Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial

HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective...

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Published in:	Current controlled trials in cardiovascular medicine Vol. 25; no. 1; pp. 311 - 23
Main Authors:	Namale, Phiona E, Boloko, Linda, Vermeulen, Marcia, Haigh, Kate A, Bagula, Fortuna, Maseko, Alexis, Sossen, Bianca, Lee-Jones, Scott, Msomi, Yoliswa, McIlleron, Helen, Mnguni, Ayanda Trevor, Crede, Thomas, Szymanski, Patryk, Naude, Jonathan, Ebrahim, Sakeena, Vallie, Yakoob, Moosa, Muhammed Shiraz, Bandeker, Ismail, Hoosain, Shakeel, Nicol, Mark P, Samodien, Nazlee, Centner, Chad, Dowling, Wentzel, Denti, Paolo, Gumedze, Freedom, Little, Francesca, Parker, Arifa, Price, Brendon, Schietekat, Denzil, Simmons, Bryony, Hill, Andrew, Wilkinson, Robert J, Oliphant, Ida, Hlungulu, Siphokazi, Apolisi, Ivy, Toleni, Monica, Asare, Zimkhitha, Mpalali, Mkanyiseli Kenneth, Boshoff, Erica, Prinsloo, Denise, Lakay, Francisco, Bekiswa, Abulele, Jackson, Amanda, Barnes, Ashleigh, Johnson, Ryan, Wasserman, Sean, Maartens, Gary, Barr, David, Schutz, Charlotte, Meintjes, Graeme
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 08-05-2024 BioMed Central BMC
Subjects:	AIDS-Related Opportunistic Infections - diagnosis AIDS-Related Opportunistic Infections - drug therapy AIDS-Related Opportunistic Infections - microbiology AIDS-Related Opportunistic Infections - mortality Analysis Antitubercular Agents - adverse effects Antitubercular Agents - therapeutic use Biomarkers Care and treatment Clinical Trials, Phase III as Topic Complications and side effects Corticosteroids Diagnosis Disseminated tuberculosis Dosage and administration Drug dosages Drug Therapy, Combination Equivalence Trials as Topic Fatalities Health aspects High dose rifampicin HIV HIV (Viruses) HIV infection HIV Infections - complications HIV Infections - drug therapy Hospitalization Humans Infectious diseases Levofloxacin Levofloxacin - therapeutic use Medical research Medicine, Experimental Mortality Prednisone Prednisone - administration & dosage Prednisone - adverse effects Prednisone - therapeutic use Product development Randomised controlled trial Rifampin Rifampin - administration & dosage Rifampin - therapeutic use Rifapentine Risk factors Study Protocol Testing Time Factors Treatment Outcome Tuberculosis Tuberculosis - diagnosis Tuberculosis - drug therapy Tuberculosis - mortality South Africa United Kingdom > UK Africa Levofloxacin Prednisone Disseminated tuberculosis HIV High dose rifampicin Randomised controlled trial
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Summary:	HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	1745-6215 1745-6215
DOI:	10.1186/s13063-024-08119-4