A Randomized Trial of Efficacy and Safety of Adjunctive Vitamin D in the Treatment of Active Tuberculosis in India
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A Randomized Trial of Efficacy and Safety of Adjunctive Vitamin D in the Treatment of Active Tuberculosis in India by © Peter Daley MD FRCPC DTM+H A Thesis submitted to the School of Graduate Studies in partial fulfillment of the requirements for the degree of Masters in Science Clinical Epidemiology Memorial University of Newfoundland May 2014 St. John’s Newfoundland ABSTRACT Background: Vitamin D supplementation may benefit patients with active tuberculosis (TB) Design: A randomized, double-blinded, placebo-controlled clinical trial comparing standard active TB treatment to active TB treatment plus supplemental high dose oral vitamin D3 was performed in India. Methods: Treatment naïve, smear positive, HIV negative, pulmonary TB patients were randomized into two equal groups. Results: 247 patients were randomized, 121 to vitamin D and 126 to placebo. Baseline characteristics in both groups were similar. 101 patients in the vitamin D arm and 110 patients in the placebo arm were analyzed. Median time to culture conversion in the vitamin D group was 43.0 days (95% C.I. = 33.3 to 52.8), as compared to was 42.0 days (33.9 to 50.1) in the placebo group (p=0.95 by log rank test). Hypercalcemia was not observed. Conclusions: Vitamin D supplementation was safe but did not influence time to culture conversion. Word Count: 145 Clinicaltrials.gov NCT00366470 Clinical Trials Registry of India CTRI/2007/091/00008 20-10-2009 Drugs Controller General of India DCGI-F-NO: 12-01-2006-DC(pt.51) dt 11-09-2009 India Health Ministry Screening Committee 5/8/9/66/2007-ECO-1 dt 13-07-2009 ii ACKNOWLEDGEMENTS Adrian Martineau, for dose and design suggestions and toxicity data Madhukar Pai, for inspiration and instruction Marek Smieja, for early support DJ Christopher, for permission to recruit from CMC DOTS clinic Joel Nesaraj, for permission to recruit from Bethesda Hospital, Ambur Om Prakash, for data management and programming Saravanan, Pratheema and Naeem, for recruitment assistance Arun Jose, for biochemistry testing Linto Thomas, for blood collection and data entry Raja Sivanandan and Asha Frederick, district TB officers, for assistance in recruitment R. Jeyamurugan and M. Anandan, senior TB lab supervisors, for assistance in recruitment Walter Schlech, for serving as contact with Dalhousie University Heather Haldane, for assistance in ethics submissions and permissions at Dalhousie University Prathap Tharyan, for support and advice iii Table of Contents ABSTRACT ....................................................................................................................... ii ACKNOWLEDGEMENTS ............................................................................................... iii Table of Contents ............................................................................................................... iv List of Tables ....................................................................................................................... v List of Figures .................................................................................................................... vi List of Plates ..................................................................................................................... vii List of Symbols, Nomenclature or Abbreviations ........................................................... viii List of Appendices ............................................................................................................. ix Introduction ........................................................................................................................ 10 Methods ............................................................................................................................. 18 Results................................................................................................................................ 25 Discussion .......................................................................................................................... 44 Bibliography ...................................................................................................................... 49 Appendix ............................................................................ ...................................................55 iv List of Tables Table 1 : Previous Randomized Trials of Vitamin D Supplementation in Tuberculosis ... 16 Table 2: Socio demographic characteristics....................................................................... 27 Table 3: Primary Outcome – Time to Culture Conversion (First Negative Culture) ........ 