Clinical trial NCT04557176: TB Screening Improves Preventive Therapy Uptake
Official title: TB Screening Improves Preventive Therapy Uptake Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Tuberculosis
Latent Tuberculosis
Tuberculosis Prevention
HIV
Keywords: Tuberculosis
Latent tuberculosis
Tuberculosis preventive therapy
HIV
C-reactive protein
Symptom screening
Intensified case finding
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Makerere University
name: Infectious Diseases Research Collaboration, Uganda
name: Johns Hopkins University
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2020-09-21
Enrollment: 1719
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

Brief summary: HIV-infected people have an increased risk of developing active tuberculosis (TB). To reduce the burden of TB among people living with HIV (PLHIV), the World Health Organization (WHO) recommends systematic TB screening followed by 1) confirmatory TB testing for all those who screen positive and 2) TB preventive therapy (TPT) for all TPT-eligible PLHIV who screen negative.

The objective of the TB Screening Improves Preventive Therapy Uptake (TB SCRIPT) trial is to determine whether TB screening based on C-reactive protein (CRP) levels, measured using a rapid and low-cost point-of-care (POC) assay, improves TPT uptake and clinical outcomes of PLHIV, relative to symptom-based TB screening.

Detailed description: The overall objective of the TB SCRIPT trial is to evaluate the effectiveness and cost-effectiveness of POC CRP-based TB screening, which is the next step required for successful scale-up of both systematic TB screening and TPT. The study's central hypothesis is that compared to symptom-based TB screening, a TB screening strategy based on CRP levels measured at the point-of-care will improve TPT uptake, thereby reducing TB incidence and its associated mortality among PLHIV.

To test this hypothesis, the investigators will conduct an individual randomized control trial enrolling PLHIV presenting to clinics in Uganda for routine antiretroviral therapy (ART) initiation. Eligible participants will be randomized to either POC CRP-based TB screening (intervention arm) or symptom-based TB screening (control arm). In both arms, screen-positive participants will undergo confirmatory TB testing; participants found to have prevalent TB will be initiated on standard TB treatment. In both arms, screen-negative participants will be assessed for TPT eligibility; TPT-eligible participants will be initiated on standard TPT. All participants will be followed for 2 years.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Confirmed HIV+ test result
* CD4 T lymphocyte count of ≤ 350 cells/μL
* Capacity to provide written (or witnessed verbal, if illiterate) informed consent

Exclusion Criteria:

* Completed treatment for active pulmonary or extra-pulmonary TB within the past 2 years
* Completed a full course of TPT within the past year
* Actively taking any internationally-approved medication for TB treatment for any reason, within 2 weeks of study entry
* Prior history of combined ART for HIV treatment for any duration (does not include single-dose ART for prevention of vertical transmission of HIV)
* Currently resides 25 km outside their enrollment site, plans to move 25 km outside their enrollment site in the next 2 years, or plans to transfer their HIV care from their current enrollment site

Primary outcomes:
measure: Microbiologically-confirmed incident TB and all-cause mortality
timeFrame: two years
Secondary outcomes:
measure: TB incidence: number diagnosed
timeFrame: two years
measure: TB incidence: incidence
timeFrame: two years
measure: TB incidence: Time to microbiologically-confirmed incident TB diagnosis
timeFrame: two years
measure: TB incidence: incidence rate
timeFrame: two years
measure: TB incidence: drug resistant TB
timeFrame: two years
measure: TB incidence: drug resistant TB among people receiving TPT
timeFrame: two years
measure: Mortality: number of deaths from any cause
timeFrame: two years
measure: Mortality: time to death from any cause
timeFrame: two years
measure: Mortality: all-cause death rate
timeFrame: two years
measure: Mortality: number who died from TB
timeFrame: two years
measure: TPT uptake: number screen-negatives prescribed TPT
timeFrame: two years
measure: TPT uptake: number screen-positives prescribed TPT
timeFrame: two years
measure: TPT uptake: number initiated on TPT
timeFrame: two years
measure: TPT uptake: time to TPT initiation
timeFrame: two years
measure: TPT uptake: number completing TPT
timeFrame: two years
measure: Prevalent TB diagnosis: number microbiologically-confirmed prevalent TB cases detected by screening test
timeFrame: two years
measure: Prevalent TB diagnosis: number microbiologically-confirmed prevalent TB cases missed by screening test
timeFrame: two years
measure: Prevalent TB diagnosis: number diagnosed with microbiologically-confirmed prevalent TB
timeFrame: two years
measure: Prevalent TB treatment: Number treated for prevalent TB
timeFrame: two years
measure: Prevalent TB treatment: number with microbiologically-confirmed prevalent TB completing treatment
timeFrame: two years
measure: Prevalent TB treatment: time to treatment of microbiologically-confirmed prevalent TB
timeFrame: two years
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Kampala Capital City Authority Clinic
Study officials:
affiliation: University of California, San Francisco
name: Christina Yoon, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: WHO. Global Tuberculosis Report 2017. Geneva, Switzerland. World Health Organization 2017.
