CTRI/2018/07/014995 [Registered on: 20/07/2018] Trial Registered Prospectively
Last Modified On:
10/01/2020
Post Graduate Thesis
No
Type of Trial
BA/BE
Type of Study
Study Design
Randomized, Crossover Trial
Public Title of Study
Pharmacokinetic study of two formulations of Azathioprine Tablets 50 mg in Adult Subjects with Rheumatoid Arthritis.
Scientific Title of Study
A Randomized, Open-Label, Two-Period, Two-Treatment, TwoSequence, Crossover, Multicenter, Single-Dose, Bioequivalence Study of Azathioprine Scored Tablets 50 mg of Alkem Laboratories Limited and ‘IMURAN’ (Azathioprine) Scored Tablets 50 mg of Prometheus Laboratories Inc., USA in Adult Subjects with Rheumatoid Arthritis under Fasting Conditions.
Trial Acronym
Nil
Secondary IDs if Any
Secondary ID
Identifier
CRL031818 version 1.0 dated 07 May 2018
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Ethics Committee, Meditrina Institute of Medical Sciences
Approved
Institutional Ethics Committee, Aman Hospital
Submittted/Under Review
Institutional EthicsCommittee, Dr. Jivraj Mehta
Approved
Medilink Ethics Committee Basement Medilink Hospital Research Centre
Approved
Shree Hospital Ethics Committee
Approved
Sushruta Hospital Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
Rheumatoid Arthritis under Fasting Conditions.,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Azathioprine Scored Tablets 50 mg of Alkem Laboratories Limited, India.
In the morning single oral dose , one tablet or two tablets of 50 mg, will be administered in a sitting posture once in a day for 1 day with 240 ml of ambient temperature water.
Comparator Agent
IMURAN (Azathioprine) Scored Tablets 50 mg of Prometheus Laboratories Inc., USA
In the morning single oral dose , one tablet or two tablets of 50 mg, will be administered in a sitting posture once in a day for 1 day with 240 ml of ambient temperature water.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
65.00 Year(s)
Gender
Both
Details
Subjects who qualify for the study should meet the following inclusion criteria:
1. Males or non-pregnant or non-lactating females between 18-65 years of age (both inclusive). All males and females of childbearing potential must practice an acceptable method of contraception.
2. RA subjects on maintenance therapy with single fixed dose of Azathioprine 50 mg/100 mg per day with or without a fixed dose (maximum of 30 mg/week) of Methotrexate.
3. Subjects with prior/current use of corticosteroids usage can be enrolled provided that they should be on or off maintenance for at least 2 weeks prior to enrollment. The maximal daily dose of corticosteroid at Baseline must not exceed the equivalent of 10 mg of prednisone and subjects willing to not change their concurrent medications during the study.
4. All subjects should have a Body Mass Index (BMI) less than or equal to 30 but greater than or equal to 18. BMI values should be rounded to the nearest integer. (e.g. 30.4 rounds down to 30, while 17.5 rounds up to 18).
5. Able to provide written informed consent to participate in the study.
6. Able to comply with study requirements and assessments.
ExclusionCriteria
Details
Subjects with any of the following criteria should be excluded:
1. History of allergic responses to Azathioprine, or other related drugs and any of its formulation ingredients.
2. Institutionalized subjects.
3. Subjects receiving Disease Modifying Anti-Rheumatic Drugs (DMARDs) other than allowed in the study.
4. Subjects who have changed their dose or regimen of Azathioprine in the last 4 weeks.
5. Subjects with presence of TPMT mutation and/or presence of NUDT15 mutation who are at increased risk of drug toxicity.
6. Subjects with Hemoglobin level less than 10 gm%.
7. Subjects with inadequate hepatic, renal and bone marrow function. Hepatic function: Alanine Transaminase (ALT) / Aspartate Transaminase (AST) / Alkaline Phosphatase / Bilirubin > 2 x upper limit of normal. Renal function: Serum Creatinine> 2 x upper limit of normal.
Bone marrow function: ANC less than or equal to 1500/mm3 and WBC less than or equal to 4000/mm3 (should meet both), total platelet count less than 1 x lower limit of normal range.
8. Subjects who are receiving xanthine oxidase inhibitor (e.g. allopurinol, oxipurinol and thiopurinol), aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine), drugs affecting leucocyte production e.g. cotrimoxazole, ACE inhibitors, warfarin, ribavirin or similar drugs.
