CTRI Number	CTRI/2018/01/011176 [Registered on: 08/01/2018] Trial Registered Prospectively
Last Modified On:	10/07/2021
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)	Closed to Recruitment of Participants
Publication Details Modification(s)	One manuscript published in BMJ Open 2018
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.