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

Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial. Namale, P. E., Boloko, L., Vermeulen, M., Haigh, K. A., Bagula, F., Maseko, A., Sossen, B., Lee-Jones, S., Msomi, Y., McIlleron, H., Mnguni, A. T., Crede, T., Szymanski, P., Naude, J., Ebrahim, S., Vallie, Y., Moosa, M. S., Bandeker, I., Hoosain, S., Nicol, M. P., Samodien, N., Centner, C., Dowling, W., Denti, P., Gumedze, F., Little, F., Parker, A., Price, B., Schietekat, D., Simmons, B., Hill, A., Wilkinson, R. J., Oliphant, I., Hlungulu, S., Apolisi, I., Toleni, M., Asare, Z., Mpalali, M. K., Boshoff, E., Prinsloo, D., Lakay, F., Bekiswa, A., Jackson, A., Barnes, A., Johnson, R., Wasserman, S., Maartens, G., Barr, D., Schutz, C., & Meintjes, G. Trials, 25(1):311, May, 2024.

Paper doi abstract bibtex

Abstract 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

@article{namale_testing_2024,
	title = {Testing novel strategies for patients hospitalised with {HIV}-associated disseminated tuberculosis ({NewStrat}-{TB}): protocol for a randomised controlled trial},
	volume = {25},
	issn = {1745-6215},
	shorttitle = {Testing novel strategies for patients hospitalised with {HIV}-associated disseminated tuberculosis ({NewStrat}-{TB})},
	url = {https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-024-08119-4},
	doi = {10.1186/s13063-024-08119-4},
	abstract = {Abstract 
             
              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},
	language = {en},
	number = {1},
	urldate = {2025-06-24},
	journal = {Trials},
	author = {Namale, Phiona E. and Boloko, Linda and Vermeulen, Marcia and Haigh, Kate A. and Bagula, Fortuna and Maseko, Alexis and Sossen, Bianca and Lee-Jones, Scott and Msomi, Yoliswa and McIlleron, Helen and Mnguni, Ayanda Trevor and Crede, Thomas and Szymanski, Patryk and Naude, Jonathan and Ebrahim, Sakeena and Vallie, Yakoob and Moosa, Muhammed Shiraz and Bandeker, Ismail and Hoosain, Shakeel and Nicol, Mark P. and Samodien, Nazlee and Centner, Chad and Dowling, Wentzel and Denti, Paolo and Gumedze, Freedom and Little, Francesca and Parker, Arifa and Price, Brendon and Schietekat, Denzil and Simmons, Bryony and Hill, Andrew and Wilkinson, Robert J. and Oliphant, Ida and Hlungulu, Siphokazi and Apolisi, Ivy and Toleni, Monica and Asare, Zimkhitha and Mpalali, Mkanyiseli Kenneth and Boshoff, Erica and Prinsloo, Denise and Lakay, Francisco and Bekiswa, Abulele and Jackson, Amanda and Barnes, Ashleigh and Johnson, Ryan and Wasserman, Sean and Maartens, Gary and Barr, David and Schutz, Charlotte and Meintjes, Graeme},
	month = may,
	year = {2024},
	pages = {311},
}

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