9. Subjects undergoing concomitant chemotherapy.
10. Received live attenuated vaccine with in last 3 months.
11. History of or currently receiving doxorubicin.
12. Subjects with severe infections (e.g. active hepatitis, pneumonia, or pyelonephritis) within 2 months of screening. Less severe infections (such as acute upper respiratory tract infection [colds] or a simple urinary tract infection) need not be considered as exclusion and should be kept at the discretion of the investigator.
13. Subjects with a non-tuberculous mycobacterial infection or opportunistic infection (e.g. cytomegalovirus, pneumocystis carinii, aspergillosis) within 6 months prior to screening.
14. Subjects who have a known history of demyelinating disease suggestive of multiple sclerosis or optic neuritis.
15. Subjects who have presence of a transplanted organ (with the exception of a corneal transplant more than 3 months prior to screening).
16. Subjects who have a history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (e.g. nodes in the posterior triangle of the neck, infra-clavicular, epitrochlear, or periaortic areas), or splenomegaly.
17. Subjects who have any current known malignancy or malignancy within 5 years prior to screening (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence).
18. Subjects who have other inflammatory diseases i.e. Systemic Lupus Erythematosus (SLE), Multiple sclerosis, Ankylosing spondylitis etc.
19. Subjects who have a history of latent or active granulomatous infection, including tuberculosis (TB), histoplasmosis, or coccidioidomycosis.
20. Use of prohibited medications (listed in Section 9.0) within 30 days prior to enrollment in the study.
21.Consumption of grapefruit, grapefruit-like or grapefruit containing products within 7 days of drug administration.
22. Ingestion of any alcoholic, caffeine or xanthine containing food or beverage within the 48 hours prior to randomization.
23. Major surgery to the gastrointestinal tract, the liver or kidney within 4 weeks of study entry (Check-in day) which may impact on the pharmacokinetics of Azathioprine.
24. History of drug dependence, history of alcoholism in the past 2 years prior to screening.
25. History of difficulty in swallowing, or any gastrointestinal disease which could affect drug absorption.
26. Donation or loss of blood or plasma of one unit (about 450 mL whole blood or 220 mL plasma) in the previous 60 days.
27. History of difficulty with donating blood or difficulty in accessibility of veins or intolerance to venipuncture.
28. History of allergic response to heparin.
29. A positive hepatitis screen (includes subtypes B and C).
30. A positive test result for HIV antibody or syphilis (RPR/VDRL).
31. Any significant ECG changes.
32. Any significant disease or condition which might compromise the haemopoeitic, gastrointestinal (e.g. pancreatitis), renal, hepatic, cardiovascular, respiratory, central nervous system, diabetes, psychosis, or any other body system.
33. Participation in any investigational drug study within 30 days prior to initial dose of study drug.
34. Any food allergy, intolerance, restriction or special diet that, in the opinion of the Principal Investigator or Sub-Investigator, could contraindicate the subject’s participation in this study .
35. Any other condition that, in the investigator’s judgment, might increase the risk to the subject or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Not Applicable
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
Pharmacokinetic parameters Cmax, AUCt, AUCi, Tmax, Kel, tHalf and AUC_%Extrap_obs
In each period, total 15 venous blood samples (06 mL each) will be collected, at pre-dose (0.0 hour) and at 0.167, 0.333, 0.5, 0.667, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0 and 8.0 hours
Secondary Outcome
Outcome
TimePoints
To evaluate the safety of Investigational Products.
NA
Target Sample Size
Total Sample Size="64" Sample Size from India="64" Final Enrollment numbers achieved (Total)= "0" Final Enrollment numbers achieved (India)="64"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
A Randomized, Open-Label, Two-Period, Two-Treatment, TwoSequence, Crossover, Multicenter, Single-Dose, Bioequivalence Study of Azathioprine Scored Tablets 50 mg of Alkem Laboratories Limited and ‘IMURAN®’ (Azathioprine) Scored Tablets 50 mg of Prometheus Laboratories Inc., USA in Adult Subjects with Rheumatoid Arthritis under Fasting Conditions.
64 subjects will be required to be enrolled (randomized) in the study for approx. 60 days that includes screening period and treatment period.
The end of the study will be the date of the last study visit for the last subject in the study.
The study will commence only after the approval from the Local Regulatory Approval (DCGI).