CTRI/2016/07/007083 [Registered on: 12/07/2016] Trial Registered Prospectively
Last Modified On:
19/03/2019
Post Graduate Thesis
No
Type of Trial
BA/BE
Type of Study
Study Design
Randomized, Crossover Trial
Public Title of Study
This is a study to compare two formulations of Clozapine in Schizophrenic Patients
Scientific Title of Study
A Multicentric, Open-label, Randomized, Two-treatment, Two-sequence, Two-period, Crossover, Steady-state Clinical Bioequivalence Study of ZIPROC-100 (Clozapine) 100 mg Tablets of Torrent Pharma Philippines Inc., Philippines (Test) with LEPONEX®(Clozapine) 100 mg tablets of Novartis Healthcare Philippines, Inc., Philippines (Reference) in Schizophrenic Patients who are Receiving Stable Daily Dose of Clozapine 100 mg BID under Fasting Conditions
Trial Acronym
None
Secondary IDs if Any
Secondary ID
Identifier
TPL-01, Version 1.0 dated 11 May 2016
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Dr Sonika Newar
Designation
Medical Monitor
Affiliation
JSS Medical Research India Limited
Address
JSS Medical Research India Limited
6th Floor, Vatika Mindscapes (Tower B)
Plot 12/2, Sector 27D,
Faridabad HARYANA 121003 India
Phone
91-8800799887
Fax
91-0129-6613520
Email
Sonika.Newar@jssresearch.com
Details of Contact Person Public Query
Name
Dr Shariq Anwar
Designation
Head - Operations (Monitoring)
Affiliation
JSS Medical Research India Limited
Address
JSS Medical Research India Limited
6th Floor, Vatika Mindscapes (Tower B)
Plot 12/2, Sector 27D,
Faridabad HARYANA 121003 India
Phone
91-0129-6613520
Fax
91-0129-6613520
Email
shariq.anwar@jssresearch.com
Source of Monetary or Material Support
Torrent Pharmaceuticals Limited (Research Centre)
Village Bhat, District Gandhinagar-382 428
Gujarat, India.
Primary Sponsor
Name
Torrent Pharmaceuticals Limited
Address
Research Centre, Village Bhat, District Gandhinagar-382 428
Gujarat, India.
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
India
Sites of Study
No of Sites = 6
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr Timirkumar Chandrakant Shah
Divyam Hospital
Psychiatry Department, Block No.- 84, Canal Road, Palsana Cross Roads, Palsana, Pin Code- 394315, India Surat GUJARAT
91-9825137443
drtcshah@gmail.com
Dr Rajendra Someshwar Anand
Kanoria Hospital and Research Centre
Room No-301, Psychiatry Clinical Research Department, Airport-Gandhinagar Highway, Village- Bhat, Pin Code-382428, India Gandhinagar GUJARAT
Clozapine 100 mg tablets will be administered twice daily orally (every12-hours) with 240 mL of water for 10 consecutive days.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
55.00 Year(s)
Gender
Both
Details
• Patients of either sex, aged 18 to 55 years (both inclusive) having clinical diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria (DSM-V TR)
• Patients with body mass index between 18 and 25 kg/m2
• Patients who are appropriate candidates for Clozapine therapy (as stated in ZIPROC-100 and LEPONEX® package inserts) and have been taking a stable dose of Clozapine 100 mg twice daily for at least three months before enrolment in the study
• Patients who are healthy as determined by physical examination, medical history, and no significant abnormality in any of the laboratory parameters, including electrocardiogram and Chest x-ray
• Ability to comprehend the full nature and purpose of the study, including possible risks and adverse events (AEs); ability to co-operate with the investigator and study team and to comply with the requirements of the entire study
• Patients/legally acceptable representative has given written consent after being advised of the nature and risks of the study
• Patients must have adequate hematologic reserve:
Hemoglobin (Hb) ≥ 11 gm/dL
White blood cells (WBC) ≥ 4000 /mm3 or /μL
Platelets ≥ 100,000 mm3 or /μL
Absolute neutrophil count (ANC) ≥ 2000 /mm3 or /μL
• Adequate and stable hepatic function at screening as defined by:
Bilirubin ≤ 1.5 × ULN (upper limit of normal)
Aspartate aminotransferase/alanine aminotransferase (AST/
ALT) ≤ 1.5 × ULN
Total triglycerides ≤ 1.5 × ULN
Total cholesterol ≤ 1.5 × ULN
• Adequate renal function at screening as defined by:
Creatinine ≤ ULN for the clinical laboratory
Serum potassium ≤ ULN
Serum magnesium ≤ ULN
• Female patients of childbearing potential must have a negative urine pregnancy test at screening and check-in
ExclusionCriteria
Details
• 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
• Elderly patients with diagnosed dementia related psychosis
• Patients with medical or surgical condition that might interfere with the absorption, metabolism, or excretion of Clozapine or other study medications
