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CTRI Number  CTRI/2017/08/009356 [Registered on: 11/08/2017] Trial Registered Prospectively
Last Modified On: 13/12/2017
Post Graduate Thesis  No 
Type of Trial  BA/BE 
Type of Study   Interventional 
Study Design  Randomized, Crossover Trial 
Public Title of Study   Bio equivalence study of Tablet Imatinib Mesylate 400 mg in adult patients with Chronic Myeloid Leukemia and /or Gastrointestinal Stromal Tumor who are on stable dose of Tablet Imatinib Mesylate 400 mg under fed condition. 
Scientific Title of Study   A multicenter, open label, randomized, balanced, steady state, two treatment, two period, two sequence, two-way crossover, multiple dose, bioequivalence study of Imatinib Mesylate Tablet 400 mg of Natco Pharma Limited, India with Gleevec® (Imatinib Mesylate) Tablet 400 mg of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 in adult human patients with Chronic Myeloid Leukemia and/or Gastrointestinal Stromal Tumor stabilized on Imatinib Mesylate 400 mg under fed condition. 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
16-VIN-0694 version 01 dated 30 May 2017  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Ashoka Kumar Singh 
Designation  Head - 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

Ahmadabad
GUJARAT
380 015
India 
Phone  7930013000  
Fax    
Email  Ashoka.Singh@veedacr.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Yogesh Patel 
Designation  Senior Manager- Medical Monitor 
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  7930013000  
Fax  07930013000  
Email  Yogesh.AP@veedacr.com  
 
Details of Contact Person
Public Query  
Name  Dr Ashoka Kumar Singh 
Designation  Head - 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  7930013000  
Fax    
Email  Ashoka.Singh@veedacr.com  
 
Source of Monetary or Material Support  
Natco Pharma Limited India NATCO Road No 2 Banjara Hills Hyderabad 500 034  
 
Primary Sponsor  
Name  Natco Pharma Limited 
Address  Natco House, Road no. 2 Banjara Hills, Hyderabad 500 034 
Type of Sponsor  Pharmaceutical industry-Indian 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study
Modification(s)  
No of Sites = 7  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Gopichand M  City Cancer Centre Cancer Hospital & Research  33 25 33 Ch.Venkata Krishnayya Street Suryraopet Vijayawada-520002
Krishna
ANDHRA PRADESH 		 9885256059
0866243077
mgopichand@yahoo.com 
Dr Kartikeya Jain  Kailash cancer hospital & Research centre  Muniseva ashram, Goraj, Waghodia Vadodara-391760, Gujarat,India
Vadodara
GUJARAT 		 91-26-53961300
91-26-68268048
kartikeya.jain@greenashram.org 
Dr T Kasi Vishwanathan  Meenakshi Mission Hospital And Research Centre   Centre Lake area Melur Raod Madurai 625 107 TamilNadu
Madurai
TAMIL NADU 		 9578145291
4522586353
clinicalresearch@mmhrc.in 
Dr Asis Mukhopadhyay  Netaji Subhas Chandra Bose Cancer Research Institute,   Netaji Subhas Chandra Bose Cancer Research Institute A Unit of Himadri Memorial Cancer Welfare trust 16 A Park lane Kolkata 700016 West Bengal
Kolkata
WEST BENGAL 		 9874210008
03322264704
ncri.clinicalresearch@gmail.com 
Dr Satheesh CT  Shettys hospital  plot no 11&12, 12th F main, keveri nagar, Bommanahalli, Bangalore-5600068,Karnataka,India
Bangalore
KARNATAKA 		 91-80-25831613
91-80-25831613
shettyshospital@gmail.com 
Dr Rajeev L K   Sri Venkateshwara Hospitals  86 Hosur Main road Madiwala Bangalore 560068
Bangalore
KARNATAKA 		 9880585797
0802530006
lkrajeev@gmail.com 
Dr KC Lakshimiah  Srinivasam Cancer Care Multispeciality Hospitals  #36,1st "A" Main , 5th Cross (Nethravathi Street), Maruthi nagar, nagarbhavi main road, Bangalore-560072, Karnataka.
Bangalore
KARNATAKA 		 80420099074
8026483304
kcluck@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 7  
Name of Committee  Approval Status 
Institutional Ethics Committee City Cancer Centre Cancer Hospital and Research   Approved 
Institutional Ethics Committee Meenakshi Mission Hospital and Research Centre  Approved 
Institutional Ethics Committee Netaji Subhas Chandra Bose Cancer Research Institute  Approved 
Kailash cancer & Medical Centre Intitutional Ethics Committee  Approved 
SCCMH Institutional Ethics Committee  Approved 
Shettys Hospital Ethics Committee  Approved 
Sri Venkateshwara Hospital Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  Chronic Myeloid Leukemia and or Gastrointestinal Stromal Tumor,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Gleevec® (Imatinib Mesylate) Tablets 400 mg  Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936  
Intervention  Imatinib Mesylate Tablets 400 mg  Manufactured by: Natco Pharma Limited, India 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  65.00 Year(s)
Gender  Both 
Details  1. Men and women, of age in between 18 years to 65 years (both inclusive).
2. Ability to provide written informed consent prior to participation in the study.
3. Chronic phase Chronic Myeloid Leukemia (CML) patients with documented evidence of Philadelphia positive chromosome who are on stable dose regimen of 400 mg once daily dose of Imatinib.
And/Or
Kit (CD 117) positive Gastrointestinal Stromal Tumor (GIST) (with documented evidence), who are on a stable dose regimen of 400 mg once daily dose of Imatinib.
4. Adequate organ function, defined as the following:
Hemoglobin > 9 mg/dL
Total bilirubin < 1.5 x upper limit of normal (ULN)
SGOT and SGPT < 2.5 x ULN
Serum Creatinine < 1.5 x ULN
Absolute neutrophil count (ANC) ≥1.5 x 109/L
Platelets ≥ 100 x 109/L
HbA1c < 9 %
5. Females of child-bearing potential (FOCP) must have negative pregnancy test at screening and must agree to use an acceptable method of birth control such as sexual abstinence or at least 2 reliable modes of contraception, one of which must be a double-barrier method (e.g., condom with spermicidal gel or diaphragm with spermicidal gel) or IUD or vaginal spermicidal suppository from screening until 14 days after last dose of study drug. [Note: Use of hormonal contraception (pills/hormonal intrauterine device etc,) is not allowed.] Patient agrees to accept the risk that pregnancy could still result despite using birth control devices.
OR
Post-menopausal females defined as 12 consecutive months of amenorrhea.
OR
Surgically sterilized females with documented evidence of hysterectomy / bilateral salpingectomy / bilateral oophorectomy. Females without documented evidence of surgery and those who has undergone tubal ligation will be considered of child bearing potential.
6. Male patient must agree to use an acceptable method of birth control such as sexual abstinence or barrier method of contraception (i.e. condom) from screening until 14 days after last dose of study drug. Patient agrees to accept the risk that pregnancy in female partner could still result despite using birth control devices.
7. No history of participation in any clinical study within the past 90 days.
 
