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The endTB observational study protocol: treatment of MDR-TB with bedaquiline or delamanid containing regimens.

ABSTRACT: BACKGROUND:At a time when programs were struggling to design effective regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB), the marketing authorization of bedaquiline and delamanid was a critical development in the MDR-TB treatment landscape. However, despite their availability for routine programmatic use, the uptake of these drugs has remained slow; concerns included a lack of evidence on safety and efficacy and the need to protect the new drugs from the development of acquired resistance. As part of the endTB Project, we aimed to address these barriers by generating evidence on safety and efficacy of bedaquiline or delamanid based MDR-TB regimens. METHODS:This is a protocol for a multi-center prospective cohort study to enroll 2600 patients from April 2015 through September 2018 in 17 countries. The protocol describes inclusion of patients started on treatment with bedaquiline- or delamanid- containing regimens under routine care, who consented to participate in the endTB observational study. Patient follow-up was according to routine monitoring schedules recommended for patients receiving bedaquiline or delamanid as implemented at each endTB site. Therefore, no additional tests were performed as a part of the study. Data were to be collected in a customized, open-source electronic medical record (EMR) system developed as a part of the endTB Project across all 17 countries. DISCUSSION:The endTB observational study will generate evidence on safety and efficacy of bedaquiline- and delamanid-containing regimens in a large, extremely heterogeneous group of MDR-TB patients, from 17 epidemiologically diverse countries. The systematic, prospective data collection of repeated effectiveness and safety measures, and analyses performed on these data, will improve the quality of evidence available to inform MDR-TB treatment and policy decisions. Further, the resources available to countries through implementation of the endTB project will have permitted countries to: gain experience with the use of these drugs in MDR-TB regimens, improve local capacity to record and report adverse events (pharmacovigilance), and enhance significantly the body of data available for safety evaluation of these drugs and other novel treatments. TRIAL REGISTRATION:This study was registered on 24 August 2017 at clincaltrials.gov (Registration number: NCT03259269).

SUBMITTER: Khan U

PROVIDER: S-EPMC6701145 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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The endTB observational study protocol: treatment of MDR-TB with bedaquiline or delamanid containing regimens.

Khan Uzma U Huerga Helena H Khan Aamir J AJ Mitnick Carole D CD Hewison Catherine C Varaine Francis F Bastard Mathieu M Rich Michael M Franke Molly F MF Atwood Sidney S Khan Palwasha Y PY Seung Kwonjune J KJ

BMC infectious diseases 20190820 1

<h4>Background</h4>At a time when programs were struggling to design effective regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB), the marketing authorization of bedaquiline and delamanid was a critical development in the MDR-TB treatment landscape. However, despite their availability for routine programmatic use, the uptake of these drugs has remained slow; concerns included a lack of evidence on safety and efficacy and the need to protect the new drugs from the development ...[more]

PMID: 31429722

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Project description:BackgroundMultidrug-resistant tuberculosis (MDR-TB) are unsatisfied to treat, pressing more effective and innovative treatment regimens. New efficient regimens for MDR-TB have obtained high treatment success rates. However, those regimens without drug susceptibility testing (DST) are also likely to contribute to the emergence of resistance. Precision treatments guided by DST might optimize the patients' treatment outcome individually and minimize resistance amplification.MethodsTB-TRUST is a phase III, multicenter, open-label, randomized controlled clinical trial of non-inferiority comparing the treatment success rate between the World Health Organization (WHO) shorter regimen and the refined ultra-short regimen for fluoroquinolones and second-line injectable drugs susceptible rifampicin-resistant TB. The control arm uses the WHO injectable-containing shorter regimen for 36-44 weeks depending on time of sputum smear conversion. The investigational arm uses a refined ultra-short regimen guided by molecular DST to pyrazinamide via whole-genome sequencing (WGS) to optimize the treatment of pyrazinamide-susceptible patients with levofloxacin, linezolid, cycloserine and pyrazinamide for 24-32 weeks and pyrazinamide-resistant with levofloxacin, linezolid, cycloserine and clofazimine for 36-44 weeks. The primary outcome is the treatment success rate without relapse at 84 weeks after treatment initiation. Secondary outcomes include the time of sputum culture conversion and occurrence of adverse events. Assuming α = 0.025 level of significance (one-sided test), a power of 80%, a < 10% difference in treatment success rate between control arm and investigational (80% vs. 82%), and a 5% lost follow-up rate, the number of participants per arm to show non-inferiority was calculated as 177(354 in total).DiscussionRapid molecular testing distinguishes patients who are eligible for shorter regimen with fluoroquinolone and the WGS-guided results shorten the treatment to 6 months for pyrazinamide susceptible patients. It's foreseeable that not only novel developed medicines, but also traditional powerful medicines with the susceptibility confirmed by DST are the key factors to ensure the effect of anti-MDR-TB drugs. As a DST-guided precision treatment, TB-TRUST are expected to optimize therapy outcome in more patients who cannot afford the expensive new medicines and minimize and even avoid resistance amplification with the rational use of anti-TB drugs.Trail registrationClinicalTrial.gov, NCT03867136 . Registered on March 7, 2019.

Project description:IntroductionDiabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.MethodsThe study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.ResultsBody mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).ConclusionDespite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.

Dataset Information

The endTB observational study protocol: treatment of MDR-TB with bedaquiline or delamanid containing regimens.

Publications

The endTB observational study protocol: treatment of MDR-TB with bedaquiline or delamanid containing regimens.

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