citation: Durovni B, Saraceni V, Moulton LH, Pacheco AG, Cavalcante SC, King BS, Cohn S, Efron A, Chaisson RE, Golub JE. Effect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: a stepped wedge, cluster-randomised trial. Lancet Infect Dis. 2013 Oct;13(10):852-8. doi: 10.1016/S1473-3099(13)70187-7. Epub 2013 Aug 16.
citation: TEMPRANO ANRS 12136 Study Group; Danel C, Moh R, Gabillard D, Badje A, Le Carrou J, Ouassa T, Ouattara E, Anzian A, Ntakpe JB, Minga A, Kouame GM, Bouhoussou F, Emieme A, Kouame A, Inwoley A, Toni TD, Ahiboh H, Kabran M, Rabe C, Sidibe B, Nzunetu G, Konan R, Gnokoro J, Gouesse P, Messou E, Dohoun L, Kamagate S, Yao A, Amon S, Kouame AB, Koua A, Kouame E, Ndri Y, Ba-Gomis O, Daligou M, Ackoundze S, Hawerlander D, Ani A, Dembele F, Kone F, Guehi C, Kanga C, Koule S, Seri J, Oyebi M, Mbakop N, Makaila O, Babatunde C, Babatounde N, Bleoue G, Tchoutedjem M, Kouadio AC, Sena G, Yededji SY, Assi R, Bakayoko A, Mahassadi A, Attia A, Oussou A, Mobio M, Bamba D, Koman M, Horo A, Deschamps N, Chenal H, Sassan-Morokro M, Konate S, Aka K, Aoussi E, Journot V, Nchot C, Karcher S, Chaix ML, Rouzioux C, Sow PS, Perronne C, Girard PM, Menan H, Bissagnene E, Kadio A, Ettiegne-Traore V, Moh-Semde C, Kouame A, Massumbuko JM, Chene G, Dosso M, Domoua SK, N'Dri-Yoman T, Salamon R, Eholie SP, Anglaret X. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. N Engl J Med. 2015 Aug 27;373(9):808-22. doi: 10.1056/NEJMoa1507198. Epub 2015 Jul 20.
citation: Rangaka MX, Wilkinson RJ, Boulle A, Glynn JR, Fielding K, van Cutsem G, Wilkinson KA, Goliath R, Mathee S, Goemaere E, Maartens G. Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial. Lancet. 2014 Aug 23;384(9944):682-90. doi: 10.1016/S0140-6736(14)60162-8. Epub 2014 May 13.
citation: Grant AD, Charalambous S, Fielding KL, Day JH, Corbett EL, Chaisson RE, De Cock KM, Hayes RJ, Churchyard GJ. Effect of routine isoniazid preventive therapy on tuberculosis incidence among HIV-infected men in South Africa: a novel randomized incremental recruitment study. JAMA. 2005 Jun 8;293(22):2719-25. doi: 10.1001/jama.293.22.2719.
