Rifapentine and isoniazid for prevention of tuberculosis in people with diabetes (PROTID): protocol for a randomised controlled trial

Nyanda Elias Ntinginya, Lindsey Te Brake, Issa Sabi, Nyasatu Chamba, Kajiru Kilonzo, Sweetness Laizer, Irene Andia-Biraro, Davis Kibirige, Andrew Peter Kyazze, Sandra Ninsiima, Julia A Critchley, Renee Romeo, Josephine van de Maat, Willyhelmina Olomi, Lucy Mrema, David Magombola, Issakwisa Habakkuk Mwayula, Katrina Sharples, Philip C Hill, Reinout van Crevel, PROTID Consortium, Nyanda Elias Ntinginya, Lindsey Te Brake, Issa Sabi, Nyasatu Chamba, Kajiru Kilonzo, Sweetness Laizer, Irene Andia-Biraro, Davis Kibirige, Andrew Peter Kyazze, Sandra Ninsiima, Julia A Critchley, Renee Romeo, Josephine van de Maat, Willyhelmina Olomi, Lucy Mrema, David Magombola, Issakwisa Habakkuk Mwayula, Katrina Sharples, Philip C Hill, Reinout van Crevel, PROTID Consortium

Abstract

Background: Diabetes mellitus (DM) increases the risk of tuberculosis (TB) and will hamper global TB control due to the dramatic rise in type 2 DM in TB-endemic settings. In this trial, we will examine the efficacy and safety of TB preventive therapy against the development of TB disease in people with DM who have latent TB infection (LTBI), with a 12-week course of rifapentine and isoniazid (3HP).

Methods: The 'Prevention of tuberculosis in diabetes mellitus' (PROTID) consortium will randomise 3000 HIV-negative eligible adults with DM and LTBI, as evidenced by a positive tuberculin skin test or interferon gamma release assay, to 12 weeks of 3HP or placebo. Participants will be recruited through screening adult patients attending DM clinics at referral hospitals in Tanzania and Uganda. Patients with previous TB disease or treatment with a rifamycin medication or isoniazid (INH) in the previous 2 years will be excluded. The primary outcome is the occurrence of definite or probable TB disease; secondary outcome measures include adverse events, all-cause mortality and treatment completion. The primary efficacy analysis will be intention-to-treat; per-protocol analyses will also be carried out. We will estimate the ratio of TB incidence rates in intervention and control groups, adjusting for the study site using Poisson regression. Results will be reported as efficacy estimates (1-rate ratio). Cumulative incidence rates allowing for death as a competing risk will also be reported. Approximately 1000 LTBI-negative, HIV-negative participants will be enrolled consecutively into a parallel cohort study to compare the incidence of TB in people with DM who are LTBI negative vs positive. A number of sub-studies will be conducted among others to examine the prevalence of LTBI and active TB, estimate the population impact and cost-effectiveness of LTBI treatment in people living with DM in these African countries and address gaps in the prevention and therapeutic management of combined TB-DM.

Discussion: PROTID is anticipated to generate key evidence to guide decisions over the use of TB preventive treatment among people with DM as an important target group for better global TB control.

Trial registration: ClinicalTrials.gov NCT04600167 . Registered on 23 October 2020.

Keywords: Diabetes mellitus; Isoniazid; Latent tuberculosis infection; Preventive treatment; Rifapentine.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
The clinical research flow chart. Explanatory footnotes: The number of participants enrolled in the screening phase (n = 6000) is an estimate to yield n = 3000 randomised. Screened participants eligible for the RCT or cohort study will be consecutively recruited. Follow-up will consist of 4-monthly scheduled visits for the first 24 months and inter-lock with routine DM clinic care after 24 months. Details of the sub-studies are not provided in this trial protocol paper
Fig. 2
Fig. 2
Project organogram with Work Package (WP) 2 representing the PROTID trial