• Patients with history of granulocytopenia or myeloproliferative disorder, either drug-induced or idiopathic
• Patients with history of clinically significant cardiovascular, renal, hepatic, respiratory, endocrine (except noninsulin-dependent diabetes mellitus), or gastrointestinal disease
• Patient’s positive for HIV, HBs Ag or HCV
• Patients with history of epilepsy or seizures or are comatose or experiencing severe central nervous system depression
• Patients who are unable to communicate with the investigator and study team
• Patients with a history of allergic reactions to Clozapine or chemically related psychotropic drugs
• Patients having concurrent primary psychiatric or neurological diagnosis, including organic mental disorder (DSM-V criteria), mental retardation, severe tardive dyskinesia, or idiopathic Parkinson’s disease
• Patients who had undergone electroconvulsive therapy within the past 1 month
• Patients have demonstrated clinically significant homicidal behaviour within the past 12 months
• Patients have received any investigational drug within the past 90 days
• Patients having a history of narrow-angle glaucoma
• Patients requiring 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
• Patients with known history of phenylketonuria
• 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)
• Concurrent use of antihypertensive medication or any medication that might pre-dispose to orthostatic hypotension
• Positive tests for drug or alcohol abuse at screening and before check-in
• A history of alcohol or drug dependence by DSM-V criteria during the 6-month period immediately prior to study entry
• History of multiple syncopal episodes
• Patients who smoke more than 10 cigarettes / day or unable to abstain from smoking during the study
• Expected changes in concomitant medication during the period of study
Method of Generating Random Sequence
Other
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
• AUC0-tau ss: Area under the plasma concentration – time curve over the steady state dosing interval
• Cmax ss: Maximum concentration over the steady state dosing interval
On Day 10 and Day 20
Secondary Outcome
Outcome
TimePoints
• Cmin ss: Minimum concentration over the steady state dosing interval
• Cavg ss: Average concentration over the steady state dosing interval
• Tmax ss: Time of maximum measured plasma concentration over the steady state dosing interval
• Percentage fluctuation: [100 × (Cmax ss - Cmin ss)/Cavg ss]
• Swing [Cmax ss – C min ss/Cmin ss] × 100
• Cpd (pre-dose concentration)-Pre-dose concentrations determined before a dose at steady state
Cmin ss, Cavg ss, Tmax ss, Percentage fluctuation, Swing on Day 10 and Day 20
Cpd (pre-dose concentration) on Day 7 to Day 10; Day 17 to Day 20
Target Sample Size
Total Sample Size="56" Sample Size from India="56" Final Enrollment numbers achieved (Total)= "" Final Enrollment numbers achieved (India)=""
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
This study is a multi-centric, open-label, randomized, two-treatment, two-sequence, two-period, crossover, steady-state clinical bioequivalence study of ZIPROC-100 (Clozapine) 100 mg tablets of Torrent Pharma Philippines Inc., Philippines (Test) with LEPONEX® (Clozapine)100 mg tablets of Novartis Healthcare Philippines, Inc., Philippines (Reference) in schizophrenic patients who are receiving stable daily dose of Clozapine 100 mg BID under fasting conditions. Patients will be randomized in 1:1 ratio to either Test or Reference (as per the randomization schedule) and 100 mg tablets will be administered twice daily orally for 10 days (each period) followed by crossover without washout period under fasting conditions. Plasma concentration of clozapine will be quantified using a validated liquid chromatography-mass spectrometry (LC-MC/MS) analytical method.
Statistical analyses will be performed on individual PK parameters (AUC0-tau ss, Cmax ss, Cmin ss, Cavg ss,Tmax ss, percentage fluctuation, swing, and Cpd) of Clozapine obtained for different time points for ZIPROC-100 versus LEPONEX® using the SAS® package (SAS® Institute Inc., USA, Version 9.2or higher).
Arithmetic means, standard deviations and coefficients of variation will be calculated for all the PK parameters. Additionally, geometric means will be calculated AUC0-tau ss, Cmax ss, Cmin ss, Cavg ss, Tmax ss, percentage fluctuation, swing, and Cpd. ANOVA, ratio analysis, 90 % confidence interval (CI), inter- and intra-subject variability, and power will be calculated for the primary PK parameters(AUC0-tau ss, Cmax ss) using the SAS® package (SAS® Institute Inc., USA, Version 9.2 or higher).