citation: Churchyard GJ, Fielding KL, Lewis JJ, Coetzee L, Corbett EL, Godfrey-Faussett P, Hayes RJ, Chaisson RE, Grant AD; Thibela TB Study Team. A trial of mass isoniazid preventive therapy for tuberculosis control. N Engl J Med. 2014 Jan 23;370(4):301-10. doi: 10.1056/NEJMoa1214289.
citation: WHO. Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings. Geneva, Switzerland. World Health Organization 2011.
citation: Latent tuberculosis infection: updated and consolidated guidelines for programmatic management [Internet]. Geneva: World Health Organization; 2018. Available from http://www.ncbi.nlm.nih.gov/books/NBK531235/
citation: Getahun H, Kittikraisak W, Heilig CM, Corbett EL, Ayles H, Cain KP, Grant AD, Churchyard GJ, Kimerling M, Shah S, Lawn SD, Wood R, Maartens G, Granich R, Date AA, Varma JK. Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies. PLoS Med. 2011 Jan 18;8(1):e1000391. doi: 10.1371/journal.pmed.1000391.
citation: WHO. High-priority target product profiles for new tuberculosis diagnostics: report of a consensus meeting. Geneva, Switzerland. World Health Organization 2014.
citation: Lawn SD, Brooks SV, Kranzer K, Nicol MP, Whitelaw A, Vogt M, Bekker LG, Wood R. Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: a prospective study. PLoS Med. 2011 Jul;8(7):e1001067. doi: 10.1371/journal.pmed.1001067. Epub 2011 Jul 26.
citation: Kufa T, Mngomezulu V, Charalambous S, Hanifa Y, Fielding K, Grant AD, Wada N, Chaisson RE, Churchyard GJ, Gounder CR. Undiagnosed tuberculosis among HIV clinic attendees: association with antiretroviral therapy and implications for intensified case finding, isoniazid preventive therapy, and infection control. J Acquir Immune Defic Syndr. 2012 Jun 1;60(2):e22-8. doi: 10.1097/QAI.0b013e318251ae0b.
citation: Swindells S, Komarow L, Tripathy S, Cain KP, MacGregor RR, Achkar JM, Gupta A, Veloso VG, Asmelash A, Omoz-Oarhe AE, Gengiah S, Lalloo U, Allen R, Shiboski C, Andersen J, Qasba SS, Katzenstein DK; AIDS Clinical Trials Group 5253 Study Team. Screening for pulmonary tuberculosis in HIV-infected individuals: AIDS Clinical Trials Group Protocol A5253. Int J Tuberc Lung Dis. 2013 Apr;17(4):532-9. doi: 10.5588/ijtld.12.0737.
citation: Henostroza G, Harris JB, Chitambi R, Siyambango M, Turnbull ER, Maggard KR, Kruuner A, Kapata N, Reid SE. High prevalence of tuberculosis in newly enrolled HIV patients in Zambia: need for enhanced screening approach. Int J Tuberc Lung Dis. 2016 Aug;20(8):1033-9. doi: 10.5588/ijtld.15.0651.
citation: DERBES VJ, JACOBS S, LINN RH, TURNER M, WALSH JJ. C-reactive protein in pulmonary tuberculosis. Am Rev Tuberc. 1956 Sep;74(3):464-7. doi: 10.1164/artpd.1956.74.3.464. No abstract available.
citation: Ganter U, Arcone R, Toniatti C, Morrone G, Ciliberto G. Dual control of C-reactive protein gene expression by interleukin-1 and interleukin-6. EMBO J. 1989 Dec 1;8(12):3773-9. doi: 10.1002/j.1460-2075.1989.tb08554.x.
