Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial

Chandrasekaran Padmapriyadarsini, Perumal K Bhavani, Mohan Natrajan, Chinnayan Ponnuraja, Hemanth Kumar, Sivaramakrishnan N Gomathy, Randeep Guleria, Shaheed M Jawahar, Manjula Singh, Tanjore Balganesh, Soumya Swaminathan, Chandrasekaran Padmapriyadarsini, Perumal K Bhavani, Mohan Natrajan, Chinnayan Ponnuraja, Hemanth Kumar, Sivaramakrishnan N Gomathy, Randeep Guleria, Shaheed M Jawahar, Manjula Singh, Tanjore Balganesh, Soumya Swaminathan

Abstract

Introduction: Shorter duration of treatment for the management of drug-susceptible pulmonary tuberculosis (TB) would be a significant improvement in the care of patients suffering from the disease. Besides newer drugs and regimens, other modalities like host-directed therapy are also being suggested to reach this goal. This study's objective is to assess the efficacy and safety of metformin-containing anti-TB treatment (ATT) regimen in comparison to the standard 6-month ATT regimen in the treatment of patients with newly diagnosed sputum smear-positive drug-sensitive pulmonary TB.

Methods and analysis: We are conducting a multicentric, randomised open-label controlled clinical trial to achieve the study objective. The intervention group will receive isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) along with 1000 mg of daily metformin (Met) for the first 2 months while the control group will receive only HRZE. After 2 months, both the groups will receive HRE daily for 4 months. The primary endpoint is time to sputum culture conversion. Secondary endpoints will include time to detection of Mycobacterium tuberculosis in sputum, pharmacokinetics and pharmacogenomics of study drugs, drug-drug interactions, safety and tolerability of the various combinations and measurement of autophagy and immune responses in the study participants.

Ethics and dissemination: The ethics committee of the participating institutes have approved the study. Results from this trial will contribute to evidence towards constructing a shorter, effective and safe regimen for patients with TB. The results will be shared widely with the National Programme managers, policymakers and stakeholders through open access publications, dissemination meetings, conference abstracts and policy briefs. This is expected to provide a new standard of care for drug-sensitive patients with pulmonary TB who will not only reduce the number of clinic visits and lost to follow-up of patients from treatment but also reduce the burden on the healthcare system.

Trial registration number: CTRI/2018/01/011176; Pre-results.

Keywords: clinical trials; public health; respiratory infections; tuberculosis.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

References

    1. World Health Organization. Global Tuberculosis Report. Geneva, 2017. Accessed
    1. Kuijl C, Savage ND, Marsman M, et al. . Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1. Nature 2007;450:725–30. 10.1038/nature06345
    1. Ejim L, Farha MA, Falconer SB, et al. . Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol 2011;7:348–50. 10.1038/nchembio.559
    1. Bhatt K, Salgame P. Host innate immune response to Mycobacterium tuberculosis. J Clin Immunol 2007;27:347–62. 10.1007/s10875-007-9084-0
    1. Behar SM, Divangahi M, Remold HG. Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy? Nat Rev Microbiol 2010;8:668–74. 10.1038/nrmicro2387
    1. Gutierrez MG, Master SS, Singh SB, et al. . Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 2004;119:753–66. 10.1016/j.cell.2004.11.038
    1. Kim J, Kundu M, Viollet B, et al. . AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011;13:132–41. 10.1038/ncb2152
    1. Kumar D, Nath L, Kamal MA, et al. . Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell 2010;140:731–43. 10.1016/j.cell.2010.02.012
    1. Singhal A, Jie L, Kumar P, et al. . Metformin as adjunct antituberculosis therapy. Sci Transl Med 2014;6:263ra159 10.1126/scitranslmed.3009885
    1. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events. Version 2.1, 2017. (Accessed on 29 Mar 2018).
    1. Wang JY, Wang JT, Tsai TH, et al. . Adding moxifloxacin is associated with a shorter time to culture conversion in pulmonary tuberculosis. Int J Tuberc Lung Dis 2010;14:65–71.
    1. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999;3:S231–79.
    1. El-Mir MY, Nogueira V, Fontaine E, et al. . Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000;275:223–8. 10.1074/jbc.275.1.223
    1. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000;348 Pt 3:607–14. 10.1042/bj3480607
    1. Hardie DG. The AMP-activated protein kinase pathway--new players upstream and downstream. J Cell Sci 2004;117:5479–87. 10.1242/jcs.01540
    1. Davis BJ, Xie Z, Viollet B, et al. . Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 2006;55:496–505. 10.2337/diabetes.55.02.06.db05-1064
    1. Tan HY, Wang N, Li S, et al. . The reactive oxygen species in macrophage polarization: Reflecting its dual role in progression and treatment of human diseases. Oxid Med Cell Longev 2016;2016:1–16. 10.1155/2016/2795090
    1. Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327:951 10.1136/bmj.327.7421.951
    1. Levri KM, Slaymaker E, Last A, et al. . Metformin as a treatment for overweight and obese adults. Ann Fam Med 2005;3:457–61.
    1. Technical and operational guidelines for TB control in India. 2016. (Accessed on 17 Nov 2018).
    1. Bark CM, Furin JJ, Johnson JL. Approaches to clinical trials of new anti-TB drugs. Clin Investig 2012;2:359–70. 10.4155/cli.12.22
    1. Sullivan T, Ben Amor Y, Amor BY. The co-management of tuberculosis and diabetes: challenges and opportunities in the developing world. PLoS Med 2012;9:e1001269 10.1371/journal.pmed.1001269
    1. Marupuru S, Senapati P, Pathadka S, et al. . Protective effect of metformin against tuberculosis infections in diabetic patients: an observational study of south Indian tertiary healthcare facility. Braz J Infect Dis 2017;21:312–6. 10.1016/j.bjid.2017.01.001

Source: PubMed

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