31 Table 4: Secondary Outcome – Time to Culture Conversion (First of Two Consecutive Negative Cultures) ............................................................................................................. 32 Table 5: Secondary Outcome – Time to Smear Conversion (First Negative Smear) ........ 34 Table 6: Secondary Outcome – Time to Smear Conversion (First of Two Consecutive Negative Smears) ............................................................................................................... 35 Table 7: Secondary Outcome - Percent Sputum Culture Negative at day 56 .................... 36 Table 8: Secondary Outcome – Change in Vitamin D Levels ........................................... 38 Table 9: Serious Adverse Events (Chronological Order) .................................................. 42 Table 10: Adverse Events .................................................................................................. 44 v List of Figures Figure 1: Participant Flow ................................................................................................. 26 Figure 2 : Primary Outcome – Time to Culture Conversion (First Negative Culture) ...... 32 Figure 3: Primary Outcome – Time to Culture Conversion (First of Two Consecutive Negative Cultures) ............................................................................................................. 33 Figure 4: Secondary Outcome – Time to Smear Conversion (First Negative Smear) ....... 34 Figure 5: Secondary Outcome – Time to Smear Conversion (First of Two Consecutive Negative Smears) ............................................................................................................... 36 Figure 6 – Secondary Outcome - Time to Detection in Liquid Culture by Intervention ... 37 Figure 7: Safety - Calcium levels ....................................................................................... 40 vi List of Plates None vii List of Symbols, Nomenclature or Abbreviations In Order of Appearance TB Tuberculosis HIV Human Immunodeficiency Virus RNTCP Revised National TB Control Program DOTS Directly Observed Therapy, Short course 25(OH)D 25-hydroxyvitamin D 1,25(OH)2D 1,25-dihydroxyvitamin D PTH Parathyroid hormone VDR Vitamin D receptor ATT Anti-TB treatment SAE Serious adverse events AE Adverse events BMI Body Mass Index viii List of Appendices Appendix 1 Consent Form Appendix 2 Tamil Consent Form Appendix 3 Ethics Approval Christian Medical College Vellore Appendix 4 Ethics Approval Dalhousie University Appendix 5 Case Report Form Clinical Appendix 6 Case Report Form Laboratory Appendix 7 Drugs Controller General of India Approval Appendix 8 Health Ministry Screening Committee Approval ix 10 Introduction Tuberculosis (TB) is a disease recognized from antiquity, which continues to remain one of the most important infectious diseases in the world. The World Health Organization annual TB report for 2012, containing data from 204 countries, summarized progress towards TB elimination.(1) The global TB mortality rate has decreased 41% since 1990, and is on target to achieve the Millennium Development Goal of 50% reduction by 2015. Access to TB care has increased significantly, collaborative approaches to TB and Human Immunodeficiency Virus (HIV) coinfection have been initiated, and new diagnostics have been developed. Despite this evidence of progress, there were 8.7 million new cases of TB in 2011, with 1.4 million deaths.(1) India continues to be the highest TB burden country in the world, with over 2 million cases of active TB every year.(2) TB kills nearly 280,000 men, women and children annually and is one of the leading causes of death in India. While the Revised National TB Control Program (RNTCP) has made progress, TB incidence continues to be high, and serious forms of drug-resistance have emerged, especially in urban hot spots. TB is caused by Mycobacterium tuberculosis complex, a group of bacterial pathogens with a cell wall containing large amounts of mycolic acid, inhaled into the lung, which disseminate throughout the body. It is estimated that one third of humans are infected with TB, however, this infection will remain latent (asymptomatic) for life in most people. The risk of disease activation from latent to active form is considerably increased in the presence of immunosuppression such as that caused by HIV infection.(3) Once activated, the infection damages tissue, and the body creates granulomatous 11 inflammation in an attempt to contain the spread of the organism. Without treatment among sputum smear positive pulmonary TB cases without HIV, 10 year mortality is 70%.(4) Diagnostic tools for TB are not ideal.(5) Culture of sputum in solid or liquid medium is the reference standard, but may take as long as six weeks for results. Sputum smear visualizes mycobacteria using acid fast staining, is rapid and cheap and correlates with burden of pulmonary disease,