citation: Ogawa T, Uchida H, Kusumoto Y, Mori Y, Yamamura Y, Hamada S. Increase in tumor necrosis factor alpha- and interleukin-6-secreting cells in peripheral blood mononuclear cells from subjects infected with Mycobacterium tuberculosis. Infect Immun. 1991 Sep;59(9):3021-5. doi: 10.1128/iai.59.9.3021-3025.1991.
citation: Saunders R, Robson S, Soule S, Kirsch RE. Secretion of interleukin-6 by peripheral blood mononuclear cells from patients with pulmonary tuberculosis and their contacts. J Clin Lab Immunol. 1993;40(1):19-28.
citation: Flesch IE, Kaufmann SH. Role of cytokines in tuberculosis. Immunobiology. 1993 Nov;189(3-4):316-39. doi: 10.1016/S0171-2985(11)80364-5.
citation: Weinhold B, Ruther U. Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene. Biochem J. 1997 Oct 15;327 ( Pt 2)(Pt 2):425-9. doi: 10.1042/bj3270425.
citation: Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999 Feb 11;340(6):448-54. doi: 10.1056/NEJM199902113400607. No abstract available.
citation: Lawn SD, Wiktor S, Coulibaly D, Ackah AN, Lal RB. Serum C-reactive protein and detection of tuberculosis in persons co-infected with the human immunodeficiency virus. Trans R Soc Trop Med Hyg. 2001 Jan-Feb;95(1):41-2. doi: 10.1016/s0035-9203(01)90328-1. No abstract available.
citation: Kihara M, Kamakura M, Feldman MD. Introduction: HIV/AIDS surveillance in a new era. J Acquir Immune Defic Syndr. 2003 Feb;32 Suppl 1:S1-2. doi: 10.1097/00126334-200302011-00001. No abstract available.
citation: Drain PK, Kupka R, Msamanga GI, Urassa W, Mugusi F, Fawzi WW. C-reactive protein independently predicts HIV-related outcomes among women and children in a resource-poor setting. AIDS. 2007 Oct 1;21(15):2067-75. doi: 10.1097/QAD.0b013e32826fb6c7.
citation: Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D, Paton NI, Neaton JD; INSIGHT SMART Study Group. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008 Oct 21;5(10):e203. doi: 10.1371/journal.pmed.0050203.
citation: Tien PC, Schneider MF, Cox C, Cohen M, Karim R, Lazar J, Young M, Glesby MJ. HIV, HAART, and lipoprotein particle concentrations in the Women's Interagency HIV Study. AIDS. 2010 Nov 27;24(18):2809-17. doi: 10.1097/QAD.0b013e32833fcb3b.
citation: Neuhaus J, Jacobs DR Jr, Baker JV, Calmy A, Duprez D, La Rosa A, Kuller LH, Pett SL, Ristola M, Ross MJ, Shlipak MG, Tracy R, Neaton JD. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis. 2010 Jun 15;201(12):1788-95. doi: 10.1086/652749.
citation: Shikuma CM, Ribaudo HJ, Zheng Y, Gulick RM, Meyer WA, Tashima KT, Bastow B, Kuritzkes DR, Glesby MJ; AIDS Clinical Trials Group A5095 Study Team. Change in high-sensitivity c-reactive protein levels following initiation of efavirenz-based antiretroviral regimens in HIV-infected individuals. AIDS Res Hum Retroviruses. 2011 May;27(5):461-8. doi: 10.1089/aid.2010.0154. Epub 2010 Nov 23.
citation: Lawn SD, Obeng J, Acheampong JW, Griffin GE. Resolution of the acute-phase response in West African patients receiving treatment for pulmonary tuberculosis. Int J Tuberc Lung Dis. 2000 Apr;4(4):340-4.
citation: Polzin A, Pletz M, Erbes R, Raffenberg M, Mauch H, Wagner S, Arndt G, Lode H. Procalcitonin as a diagnostic tool in lower respiratory tract infections and tuberculosis. Eur Respir J. 2003 Jun;21(6):939-43. doi: 10.1183/09031936.03.00055103.