References

    1. WHO. Global tuberculosis report 2021. Geneva: World Health Organization; 2021. [cited 2022 23 May]. Available from: .
    1. WHO. Evidence to decision framework: appendix to the guidelines on the management of latent tuberculosis infection. Geneva: World Health Organization; 2015. [cited 2022 23 May]. Available from: .
    1. Getahun H, Matteelli A, Chaisson RE, Raviglione M. Latent Mycobacterium tuberculosis infection. N Engl J Med. 2015;372(22):2127–2135. doi: 10.1056/NEJMra1405427.
    1. Houben RM, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 2016;13(10):e1002152. doi: 10.1371/journal.pmed.1002152.
    1. Sharma SK, Sharma A, Kadhiravan T, Tharyan P. Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB. Cochrane Database Syst Rev. 2013;7. 10.1002/14651858.CD007545.pub2.
    1. Alsdurf H, Hill PC, Matteelli A, Getahun H, Menzies D. The cascade of care in diagnosis and treatment of latent tuberculosis infection: a systematic review and meta-analysis. Lancet Infect Dis. 2016;16(11):1269–1278. doi: 10.1016/S1473-3099(16)30216-X.
    1. Jeon CY, Murray MB. Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Med. 2008;5(7):e152. doi: 10.1371/journal.pmed.0050152.
    1. Stevenson CR, Critchley JA, Forouhi NG, Roglic G, Williams BG, Dye C, Unwin NC. Diabetes and the risk of tuberculosis: a neglected threat to public health? Chronic Illn. 2007;3(3):228–245. doi: 10.1177/1742395307081502.
    1. Baker MA, Harries AD, Jeon CY, Hart JE, Kapur A, Lonnroth K, et al. The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC Med. 2011;9(1):81. doi: 10.1186/1741-7015-9-81.
    1. Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN, Mbanya JC, Pavkov ME, Ramachandaran A, Wild SH, James S, Herman WH, Zhang P, Bommer C, Kuo S, Boyko EJ, Magliano DJ. IDF diabetes atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2021;109119:109119. doi: 10.1016/j.diabres.2021.109119.
    1. Pan SC, Ku CC, Kao D, Ezzati M, Fang CT, Lin HH. Effect of diabetes on tuberculosis control in 13 countries with high tuberculosis: a modelling study. Lancet Diabetes Endocrinol. 2015;3(5):323–330. doi: 10.1016/S2213-8587(15)00042-X.
    1. Awad SF, Huangfu P, Ayoub HH, Pearson F, Dargham SR, Critchley JA, Abu-Raddad LJ. Forecasting the impact of diabetes mellitus on tuberculosis disease incidence and mortality in India. J Glob Health. 2019;9(2):020415. doi: 10.7189/jogh.09.020415.
    1. Ruslami R, Aarnoutse RE, Alisjahbana B, Van Der Ven AJAM, Van Crevel R. Implications of the global increase of diabetes for tuberculosis control and patient care. Trop Med Int Health. 2010;15(11):1289–1299. doi: 10.1111/j.1365-3156.2010.02625.x.
    1. Harries AD, Kumar AMV, Satyanarayana S, Lin Y, Zachariah R, Lönnroth K, Kapur A. Addressing diabetes mellitus as part of the strategy for ending TB. Trans R Soc Trop Med Hyg. 2016;110(3):173–179. doi: 10.1093/trstmh/trv111.
    1. McAllister SM, Koesoemadinata RC, Santoso P, Soetedjo NNM, Kamil A, Permana H, Ruslami R, Critchley JA, van Crevel R, Hill PC, Alisjahbana B. High tuberculosis incidence among people living with diabetes in Indonesia. Trans R Soc Trop Med Hyg. 2020;114(2):79–85. doi: 10.1093/trstmh/trz100.
    1. Cohn DL, O’Brien RJ, Geiter LJ, Gordin F, Hershfield E, Horsburgh C. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Morb Mortal Wkly Rep. 2000;49(6):1–54.
    1. Ferebee SH, Palmer CE. Prevention of experimental tuberculosis with isoniazid. Am Rev Tuberc. 1956;73(1):1–18.
