CTRI/2017/03/008104 [Registered on: 15/03/2017] Trial Registered Prospectively
Last Modified On:
12/10/2021
Post Graduate Thesis
No
Type of Trial
BA/BE
Type of Study
Study Design
Randomized, Crossover Trial
Public Title of Study
Bio equivalence study of Clozapine tablets 100 mg vs CLOZARIL® (Clozapine) tablets 100 mg in adult schizophrenic patients.
Scientific Title of Study
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 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.
Trial Acronym
15-VIN-432
Secondary IDs if Any
Secondary ID
Identifier
15-VIN-432 Version 01 Date 12-Jun-2015
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
Phone
079-30013000
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
Phone
079-30013000
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
Phone
079-30013000
Fax
Email
ashoka.singh@veedacr.com
Source of Monetary or Material Support
Lupin Somerset
an Operating Division of Lupin Inc.,
400 Campus Drive Somerset,
NJ 08873 USA
Phone: 908-603-6059
Fax: 908-603-6060
Primary Sponsor
Name
Lupin Somerset
Address
Operating Division of Lupin Inc.,
400 Campus Drive Somerset, NJ 08873, USA. Phone : 908-603-6059. Fax : 908-603-6060
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
Veeda Clinical Research Pvt Ltd
Veeda Clinical Research Pvt. Ltd. Shivalik Plaza, Near I.I.M., Ambawadi, Ahmedabad – 380 015, India
Countries of Recruitment
India
Sites of Study
No of Sites = 6
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr Timir Shah
Divyam Hospital,
OPD of Psychiatry, Divyam Hospital, 46-Maher Park- A, Athwagate, Ring Road, Surat - 395001,Gujarat, India. Surat GUJARAT
9825137443
divyamhospital@gmail.com
Dr Bakul Buch
Hatkesh Healthcare Foundation
Department of Psychiatry, Saraswati Mandir Complex, Opposite Bhutnath Temple, College Road, Junagadh -362001, Gujarat Junagadh GUJARAT
9824017400
bakulbuch@gmail.com
Dr Rajendra Anand
Kanoria Hospital & Research Centre
Department of Psychiatry,
Hansol Gandhinagar Highway, Indira Bridge Corner, Bhat Gam-382428,Gujarat. Gandhinagar GUJARAT
9824017400
drrajendraanand@yahoo.com
Dr Ashok Kumar Goyal
Malpani Multispeciality Hospital
Malpani Multispeciality Hospital, Department of Psychiatry,SP-6, Vishwakarma Institutional Area, Road-1, Sikar Road, Jaipur- 302013, Rajasthan Jaipur RAJASTHAN
9828809333
goyalashokdr@gmail.com
Dr Vaishal Vora
Ratandeep Multispeciality Hospital
Department of Psychiatry, Second Floor, Nakshatra Complex Above HDFC bank, Maninagar Cross Road, Maninagar, Ahmedabad- 380008 Ahmadabad GUJARAT
9825440891
vnvora@gmail.com
Dr Nehal Shah
Sanjivani Superspeciality Hospital
Department of Psychiatry, 1, Uday Park Society, Near Sunrise Park, Vastrapur, Ahmedabad - 380015, Gujarat. Ahmadabad GUJARAT
Clozapine tablets 100 mg manufactured for Lupin Somerset., USA versus
Patient will be administered either Test or Reference product 100 mg orally twice daily for first 10 days followed by crossover for the next ten days as per the randomization schedule no washout period between the two treatment period.
Comparator Agent
CLOZARIL(Clozapine) 100 mg tablets Manufactured for Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936
Patient will be administered either Test or Reference product 100 mg orally twice daily for first 10 days followed by crossover for the next 10 days as per the randomization schedule no washout period between the two periods.
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 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
ExclusionCriteria
Details
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.
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 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
Outcome
TimePoints
To monitor the safety and tolerability profile of the study formulations.
NA
Target Sample Size
Total Sample Size="28" Sample Size from India="28" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
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.