citation: Schleicher GK, Herbert V, Brink A, Martin S, Maraj R, Galpin JS, Feldman C. Procalcitonin and C-reactive protein levels in HIV-positive subjects with tuberculosis and pneumonia. Eur Respir J. 2005 Apr;25(4):688-92. doi: 10.1183/09031936.05.00067604.
citation: Choi CM, Kang CI, Jeung WK, Kim DH, Lee CH, Yim JJ. Role of the C-reactive protein for the diagnosis of TB among military personnel in South Korea. Int J Tuberc Lung Dis. 2007 Feb;11(2):233-6.
citation: Breen RA, Leonard O, Perrin FM, Smith CJ, Bhagani S, Cropley I, Lipman MC. How good are systemic symptoms and blood inflammatory markers at detecting individuals with tuberculosis? Int J Tuberc Lung Dis. 2008 Jan;12(1):44-9.
citation: Kang YA, Kwon SY, Yoon HI, Lee JH, Lee CT. Role of C-reactive protein and procalcitonin in differentiation of tuberculosis from bacterial community acquired pneumonia. Korean J Intern Med. 2009 Dec;24(4):337-42. doi: 10.3904/kjim.2009.24.4.337. Epub 2009 Nov 27.
citation: Sage EK, Noursadeghi M, Evans HE, Parker SJ, Copas AJ, Edwards SG, Miller RF. Prognostic value of C-reactive protein in HIV-infected patients with Pneumocystis jirovecii pneumonia. Int J STD AIDS. 2010 Apr;21(4):288-92. doi: 10.1258/ijsa.2010.009551.
citation: Wilson D, Badri M, Maartens G. Performance of serum C-reactive protein as a screening test for smear-negative tuberculosis in an ambulatory high HIV prevalence population. PLoS One. 2011 Jan 10;6(1):e15248. doi: 10.1371/journal.pone.0015248.
citation: Lawn SD, Kerkhoff AD, Vogt M, Wood R. Diagnostic and prognostic value of serum C-reactive protein for screening for HIV-associated tuberculosis. Int J Tuberc Lung Dis. 2013 May;17(5):636-43. doi: 10.5588/ijtld.12.0811.
citation: Yoon C, Davis JL, Huang L, Muzoora C, Byakwaga H, Scibetta C, Bangsberg DR, Nahid P, Semitala FC, Hunt PW, Martin JN, Cattamanchi A. Point-of-care C-reactive protein testing to facilitate implementation of isoniazid preventive therapy for people living with HIV. J Acquir Immune Defic Syndr. 2014 Apr 15;65(5):551-6. doi: 10.1097/QAI.0000000000000085.
citation: Yoon C, Chaisson LH, Patel SM, Allen IE, Drain PK, Wilson D, Cattamanchi A. Diagnostic accuracy of C-reactive protein for active pulmonary tuberculosis: a meta-analysis. Int J Tuberc Lung Dis. 2017 Sep 1;21(9):1013-1019. doi: 10.5588/ijtld.17.0078.
citation: Shapiro AE, Hong T, Govere S, Thulare H, Moosa MY, Dorasamy A, Wallis CL, Celum CL, Grosset J, Drain PK. C-reactive protein as a screening test for HIV-associated pulmonary tuberculosis prior to antiretroviral therapy in South Africa. AIDS. 2018 Aug 24;32(13):1811-1820. doi: 10.1097/QAD.0000000000001902.
citation: Yoon C, Semitala FC, Atuhumuza E, Katende J, Mwebe S, Asege L, Armstrong DT, Andama AO, Dowdy DW, Davis JL, Huang L, Kamya M, Cattamanchi A. Point-of-care C-reactive protein-based tuberculosis screening for people living with HIV: a diagnostic accuracy study. Lancet Infect Dis. 2017 Dec;17(12):1285-1292. doi: 10.1016/S1473-3099(17)30488-7. Epub 2017 Aug 25.
