Standards for clinical trials for treating TB

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice. METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached. RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff. CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.


Design
Primary endpoint † without an intervening negative culture and without genotypic evidence of reinfection.Favourable outcome was defined as having a negative culture at the scheduled end of follow-up and not previously classified as having an unfavourable outcome.
REMoxTB (NCT00864383) 4 2008-2012 Multi-arm randomised controlled design Unfavourable outcome defined as the proportion of participants with bacteriological or clinical treatment failure or relapse within 18 months after randomisation.Relapse strains were those shown to be identical on 24-locus MIRU analysis.
STAND/NC-006 (NCT02342886) 5 * 2015 Multi-arm randomised controlled design Unfavourable outcome defined as the proportion of participants with bacteriological or clinical treatment failure or relapse 12 months after randomisation (from 50 to 54 weeks).Favourable outcome was defined as having a negative culture status (two consecutive negative cultures at least 1 week apart with no intervening positive result) at 12 months after randomisation, and not previously classified as having an unfavourable outcome.
S31/A5349 (NCT02410772) 6 2016-2018 Multi-arm randomised controlled design Favourable outcome defined as survival free of TB at 12 months after randomisation.Favourable status was assigned if a participant met all of the following criteria: was alive and free of TB at 12 months after randomisation; did not meet the criteria for unfavourable or not-assessable status; and had either an M. tuberculosis-negative result on the sputum culture at month 12,or at month 12 was unable to produce sputum or produced sputum that was contaminated but without evidence of M. tuberculosis.Unfavourable status was assigned if a participant had M. tuberculosis -positive cultures from two sputum specimens obtained at or after week 17 without an intervening negative culture, died or were withdrawn from the trial or lost to follow-up during the treatment period, had an M. tuberculosis-positive culture when last seen, died from TB during the post-treatment follow-up, or received additional treatment for TB.
TRUNCATE-TB (NCT03474198) 7 2018-2020 Strategy trial Unfavourable outcome defined as a composite of death before week 96 or ongoing TB treatment or active TB at week 96.

Drug-resistant tuberculosis
STREAM Stage 1 (NCT02409290) 8 2012-2015 Two-arm randomised controlled design Favourable outcome defined as cultures negative for M. tuberculosis at 132 weeks after randomisation and at a previous occasion during the trial period, with no intervening positive culture or previous unfavourable outcome.Unfavourable outcome defined by the initiation of two or more drug therapies that were not included in the assigned regimen, treatment extension beyond the permitted duration, death from any cause, a positive culture

Design
Primary endpoint † from one of the two most recent specimens, or no visit at 76 weeks or later.Participants who had reinfections with a different strain and those whose last two cultures were negative (including one at 76 weeks) but were lost to follow-up thereafter were considered to be unable to be assessed and were excluded from the primary analysis.
NExT (NCT02454205) Favourable outcome defined as not previously classified as unfavourable by week 73, and one of the following is true: [1] the last two culture results are negative.These two cultures must be taken from sputum samples collected on separate visits, the latest between weeks 65 and 73; or [2] the last culture result (from a sputum sample collected between weeks 65 and 73) is negative, and either there is no other post-baseline culture result or the penultimate culture result is positive due to laboratory cross contamination, and bacteriological, radiological and clinical evolution is favourable; or [3] there is no culture result from a sputum sample collected between weeks 65 and 73 or the result of that culture is positive due to laboratory cross contamination, and the most recent culture result is negative, and bacteriological, radiological, and clinical evolution is favourable.
TB-PRACTECAL (NCT02589782) 15 2017-2021 Phase 2-3, multi arm multi-stage randomised controlled trial Unfavourable status was defined as a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of TB at 72 weeks after randomization BEAT-India (CTRI/2019/01/017 310) 16 2019-2021 Uncontrolled cohort study Favourable outcome defined as 2 consecutive sputum cultures taken at least 4 weeks apart were negative, with clinical and radiological improvement at the end of treatment.
endTB-Q (NCT03896685) 14 2020-2023 Strategy trial Favourable outcome defined as the proportion of participants whose outcome is not classified as unfavourable at week 73, and for whom one of the following is true: the last two culture results are negative (these two cultures must be taken from sputum samples collected on separate visits, the latest between week 65 and week 73); the last culture result (from a sputum sample collected between week 65 and week 73) is negative, and either there is no other post-baseline culture result or the penultimate culture result is positive due to laboratory cross contamination, and bacteriological, radiological and clinical evolution is favourable; or there is no culture result from a sputum sample collected between week 65 and week 73 or the result of that culture is positive due to laboratory

Years of active enrolment
Design Primary endpoint † cross contamination; and the most recent culture result is negative; and bacteriological, radiological and clinical evolution is favourable.

2022present Duration evaluation
Favourable outcome defined as sustained cure at 76 weeks after randomisation without treatment failure or relapse.
* These trials are listed under both the drug-susceptible and drug-resistant sections due to inclusion of these two populations.In each case, study design differed for the drug-susceptible and drug-resistant populations.† The primary endpoints are listed here.Many trials had multiple secondary endpoints, with much longer follow up periods than the primary endpoints.
Bacteriological treatment failure was defined as negative culture status not attained or maintained during treatment.Clinical treatment failure was defined as a change from the protocol-specified TB treatment as a result of a lack of clinical efficacy, retreatment for TB, or TB-related death.
Unfavourable outcome defined as treatment failure (bacteriological or clinical) or disease relapse.Clinical treatment failure was defined as a change from the protocol-specified TB treatment as a result of a lack of clinical efficacy, retreatment for TB, or TB-related death through follow-up until 6 months after the end of treatment.Favourable outcome defined as resolution of clinical TB disease, negative culture status at 6 months after the end of therapy, and not previously classified as having an unfavourable outcome.Unfavourable outcome defined as the proportion of participants with bacteriological or clinical treatment failure or relapse 12 months after randomisation (from 50 to 54 weeks).Favourable outcome defined as having a negative culture status (two consecutive negative cultures at least 1 week apart with no intervening positive result) at 12 months after randomisation, and not previously classified as having an unfavourable outcome.