    1. Stennis NL, Burzynski JN, Herbert C, Nilsen D, Macaraig M. Treatment for tuberculosis infection with 3 months of isoniazid and rifapentine in New York City health department clinics. Clin Infect Dis. 2016;62(1):53–59. doi: 10.1093/cid/civ766.
    1. Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, Hackman J, Hamilton CD, Menzies D, Kerrigan A, Weis SE, Weiner M, Wing D, Conde MB, Bozeman L, Horsburgh CR, Jr, Chaisson RE. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011;365(23):2155–2166. doi: 10.1056/NEJMoa1104875.
    1. Swindells S, Ramchandani R, Gupta A, Benson CA, Leon-Cruz J, Mwelase N, Jean Juste MA, Lama JR, Valencia J, Omoz-Oarhe A, Supparatpinyo K, Masheto G, Mohapi L, da Silva Escada RO, Mawlana S, Banda P, Severe P, Hakim J, Kanyama C, Langat D, Moran L, Andersen J, Fletcher CV, Nuermberger E, Chaisson RE, BRIEF TB/A5279 Study Team One month of rifapentine plus isoniazid to prevent HIV-related tuberculosis. N Engl J Med. 2019;380(11):1001–1011. doi: 10.1056/NEJMoa1806808.
    1. Njie GJ, Morris SB, Woodruff RY, Moro RN, Vernon AA, Borisov AS. Isoniazid-rifapentine for latent tuberculosis infection: a systematic review and meta-analysis. Am J Prev Med. 2018;55(2):244–252. doi: 10.1016/j.amepre.2018.04.030.
    1. Sterling TR, Scott NA, Miro JM, Calvet G, La Rosa A, Infante R, et al. Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. AIDS. 2016;30(10):1607–1615. doi: 10.1097/QAD.0000000000001098.
    1. Sandul AL, Nwana N, Holcombe JM, Lobato MN, Marks S, Webb R, Wang SH, Stewart B, Griffin P, Hunt G, Shah N, Marco A, Patil N, Mukasa L, Moro RN, Jereb J, Mase S, Chorba T, Bamrah-Morris S, Ho CS. High rate of treatment completion in program settings with 12-dose weekly isoniazid and rifapentine for latent Mycobacterium tuberculosis infection. Clin Infect Dis. 2017;65(7):1085–1093. doi: 10.1093/cid/cix505.
    1. Belknap R, Holland D, Feng PJ, Millet JP, Cayla JA, Martinson NA, et al. Self-administered versus directly observed once-weekly isoniazid and rifapentine treatment of latent tuberculosis infection: a randomized trial. Ann Intern Med. 2017;167(10):689–697. doi: 10.7326/M17-1150.
    1. Baciewicz AM, Chrisman CR, Finch CK, Self TH. Update on rifampin, rifabutin, and rifapentine drug interactions. Curr Med Res Opin. 2013;29(1):1–12. doi: 10.1185/03007995.2012.747952.
    1. Zvada SP, Denti P, Geldenhuys H, Meredith S, van As D, Hatherill M, Hanekom W, Wiesner L, Simonsson USH, Jindani A, Harrison T, McIlleron HM. Moxifloxacin population pharmacokinetics in patients with pulmonary tuberculosis and the effect of intermittent high-dose rifapentine. Antimicrob Agents Chemother. 2012;56(8):4471–4473. doi: 10.1128/AAC.00404-12.
    1. Podany AT, Bao Y, Swindells S, Chaisson RE, Andersen JW, Mwelase T, Supparatpinyo K, Mohapi L, Gupta A, Benson CA, Kim P, Fletcher CV, AIDS Clinical Trials Group A5279 Study Team Efavirenz pharmacokinetics and pharmacodynamics in HIV-infected persons receiving rifapentine and isoniazid for tuberculosis prevention. Clin Infect Dis. 2015;61(8):1322–1327. doi: 10.1093/cid/civ464.
    1. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev. 2010;2010(1):Cd000171.
    1. Wallis RS, Kim P, Cole S, Hanna D, Andrade BB, Maeurer M, Schito M, Zumla A. Tuberculosis biomarkers discovery: developments, needs, and challenges. Lancet Infect Dis. 2013;13(4):362–372. doi: 10.1016/S1473-3099(13)70034-3.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner