TY - JOUR
T1 - Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2)
T2 - an open-label, multicentre, randomised, non-inferiority trial
AU - STREAM study collaborators
AU - Goodall, Ruth L.
AU - Meredith, Sarah K.
AU - Nunn, Andrew J.
AU - Bayissa, Adamu
AU - Bhatnagar, Anuj K.
AU - Bronson, Gay
AU - Chiang, Chen Yuan
AU - Conradie, Francesca
AU - Gurumurthy, Meera
AU - Kirenga, Bruce
AU - Kiria, Nana
AU - Meressa, Daniel
AU - Moodliar, Ronelle
AU - Narendran, Gopalan
AU - Ngubane, Nosipho
AU - Rassool, Mohammed
AU - Sanders, Karen
AU - Solanki, Rajesh
AU - Squire, S. Bertel
AU - Torrea, Gabriela
AU - Tsogt, Bazarragchaa
AU - Tudor, Elena
AU - Van Deun, Armand
AU - Rusen, I. D.
AU - Adilaa, Oyunchimeg
AU - Alexandru, Sofia
AU - Bellenger, Katharine
AU - Bennet, Jaclyn
AU - Bennet, Deborah
AU - Bindroo, Priyanka
AU - Borisagar, Ghanshyam
AU - Cook, Claire
AU - Dalai, Doljinsuren
AU - Davis, Andrew
AU - de Jong, Bouke
AU - Dodds, Wendy
AU - Duckworth, Lynette
AU - Gahima, Nonhlanhla
AU - Gebreegziabher, Belay
AU - Goldfeld, Anne
AU - Hanifa, Mahmud
AU - Hughes, Gareth
AU - Kimuli, Ivan
AU - Komrska, Jan
AU - Lomtadze, Nino
AU - Murphy, Brendan
AU - Mwelase, Thando
AU - Nalunjogi, Joanitah
AU - Patel, Leena
AU - Pirlog, Irina
N1 - Funding Information:
We wish to acknowledge the key contributions to STREAM stage 2 of three people who have died since the trial began: Donald Enarson of the International Union Against Tuberculosis and Lung Disease, Brian Danneman from Janssen Research & Development, and Iqbal Master of King Dinuzulu Hospital Complex, South Africa. All three guided us during the development of the trial but sadly are not here to see the results. STREAM stage 1 was funded by the US Agency for International Development (USAID) through the Cooperative Agreement GHN-A-00–08–0004–00. Stage 2 of STREAM was jointly funded by USAID and Janssen Research & Development. Additional funding for STREAM was provided by the Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, which is also part of the EDCTP2 programme supported by the EU. The MRC Clinical Trials Unit at University College London was supported by the MRC (MC_UU_12023/26). We thank all the participants, community action board members, and collaborators, without whom the STREAM study would not have been possible.
Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2022/11/26
Y1 - 2022/11/26
N2 - Background: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. Methods: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631. Findings: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9–19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1–31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss. Interpretation: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss. Funding: USAID and Janssen Research & Development.
AB - Background: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. Methods: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631. Findings: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9–19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1–31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss. Interpretation: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss. Funding: USAID and Janssen Research & Development.
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U2 - 10.1016/S0140-6736(22)02078-5
DO - 10.1016/S0140-6736(22)02078-5
M3 - Article
C2 - 36368336
AN - SCOPUS:85142494348
SN - 0140-6736
VL - 400
SP - 1858
EP - 1868
JO - The Lancet
JF - The Lancet
IS - 10366
ER -