citation: Yoon C, Semitala FC, Asege L, Katende J, Mwebe S, Andama AO, Atuhumuza E, Nakaye M, Armstrong DT, Dowdy DW, McCulloch CE, Kamya M, Cattamanchi A. Yield and Efficiency of Novel Intensified Tuberculosis Case-Finding Algorithms for People Living with HIV. Am J Respir Crit Care Med. 2019 Mar 1;199(5):643-650. doi: 10.1164/rccm.201803-0490OC.
citation: Rajan JV, Semitala FC, Mehta T, Seielstad M, Montalvo L, Andama A, Asege L, Nakaye M, Katende J, Mwebe S, Kamya MR, Yoon C, Cattamanchi A. A Novel, 5-Transcript, Whole-blood Gene-expression Signature for Tuberculosis Screening Among People Living With Human Immunodeficiency Virus. Clin Infect Dis. 2019 Jun 18;69(1):77-83. doi: 10.1093/cid/ciy835.
citation: Chaisson LH, Semitala FC, Asege L, Mwebe S, Katende J, Nakaye M, Andama AO, Marquez C, Atuhumuza E, Kamya M, Cattamanchi A, Yoon C. Point-of-care C-reactive protein and risk of early mortality among adults initiating antiretroviral therapy. AIDS. 2019 Apr 1;33(5):895-902. doi: 10.1097/QAD.0000000000002130.
citation: Semitala FC, Cattamanchi A, Andama A, Atuhumuza E, Katende J, Mwebe S, Asege L, Nakaye M, Kamya MR, Yoon C. Brief Report: Yield and Efficiency of Intensified Tuberculosis Case-Finding Algorithms in 2 High-Risk HIV Subgroups in Uganda. J Acquir Immune Defic Syndr. 2019 Dec 1;82(4):416-420. doi: 10.1097/QAI.0000000000002162.
citation: Uganda Ministry of Health. Report on the Population-based survey of prevalence of tuberculosis disease in Uganda 2014-2015. Kampala: MOH, 2017.
citation: PEPFAR Uganda Program data. (https://www.pepfar.gov/documents/organization/285851.)
citation: Yung-Pin C. Biased coin design with imbalance tolerance. Stochastic Models. 1999 Jan 1;15(5):953-75. doi: 10.1080/15326349908807570
citation: Pfafflin A, Schleicher E. Inflammation markers in point-of-care testing (POCT). Anal Bioanal Chem. 2009 Mar;393(5):1473-80. doi: 10.1007/s00216-008-2561-3. Epub 2008 Dec 23.
citation: Claus DR, Osmand AP, Gewurz H. Radioimmunoassay of human C-reactive protein and levels in normal sera. J Lab Clin Med. 1976 Jan;87(1):120-8.
citation: Gupta A, Montepiedra G, Aaron L, Theron G, McCarthy K, Bradford S, Chipato T, Vhembo T, Stranix-Chibanda L, Onyango-Makumbi C, Masheto GR, Violari A, Mmbaga BT, Aurpibul L, Bhosale R, Mave V, Rouzier V, Hesseling A, Shin K, Zimmer B, Costello D, Sterling TR, Chakhtoura N, Jean-Philippe P, Weinberg A; IMPAACT P1078 TB APPRISE Study Team. Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women. N Engl J Med. 2019 Oct 3;381(14):1333-1346. doi: 10.1056/NEJMoa1813060.
citation: Uganda Ministry of Health. Isoniazid preventive therapy in Uganda: a health worker's guide. Kampala: MOH, 2014.
citation: Semitala FC, Chaisson LH, Dowdy DW, Armstrong DT, Opira B, Aman K, Kamya M, Phillips PPJ, Yoon C. Tuberculosis screening improves preventive therapy uptake (TB SCRIPT) trial among people living with HIV in Uganda: a study protocol of an individual randomized controlled trial. Trials. 2022 May 12;23(1):399. doi: 10.1186/s13063-022-06371-0.