
17) Patients have a known history of phenylketonuria.
18) 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)
19) Concurrent use of antihypertensive medication or any medication that might predispose to orthostatic hypotension.
20) Concurrent use of other drugs known to suppress bone marrow function.
21) Positive tests for drug or alcohol abuse at screening or baseline.
22) 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.
23) History of multiple syncopal episodes.
24) Patients who smokes.
25) Expected changes in concomitant medication during the period of study
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
1) AUC0- : Area under the plasma concentration – time curve over the steady state dosing interval.
2) Cmax-ss: Maximum concentration over the steady state dosing interval.
3) Cmin-ss: Minimum concentration over the steady state dosing interval
 		 Day 7, 8, 9, 10 and Day 17,18,19,20 
 
Secondary Outcome  
Outcome  TimePoints 
1. Css-avg: Average concentration over the steady state dosing interval
2. Percentage fluctuation
3) Tmax: Time of maximum measured plasma concentration over the steady state dosing interval.
4) Safety and tolerability as assessed by reported adverse events (laboratory and clinical investigations, and vital signs)
 		 Day 10 and Day 20 
 
Target Sample Size   Total Sample Size="36"
Sample Size from India="36" 
Final Enrollment numbers achieved (Total)= ""
Final Enrollment numbers achieved (India)="" 
Phase of Trial   N/A 
Date of First Enrollment (India)   20/06/2013 
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="1"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Completed 
Recruitment Status of Trial (India)  Completed 
Publication Details   None 
Individual Participant Data (IPD) Sharing Statement

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

Brief Summary  

This study is a randomized, Multicenter, Open-Label, Two-Treatment, Two Sequence, Two-Period, cross over, steady state Clinical Bio-equivalence study to determine multiple oral doses clinical bioequivalence of Clozapine 100 mg tablet of Aurobindo with Clozaril® (Clozapine) 100 mg tablet of Novartis in schizophrenic patient’s already receiving Clozapine 100 mg in stable regimen patients with schizophrenia and this study will be conducted in two centers in India.

 

The Primary objective will be to determine clinical bioequivalence of test drug with the active comparator (reference drug). The secondary objective of the study is to monitor the adverse events, to ensure safety and tolerability as assessed by reported adverse events, laboratory, clinical investigations and vital signs in the schizophrenic patients.

 
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