High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial

Susan E Dorman, Payam Nahid, Ekaterina V Kurbatova, Stefan V Goldberg, Lorna Bozeman, William J Burman, Kwok-Chiu Chang, Michael Chen, Mark Cotton, Kelly E Dooley, Melissa Engle, Pei-Jean Feng, Courtney V Fletcher, Phan Ha, Charles M Heilig, John L Johnson, Erica Lessem, Beverly Metchock, Jose M Miro, Nguyen Viet Nhung, April C Pettit, Patrick P J Phillips, Anthony T Podany, Anne E Purfield, Kathleen Robergeau, Wadzanai Samaneka, Nigel A Scott, Erin Sizemore, Andrew Vernon, Marc Weiner, Susan Swindells, Richard E Chaisson, AIDS Clinical Trials Group and the Tuberculosis Trials Consortium, Susan E Dorman, Payam Nahid, Ekaterina V Kurbatova, Stefan V Goldberg, Lorna Bozeman, William J Burman, Kwok-Chiu Chang, Michael Chen, Mark Cotton, Kelly E Dooley, Melissa Engle, Pei-Jean Feng, Courtney V Fletcher, Phan Ha, Charles M Heilig, John L Johnson, Erica Lessem, Beverly Metchock, Jose M Miro, Nguyen Viet Nhung, April C Pettit, Patrick P J Phillips, Anthony T Podany, Anne E Purfield, Kathleen Robergeau, Wadzanai Samaneka, Nigel A Scott, Erin Sizemore, Andrew Vernon, Marc Weiner, Susan Swindells, Richard E Chaisson, AIDS Clinical Trials Group and the Tuberculosis Trials Consortium

Abstract

Introduction: Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen.

Methods/design: S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority.

Discussion: This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels.

Trial registration: NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1.

Keywords: Moxifloxacin; Multicenter randomized trial; Non-inferiority; Rifapentine; TB; Tuberculosis.

Conflict of interest statement

Declaration of Competing Interest The authorship team members have declared any potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Sanofi commercial interests did not influence the study design; the collection, analysis, or interpretation of data; the preparation of this manuscript; or the decision to submit this manuscript for publication. A Sanofi technical expert served on the protocol team.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1.
Figure 1.
Study schematic for the trial “Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a randomized, open-label, controlled phase 3 clinical trial (S31/A5349)” Note. R=rifampin, H=isoniazid, Z=pyrazinamide, E=ethambutol, P=rifapentine, M=moxifloxacin.
Figure 2.
Figure 2.
Geographic distribution of enrolling study sites for the trial “Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a randomized, open-label, controlled phase 3 clinical trial (S31/A5349)”

