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CTRI Number  CTRI/2018/01/011176 [Registered on: 08/01/2018] Trial Registered Prospectively
Last Modified On: 24/08/2019
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group Trial 
Public Title of Study
Modification(s)  
Metformin in Tuberculosis 
Scientific Title of Study
Modification(s)  
A phase IIB Open Label Randomized Controlled Clinical trial to Evaluate the anti-bacterial activity, pharmacokinetics, safety and tolerability of Metformin when given along with rifampicin, isoniazid, pyrazinamide and ethambutol in adults with newly diagnosed sputum positive pulmonary tuberculosis: an 8-week study 
Secondary IDs if Any  
Secondary ID  Registry 
Version 1.0; dated 10th September 2017  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr C Padmapriyadarsini  
Address  Department of Clinical Research, National Institute for Research in Tuberculosis No.1, Mayor Sathyamoorthy Road Chetput, Chennai-600 031
No.1, Mayor Sathyamoorthy Road, Chetput, Chennai-600 031
Chennai
TAMIL NADU
600031
India 
Phone  09498022949  
Fax  044-28362528  
Email  darsini69@hotmail.com  
 
Details Contact Person
Scientific Query
 
Name  Dr C Padmapriyadarsini  
Address  Department of Clinical Research, National Institute for Research in Tuberculosis No.1, Mayor Sathyamoorthy Road Chetput, Chennai-600 031
No.1, Mayor Sathyamoorthy Road, Chetput, Chennai-600 031
Chennai
TAMIL NADU
600031
India 
Phone  09498022949  
Fax  044-28362528  
Email  darsini69@hotmail.com  
 
Details Contact Person
Public Query
 
Name  Dr C Padmapriyadarsini  
Address  Department of Clinical Research, National Institute for Research in Tuberculosis No.1, Mayor Sathyamoorthy Road Chetput, Chennai-600 031
No.1, Mayor Sathyamoorthy Road, Chetput, Chennai-600 031
Chennai
TAMIL NADU
600031
India 
Phone  09498022949  
Fax  044-28362528  
Email  darsini69@hotmail.com  
 
Source of Monetary or Material Support
Modification(s)  
India TB Research Consortium Indian Council of Medical Research V. Ramalingaswami Bhawan P.O. Box No. 4911 Ansari Nagar New Delhi - 110029 
 
Primary Sponsor  
Name  National Institute for Research in Tuberculosis 
Address  No.1, Mayor Sathiyamoorthy Road Chetpet, Chennai 600031 Chennai TAMIL NADU  
Type of Sponsor  Government funding agency 
 
Details of Secondary Sponsor  
Name  Address 
Open Source Pharma Foundation  World Trade Center, 22nd floor, #N 2201 26/1 Dr Rajkumar Road, Malleshwaram West Bangalore, Karnataka 560055 India  
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 3  
Contact Person  Name of Site  Site Address  Phone/Fax/Email 
Dr Randeep Guleria MBBS MD DM  All India Institute of Medical Sciences  Ansari Nagar, (in front of Safdarjung Hospital) Aurobindo Marg New Delhi - 110608
South West
 
11-26588500
11-26588663
director.aiims@gmail.com 
Dr Mega Mamalwar Scientist B  ICMR-National AIDS Research Institute  73, ‘G’-Block MIDC Bhosari, Pune - 411026, Maharashtra , India
Pune
 
020-27331200
020-27121071
mmamulwar@nariindia.org 
Dr C Padmapriyadarsini Scientist E  ICMR-National Institute for Research in Tuberculosis  No.1, Mayor Sathiyamoorthy Road, Santosham Salai, Chetpet, Chennai, Tamil Nadu 600031, India
Chennai
 
09498022949
044-28362528
darsini69@hotmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 3  
Name of Committee  Approval Status 
All India Institute of Medical Sciences  Approved 
ICMR-National AIDS Research Institute  Approved 
ICMR-National Institute for Research inTuberculosis  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied
Modification(s)  
Health Type  Condition 
Patients  Pulmonary Tuberculosis 
Patients  Tuberculosis of lung 
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Isoniazid, Rifampicin, Ethambutol and Pyrazinamide   Control arm : Isoniazid + Rifampicin + Ethambutol + Pyrazinamide given daily 
Intervention  Metformin, Isoniazid, Rifampicin, Ethambutol, Pyrazinamide  Intervention arm : Metformin + Isoniazid + Rifampicin + Ethambutol + Pyrazinamide  
 
