Gates Open Research Gates Open Research 2017, 1:9 Last updated: 19 MAY 2021 STUDY PROTOCOL Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial [version 1; peer review: 3 approved] Ray Y. Chen 1, Laura E. Via1,2, Lori E. Dodd3, Gerhard Walzl4, Stephanus T. Malherbe4, André G. Loxton4, Rodney Dawson5, Robert J. Wilkinson 2,6,7, Friedrich Thienemann2,8, Michele Tameris 9, Mark Hatherill 9, Andreas H. Diacon10, Xin Liu11, Jin Xing12, Xiaowei Jin13, Zhenya Ma14, Shouguo Pan15, Guolong Zhang12, Qian Gao16, Qi Jiang16, Hong Zhu17, Lili Liang10, Hongfei Duan18, Taeksun Song19, David Alland20, Michael Tartakovsky21, Alex Rosenthal21, Christopher Whalen21, Michael Duvenhage21, Ying Cai1, Lisa C. Goldfeder1, Kriti Arora1, Bronwyn Smith4, Jill Winter22, Clifton E. Barry III1,2, Predict TB Study Group 1Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA 2Wellcome Centre for Infectious Diseases Research in Africa,Institute of Infectious Disease and Molecular Medicine, University of Cape Town (UCT), Cape Town, South Africa 3Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA 4South Africa Department of Science and Technology - National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 5Division of Pulmonology, Department of Medicine, University Of Cape Town Lung Institute, University of Cape Town (UCT), Cape Town, South Africa 6Francis Crick Institute, London, NW1 2AT, UK 7Department of Medicine, Imperial College London, London, W2 1PG, UK 8Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland 9South African Tuberculosis Vaccine Initiative, University of Cape Town (UCT), Cape Town, South Africa 10TASK Applied Science and Stellenbosch University, Cape Town, South Africa 11Henan Provincial Chest Hospital, Zhengzhou, Henan, China 12Henan Provincial Institute of Tuberculosis and Prevention, Henan Center for Disease Control, Zhengzhou, Henan, China 13Xinmi City Institute of Tuberculosis Prevention and Control, Xinmi, Henan, China 14Kaifeng City Institute of Tuberculosis Prevention and Control, Kaifeng, Henan, China 15Zhongmu County Health and Epidemic Prevention Station, Zhongmu, Henan, China 16Fudan University, Shanghai, China 17Sino-US Tuberculosis Collaborative Research Program, Zhengzhou, Henan, China 18Beijing Chest Hospital, Beijing, China 19Institute of Infectious Disease and Molecular Medicine, University of Cape Town (UCT), Cape Town, South Africa 20Division of Infectious Diseases, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA 21Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA 22Catalysis Foundation for Health, Emeryville, CA, USA Page 1 of 24 Gates Open Research Gates Open Research 2017, 1:9 Last updated: 19 MAY 2021 v1 First published: 06 Nov 2017, 1:9 Open Peer Review https://doi.org/10.12688/gatesopenres.12750.1 Latest published: 06 Nov 2017, 1:9 https://doi.org/10.12688/gatesopenres.12750.1 Reviewer Status Invited Reviewers Abstract Background: By the early 1980s, tuberculosis treatment was 1 2 3 shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4- version 1 month arms consistently having relapse rates of 15-20%. One trial 06 Nov 2017 report report report shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. 1. Toyin Togun , McGill University, Montreal, The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01). We Canada hypothesize that PET/CT characteristics at baseline, PET/CT changes at Emily MacLean , McGill University, one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) Montreal, Canada of standard treatment. 2. Andrew J. Nunn, University College London, Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. London, UK Those eligible start standard of care treatment. PET/CT scans are done Conor Tweed, University College London, at weeks 0, 4, and 16 or 24. Participants who do not meet early London, UK treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four 3. Beth Shoshana Zha, University of California, months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at San Francisco, San Francisco, USA week 16 to continue treatment to week 24 (Arm B) or complete Payam Nahid, University of California, San treatment at week 16 (Arm C). The primary endpoint compares the Francisco, San Francisco, USA treatment success rate at 18 months between Arms B and C. Discussion: Multiple biomarkers have been assessed to predict TB Any reports and responses or comments on the treatment outcomes. This study uses PET/CT scans and GeneXpert article can be found at the end of the article. (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. Trial Registration: NCT02821832 Keywords pulmonary tuberculosis, drug sensitive, PET/CT, GeneXpert, cycle threshold, treatment shortening, biomarkers, MERM Page 2 of 24 Gates Open Research Gates Open Research 2017, 1:9 Last updated: 19 MAY 2021 Corresponding author: Clifton E. Barry III ([email protected]) Author roles: Chen RY: Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing; Via LE: Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing; Dodd LE: Conceptualization, Data Curation, Formal Analysis, Methodology, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing; Walzl G: Conceptualization, Funding Acquisition, Investigation, Methodology, Resources, Supervision, Writing – Review & Editing; Malherbe ST: Conceptualization, Investigation, Supervision, Writing – Review & Editing; Loxton AG: Investigation, Validation, Writing – Review & Editing; Dawson R: Conceptualization, Investigation, Supervision, Writing – Review & Editing; Wilkinson RJ: Conceptualization, Investigation, Supervision, Writing – Review & Editing; Thienemann F: Conceptualization, Investigation, Methodology, Supervision, Writing – Review & Editing; Tameris M: Conceptualization, Investigation, Supervision, Writing – Review & Editing; Hatherill M: Conceptualization, Investigation, Supervision, Writing – Review & Editing; Diacon AH: Conceptualization, Investigation, Supervision, Writing – Review & Editing; Liu X: Conceptualization, Investigation, Supervision; Xing J: Investigation, Resources, Supervision; Jin X: Investigation, Supervision; Ma Z: Investigation, Supervision; Pan S: Investigation, Supervision; Zhang G: Investigation, Resources, Supervision; Gao Q: Conceptualization, Funding Acquisition, Investigation, Methodology, Supervision, Writing – Review & Editing; Jiang Q: Investigation, Validation, Writing – Review & Editing; Zhu H: Investigation, Methodology, Project Administration, Supervision; Liang L: Investigation, Methodology, Writing – Review & Editing; Duan H: Methodology, Writing – Review & Editing; Song T: Investigation, Methodology, Supervision, Writing – Review & Editing; Alland D: Conceptualization, Writing – Review & Editing; Tartakovsky M: Resources, Software, Supervision; Rosenthal A: Resources, Software, Supervision; Whalen C: Resources, Software, Supervision; Duvenhage M: Data Curation, Software, Supervision, Validation; Cai Y: Conceptualization, Data Curation, Software, Validation, Writing – Review & Editing; Goldfeder LC: Conceptualization, Project Administration, Writing – Review & Editing; Arora K: Investigation, Methodology, Project Administration, Validation, Writing – Review & Editing; Smith B: Investigation, Methodology, Project Administration, Supervision, Validation, Writing – Review & Editing; Winter J: Conceptualization, Funding Acquisition, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing; Barry III CE: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing; Competing interests: No competing interests were disclosed. Grant information: Bill and Melinda Gates