References

    1. World Health Organization. Global tuberculosis report 2018. Geneva, Switzerland: World Health Organization; 2018. Report No.: 978-92-4-156564-6.
    1. Nahid P, Dorman S, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clinical infectious diseases 2016;63:e147–e95.
    1. World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update. Geneva, Switzerland: World Health Organization; 2017.
    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. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 1999;3:S231–79.
    1. van Ingen J, Aarnoutse RE, Donald PR, et al. Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2011;52:e194–9.
    1. de Steenwinkel JE, Aarnoutse RE, de Knegt GJ, et al. Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model. American journal of respiratory and critical care medicine 2013;187:1127–34.
    1. Hu Y, Liu A, Ortega Muro F, Alameda Martin L, Mitchison D, Coates A. High-dose rifampicin kills persisters, shortens treatment duration, and reduces relapse rate in vitro and in vivo. Frontiers in microbiology 2015;6:641-.
    1. Jayaram R, Gaonkar S, Kaur P, et al. Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis. Antimicrobial agents and chemotherapy 2003;47:2118–24.
    1. Rosenthal I, Tasneen R, Peloquin C, et al. Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis. Antimicrobial agents and chemotherapy 2012;56:4331–40.
    1. Diacon AH, Patientia RF, Venter A et al. Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob Agents Chemother 2007;51:2994–2996
    1. Svensson EM, Svensson RJ, Te Brake LHM et al. The potential for treatment shortening with higher rifampicin doses: relating drug exposure to treatment response in patients with pulmonary tuberculosis. Clin Infect Dis 2018;67:34–41.
    1. Bemer-Melchior P, Bryskier A, Drugeon HB. Comparison of the in vitro activities of rifapentine and rifampicin against Mycobacterium tuberculosis complex. The Journal of antimicrobial chemotherapy 2000;46:571–6.
    1. Benator D, Bhattacharya M, Bozeman L, et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet (British edition) 2002;360:528–34.
    1. Vernon A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. Lancet (British edition) 1999;353:1843–7.
    1. Pritin package insert. Accessed 1 January 2020 at
    1. Rosenthal IM, Zhang M, Almeida D, Grosset JH, Nuermberger EL. Isoniazid or moxifloxacin in rifapentine-based regimens for experimental tuberculosis? American journal of respiratory and critical care medicine 2008;178:989–93.
    1. Dooley KE, Bliven-Sizemore EE, Weiner M, et al. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers. Clinical pharmacology and therapeutics 2012;91:881–8.
    1. Dorman S, Savic R, Goldberg S, et al. Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial. American Journal of Respiratory & Critical Care Medicine 2015;191:333–43.
    1. Savic RM, Weiner M, MacKenzie WR, et al. Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials. Clinical Pharmacology & Therapeutics 2017;102:321–31.
    1. Ji B, Lounis N, Maslo C, Truffot Pernot C, Bonnafous P, Grosset J. In vitro and in vivo activities of moxifloxacin and clinafloxacin against Mycobacterium tuberculosis. Antimicrobial agents and chemotherapy 1998;42:2066–9.
    1. Li S-Y, Irwin S, Converse P, Mdluli K, Lenaerts A, Nuermberger E. Evaluation of moxifloxacin-containing regimens in pathologically distinct murine tuberculosis models. Antimicrobial agents and chemotherapy 2015;59:4026–30.
    1. Burman WJ, Goldberg S, Johnson JL, et al. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. American journal of respiratory and critical care medicine 2006;174:331–8.
    1. Conde MB, Efron A, Loredo C, et al. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet 2009;373:1183–9.
    1. Gillespie SH, Crook AM, McHugh TD, et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. The New England journal of medicine 2014;371:1577–87.
    1. Kjellsson MC, Via LE, Goh A, et al. Pharmacokinetic evaluation of the penetration of antituberculosis agents in rabbit pulmonary lesions. Antimicrobial agents and chemotherapy 2012;56:446–57.
    1. Prideaux B, Dartois V, Staab D, et al. High-sensitivity MALDI-MRM-MS imaging of moxifloxacin distribution in tuberculosis-infected rabbit lungs and granulomatous lesions. Analytical chemistry 2011;83:2112–8.
    1. Xu P, Chen H, Xu J et al. Moxifloxacin is an effective and safe candidate agent for tuberculosis treatment: a meta-analysis. Int J Infect Dis 2017;60:35–41.
    1. Thee S, Garcia-Prats AJ, Donald PR, Hesseling AC, Schaaf HS. Fluoroquinolones for the treatment of tuberculosis in children. Tuberculosis (Edinb) 2015;95:229–245.
    1. Zignol M, Dean AS, Alikhanova N, et al. Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project. Lancet Inf Dis 2016;16:1185–1192.
    1. Blakemore R, Nabeta P, Davidow AL et al. A multisite assessment of the quantitative capabilities of the Xpert MTB/RIF assay. Am J Respir Crit Care Med 2011;184:1076–84.
    1. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 2010;363:1005–1015.
    1. Marshall JD, Abdel-Rahman S, Johnson K, Kauffman RE, Kearns GL. Rifapentine pharmacokinetics in adolescents. The Pediatric infectious disease journal 1999;18:882–8.
    1. Abdool Karim S, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. The New England journal of medicine 2010;362:697–706.
    1. Breen RAM, Smith CJ, Bettinson H, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 2004;59:704–7.
    1. Burman W, Weis S, Vernon A, et al. Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis. The international journal of tuberculosis and lung disease 2007;11:1282–9.
    1. Havlir D, Kendall M, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. The New England journal of medicine 2011;365:1482–91.
    1. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. (Accessed 11 July, 2019, at .)
