Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial
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 
Published: May 2024

Background

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.

Methods

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.

Discussion

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.

Trial registration

ClinicalTrials.gov NCT04951986. Registered on 7 July 2021

https://clinicaltrials.gov/study/NCT04951986