 
ExclusionCriteria 
Details  1. Patients in accelerated phase or blast crisis phase.
2. Patients for whom a titration away from 400 mg dose is likely during the entire study period as per Investigator’s judgement.
3. Patient received any treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide and/or imatinib.
4. History of patient with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention.
5. Patient having history of major surgery within 4 weeks prior to study entry, or who have not recovered from prior major surgery.
6. Patients with an ECOG (Eastern Cooperative Oncology group) Performance Status Score > 3.
7. Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent.
8. Patients with identified sibling donors where allogeneic bone marrow transplant is elected as first line treatment.
9. Patients who are on or may require concomitant medications which are known to be inhibitors and/or inducers of CYP3A4 family (Annexure IV).
10. History of hematopoietic stem cell transplantation.
11. History of hypersensitivity to Imatinib or any of its excipients or related group of drugs.
12. Patients who are eligible and willing to undergo transplantation during the entire study period.
13. History of patients taking certain medications that are accepted to have a risk of causing Torsades de Pointes.
14. History of patients taking medications that irreversibly inhibit platelet function or anticoagulants.
15. History of uncontrolled diseases, such as thyroidal dysfunction, diabetes mellitus, angina pectoris, heart failure, neuropsychiatric disorders.
16. Patients who are at clinically high risk of developing Tumor Lysis Syndrome as per the investigator’s evaluation.
17. Patients who have undergone thyroidectomy or patients receiving levothyroxine.
18. Patients with history of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome during the prior therapy with imatinib or any other drug.
19. Recent history (within 6 months) of alcohol and/or drug addiction.
20. Patients who are human immunodeficiency virus (HIV) and HbsAg positive.
21. History of ascites and rapid weight gain with or without superficial edema.
22. History of prior radiotherapy to bone marrow.
23. Use of other concurrent anticancer agents other than Imatinib, including chemotherapy or biologic agents.
24. Positive results for drugs of abuse (benzodiazepines, opioids, amphetamines, cannabinoids cocaine and barbiturates) in urine.
25. Positive results for alcohol as detected by Alcohol Breath Analyzer.
26. History of difficulty with donating blood or difficulty in accessibility of veins.
27. An unusual or abnormal diet, for whatever reason e.g. religious fasting.
28. High caffeine (more than 5 cups of coffee or tea/day) or tobacco (more than 9 cigarettes/ beedies/ cigars per day) consumption.
29. History of patient for whom oral administration of drug is not possible.
30. Any other condition or abnormal baseline findings that, in the investigator’s judgment, might increase the risk to the patient or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study.
 
 
Method of Generating Random Sequence   Permuted block randomization, fixed 
Method of Concealment   Pharmacy-controlled Randomization 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
To assess the bioequivalence of Imatinib Mesylate Tablet 400 mg of Natco Pharma Limited, India with Gleevec® (Imatinib Mesylate) Tab 400 mg of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 in adult human patients with Chronic Myeloid Leukemia and/or Gastrointestinal Stromal Tumor stabilized on Imatinib Mesylate 400 mg under fed condition.  A total of thirty-eight (38) blood samples will be collected during study. The pre-dose blood sample
on Day 5 to day 7 and Day 12 to 14 will be collected within 5 minutes before dosing time. On Day 7
and 14, the post-dose blood samples of 3.0 mL each will be drawn at 0.50, 1.00, 1.50, 2.00, 2.50, 3.00,
3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 18.00 and 24.00 hrs following drug administration in each period for each subject. 
 
Secondary Outcome  
Outcome  TimePoints 
To monitor the adverse events and to ensure the safety of the patients.  Physical examination on screening, prior to check-in in each period on day 0, day 4, day 11 and during post study safety assessment after last PK sample in Period II. Oral body temperature, blood pressure, pulse rate at Screening, Day 0, Day 1, Day 5, Day 6 in Period I and on Day 8, Day 12, Day 13 in Period II, On Day 7 & Day 14 at predose & 1 hr, 3 hr, 6 hr, 13 hr post dose and during post study safety assessment after last PK sample in Period II. 
 
Target Sample Size   Total Sample Size="40"
Sample Size from India="40" 
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)   21/08/2017 
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="1"
Months="0"
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   Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. 
In vivo, Imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis. 
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, Imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation
 
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