    1. Podany ATSE, Samaneka W, Mohapi L, Johnson J, Mayanja H, Lalloo U, Badal-Faesen S, Campbell K, Pham M, Miyahara S, Bryant K, Vernon A, Hafner R, Kurbatova E, Chaisson RE, Dorman S, Nahid P, Dooley K, Swindells S, and the AIDS Clinical Trials Group and the Tuberculosis Trials Consortium. Efavirenz pharmacokinetics in HIV/TB coinfected persons initiating ART while receiving high dose rifapentine. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs 2019; Netherlands.
    1. Podany ASE, Chen M, Martinson NA, Dawson R, Badal-Faesen S, Miyahara S, Kurbatova E, Whitworth WC, Chaisson RE, Dorman SE, Nahid P, Dooley K, Swindells S, for the AIDS Clinical Trials Group & Tuberculosis Trials Consortium A5349 / Study 31 Team. Efavirenz Pharmacokinetics in HIV/TB Coinfected Persons Receiving Rifapentine. Conference on Retroviruses and Opportunistic Infections (CROI) 2018; Boston, MA.
    1. Soares JF, Jeff Wu CF. Some Restricted randomization rules in sequential designs. Communications in Statistics - Theory and Methods Communications in Statistics - Theory and Methods 1983;12:2017–34..
    1. Chan SL, Yew WW, Porter JH, et al. Comparison of Chinese and Western rifapentines and improvement of bioavailability by prior taking of various meals. International journal of antimicrobial agents 1994;3:267–74.
    1. Dorman SE, Goldberg S, Stout JE, et al. Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the tuberculosis trials consortium. The Journal of infectious diseases 2012; 206:1030–40.
    1. Zvada SP, Van Der Walt JS, Smith PJ, et al. Effects of four different meal types on the population pharmacokinetics of single-dose rifapentine in healthy male volunteers. Antimicrobial agents and chemotherapy 2010;54:3390–4.
    1. Peloquin CA, Namdar R, Singleton MD, Nix DE. Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids. Chest 1999;115:12–8.
    1. Zent C, Smith P. Study of the effect of concomitant food on the bioavailability of rifampicin, isoniazid and pyrazinamide. Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 1995;76:109–13.
    1. Nunn AJ, Phillips PP, Mitchison DA. Timing of relapse in short-course chemotherapy trials for tuberculosis. Int J Tuberc Lung Dis 2010;14:241–242.
    1. Nunn AJ, Phillips PPJ, Meredith SK et al. A trial of a shorter regimen for rifampin-resistant tuberculosis. N Engl J Med 2019;380:1201–1213.
    1. A phase 3 study assessing the safety and efficacy of bedaquiline plus PA-824 plus linezolid in subjects with drug resistant pulmonary tuberculosis. NCT02333799. Accessed 13 January 2020 at
    1. Trial to evaluate the efficacy, safety and tolerability of BPaMZ in drug-sensitive (DS-TB) adult patients and drug-resistant (DR-TB) adult patients. NCT03338621. Acessed 13 January 2020 at
    1. Jindani A, Harrison TS, Nunn AJ, et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. The New England journal of medicine 2014;371:1599–608.
    1. Merle CS, Fielding K, Sow OB, et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. The New England journal of medicine 2014;371:1588–98.
    1. The Common Terminology Criteria for Adverse Events version 4.03 published on June 14, 2010 (Accessed 11 July, 2019, at .)
    1. East African/British Medical Research Council. Controlled clinical trial of four 6-month regimens of chemotherapy for pulmonary tuberculosis. Second report. Second East African/British Medical Research Council Study. The American review of respiratory disease 1976;114:471–5.
    1. East African/British Medical Research Council. Results at 5 years of a controlled comparison of a 6-month and a standard 18-month regimen of chemotherapy for pulmonary tuberculosis. The American review of respiratory disease 1977; 116:3–8.
    1. East African/British Medical Research Councils Study. Controlled clinical trial of five short-course (4-month) chemotherapy regimens in pulmonary tuberculosis. Second report of the 4th study. East African/British Medical Research Councils Study. The American review of respiratory disease 1981;123:165–70.
    1. East and Central Africa/British Medical Research Council. Controlled clinical trial of 4 short-course regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis: final report. East and Central African/British Medical Research Council Fifth Collaborative Study. Tubercle 1986;67:5–15.
    1. Singapore Tuberculosis Service/British Medical Research Council. Long-term follow-up of a clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Singapore Tuberculosis Service/British Medical Research Council. The American review of respiratory disease 1986; 133:779–83.
    1. Guidance for Industry Pulmonary Tuberculosis: Developing Drugs for Treatment. 2013. (Accessed 11 July, 2019, at .)
    1. Nunn AJ, Phillips PPJ, Gillespie SH. Design issues in pivotal drug trials for drug sensitive tuberculosis (TB). Tuberculosis Tuberculosis 2008;88:S85–S92.
    1. The Consortium for TB Biomarkers (CTB2) Biorepository (Accessed 11 July, 2019, at .)
    1. Nahid P, Saukkonen J, Mac Kenzie WR et al. CDC/NIH Workshop. Tuberculosis biomarker and surrogate endpoint research roadmap. Am J Respir Crit Care Med 2011;184:972–979
    1. Walter ND, de Jong BC, Garcia BJ et al. Adaptation of Mycobacterium tuberculosis to impaired host immunity in HIV-infected patients. J Infect Dis 2016;214:1205–1211.
    1. Walter ND, Dolganov GM, Garcia BJ et al. Transcriptional adaptation of drug-tolerant Mycobacterium tuberculosis during treatment of human tuberculosis. J Infect Dis 2015;212:990–998.
    1. Colangeli R, Jedrey H, Kim S et al. Bacterial factors that predict relapse after tuberculosis therapy. New Engl J Med 2018;379:823–833.
    1. Schulz KF, Altman DG, Moher D, Schulz K. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. bmjbritmedj BMJ: British Medical Journal 2010;340:698–702.
    1. Imperial MZ, Nahid P, Phillips PPJ et al. A patient-level pooled analysis of treatment shortening regimens for drug-susceptible pulmonary tuberculosis. Nat Med 2018. 24:1708–1715.
    1. Clinical Data Interchange Standards Consortium (CDISC) Clinical Data Acquisition Standards Harmonization (CDASH). (Accessed 11 July, 2019, at .)

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