Inclusion Criteria
Modification(s)  
Age From  18.00 Year(s)
Age To  60.00 Year(s)
Gender  Both 
Details  A patient will be eligible for entry to the trial if ALL the following conditions are satisfied
1. Male or female, aged 18 years or over.
2. Willing to give written informed consent
3. Body weight ≥ 30 kg and <65kgs.
4. At least 2 sputum smears should be positive for TB bacilli
5. At least 1 sputum should be RMP /INH sensitive by Gene Xpert /LPA
6. No prior history of ATT (i.e. < 7 daily or 3 intermittent doses of ATT)
7. Is willing to have an HIV test.
8. Agrees to use effective barrier contraception during the period of the trial
9. Residing in and around the study sites of Chennai / Vellore / Madurai / Delhi / Pune and
10.Express willingness to attend the treatment center for supervised treatment
11. Express willingness to adhere to the trial procedures and follow-up schedule
 
 
ExclusionCriteria 
Details  A Patient will not be eligible for the trial if they meet ANY of the following criteria
1. Body weight < 30 kgs or > 65 kgs
2. Has history of previous anti-TB treatment (more than a month).
3. Is infected with a strain of M tb resistant to rifampicin, and pyrazinamide by indirect susceptibility test in liquid culture.
4. Has clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis).
5. Is of poor general condition where any delay in treatment could not be tolerated (Karnofsky scale <50)
6. Has any evidence of renal impairment, including but not limited to serum creatinine levels above the upper limit of the laboratory reference range (Serum creatinine >1.2 mg/dL or blood yrea >43 mg/dL)
7. Has clinical icterus or hepatic impairment characterized by serum bilirubin level above 1.2 times upper limit of the laboratory reference range, or by alanine aminotransferase (ALT) and/ or aspartate aminotransferase (AST) levels >3 times the upper limit of the laboratory reference range
8. Psychiatric illness
9. Serology positive for HBS Ag or Hepatitis C virus antibody
10. Is pregnant or lactating
11. Known case of Diabetes mellitus /RBS> 200mg/dl /FBS>140 mg/dl
12. Has a history and/ or presence (or evidence) of neuropathy or Epilepsy.
13. Has any condition (social or medical) which in the opinion of the investigator would make trial participation unreliable or unsafe.
14. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
15. Has a known allergy to any of the drugs proposed to be used in the trial regimen
16. Has evidence of clinically significant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities.
 
 
Method of Generating Random Sequence   Permuted block randomization, fixed 
Method of Concealment   On-site computer system 
Blinding/Masking   Open Label 
Primary Outcome
Modification(s)  
Outcome  TimePoints 
The primary endpoint will be the time to sputum culture conversion.   8 weeks of treatment 
 
Secondary Outcome  
Outcome  TimePoints 
1. Drug concentrations and pharmacokinetic parameters of R, H, Z and MET in adults with pulmonary TB patients receiving MET with standard first-line ATT

2.Measurement of biomarkers and immune responses for the impact of MET on TB disease activity
3.Median time to detection (TTD) of M.tb in culture through 8 weeks of therapy between those receiving MET containing ATT regimen and the standard ATT

4. Treatment Emergent Adverse Events
 
At 1, 2, 3, 4, 5, 6, 7 & 8 weeks after randomization.  
 
Target Sample Size   Total Sample Size="316"
Sample Size from India="316" 
Phase of Trial   Phase 2 
Date of First Enrollment (India)
Modification(s)  
11/01/2018 
Date of First Enrollment (Global)  No Date Specified 
Estimated Duration of Trial   Years="3"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  
Not Applicable 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   NONE YET 
Brief Summary  

It is assumed that adding the anti-diabetic drug Metformin would have a more beneficial effect in terms of early killing of intracellular TB bacilli by influencing the host immune response. We propose to investigate the immune mediated effect of metformin on newly diagnosed sputum smear positive pulmonary TB patients and the time to intracellular killing of mycobacterium.

We plan a Phase IIB, open label, parallel arm, randomized controlled clinical trial among newly diagnosed sputum smear positive pulmonary TB patients to evaluate the anti-bacterial activity of Metformin, by measuring the time to sputum culture conversion in liquid media, when given daily for 8-weeks along with standard first-line anti-tuberculosis treatment (ATT) in adults with newly diagnosed sputum positive Pulmonary TB (PTB). We plan to determine 1, 2, 4, 6 , 8 and 12 hour post dosing concentration of rifampicin, isoniazid, pyrazinamide and Metformin in a subset of adults with newly diagnosed sputum positive PTB and to evaluate the role of metformin as host-directed therapy in PTB patients on metformin containing ATT by measuring candidate biomarkers and immune responses as an autophagy enhancer in intracellular killing of M.tb (in cell lines). These findings will be compared with the group of patients on the standard first-line daily ATT. This will be done in 316 patients, 158 patients in each treatment arm. Intervention drug, Metformin, will be given for 8 weeks of the treatment. Continuation Phase will be given for remaining 4 months as usual. Study will be completed in 3 years.














 

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