A Phase 3, Open-Label, Randomised Controlled Trial to Evaluate a 6-Month "MDR-END Plus" Regimen (Bedaquiline, Delamanid, Delpazolid, Levofloxacin and Pyrazinamide) Versus the South African Standard of Care Treatment for Rifampicin-Resistant Tuberculosis
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 294
- 试验地点
- 2
- 主要终点
- Favourable outcome at 12 months after treatment discontinuation
研究概览
简要总结
This is a phase 3, open-label, randomized clinical trial in adults and adolescents aged 15 years or older who need treatment for rifampicin-resistant tuberculosis in South Africa.
The goal of this clinical trial is to learn whether a 6-month MDR-END Plus regimen works as well as current standard of care (SoC) treatment for rifampicin-resistant tuberculosis. The trial will also learn whether the MDR-END Plus regimen is safer and easier to tolerate than SoC regimens.
The main questions this trial aims to answer are:
- Does the MDR-END Plus regimen lead to a favorable treatment outcome 12 months after treatment is stopped, compared with SoC regimens?
- Do participants receiving the MDR-END Plus regimen have fewer important safety or tolerability problems during treatment and up to 90 days after treatment is stopped, compared with SoC regimens?
Researchers will compare the MDR-END Plus regimen with South African standard of care (SoC) treatment for rifampicin-resistant tuberculosis.
Participants will:
- Be randomly assigned to receive either the MDR-END Plus regimen or SoC treatment.
- Take tuberculosis medicines for about 6 months, although treatment may be extended in some cases.
- Attend study visits during treatment and after treatment is stopped.
- Have clinical assessments, blood tests, heart tracing tests, vision and nerve assessments, and tuberculosis tests.
- Be followed for 12 months after treatment is stopped.
详细描述
This is a phase 3, multi-site, open-label, randomized controlled trial conducted in South Africa. The study will enroll adults and adolescents aged 15 years or older who require treatment for pulmonary rifampicin-resistant tuberculosis.
Participants will be randomized in a 1:1 ratio to either the investigational arm or the control arm. Randomization will be stratified by study site and HIV status. The study is open-label because participants and investigators will know which treatment is assigned.
Participants in the investigational arm will receive the MDR-END Plus regimen, consisting of bedaquiline, delamanid, delpazolid, levofloxacin, and pyrazinamide. Regimen adaptations may be made according to the drug susceptibility profile of the participant's Mycobacterium tuberculosis strain and drug suitability. Treatment may be extended according to protocol-defined criteria.
Participants in the control arm will receive South African standard of care (SoC) treatment for rifampicin-resistant tuberculosis according to national guidance and site practice.
Participants will attend study visits during treatment and after treatment discontinuation. Study assessments will include clinical evaluations, safety laboratory tests, electrocardiograms, microbiological assessments, and protocol-specified safety and tolerability assessments. Participants will be followed for 12 months after treatment discontinuation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This is an open-label trial. Participants, investigators, and care providers will not be masked to treatment assignment.
入排标准
- 年龄范围
- 15 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing and able to voluntarily provide written informed consent to participate in the study prior to initiation of any study-related procedures. For participants under the age of 18 years, signed consent may be obtained from the child's biological parent, legal guardian, or primary caregiver in the presence of the child. Minor participants must also be willing to provide written assent for study participation.
- •To the best of their knowledge and abilities at screening, participants must be willing and able to adhere to the complete follow-up schedule and all study procedures.
- •Male or female participants aged 15 years or older.
- •Participant requires treatment for pulmonary rifampicin-resistant tuberculosis based on one or more of the following:
- •Documented molecular drug susceptibility testing, such as TB nucleic acid amplification test, line probe assay, targeted next-generation sequencing, or culture-based phenotypic drug susceptibility testing on a sample obtained from the participant within 8 weeks prior to screening, even if rifampicin resistance is not re-confirmed on a sample obtained at screening; or
- •Documented or self-reported clinical symptoms or signs of pulmonary tuberculosis disease, with or without radiological changes consistent with pulmonary tuberculosis, and evidence of close contact with someone with confirmed rifampicin-resistant tuberculosis which, in the opinion of the site investigator, indicates significant exposure and a clinical decision has been made to treat the participant for rifampicin-resistant tuberculosis in routine care; or
- •Documented peripheral tuberculosis lymphadenitis or tuberculosis pleurisy with confirmed rifampicin-resistant Mycobacterium tuberculosis on lymph node biopsy or pleural fluid aspiration, along with documented symptoms or signs suggestive of pulmonary tuberculosis without culture confirmation.
- •Not yet started rifampicin-resistant tuberculosis treatment, or initiated rifampicin-resistant tuberculosis treatment in routine care within 10 days prior to enrolment.
- •Body weight of at least 30 kg.
- •Documented HIV status and/or willing to undergo HIV testing.
- •Participants living with HIV must be on antiretroviral therapy, or due to start antiretroviral therapy within 2 months of enrolment, regardless of CD4 count, provided they are clinically stable in the opinion of the site investigator.
- •Pregnant women in any trimester and breastfeeding women are eligible for inclusion.
排除标准
- •Two or more of the following four drug groups cannot be used: bedaquiline or clofazimine; delamanid or pretomanid; linezolid or delpazolid; levofloxacin or moxifloxacin, due to any of the following:
- •Documented Mycobacterium tuberculosis resistance in the current or prior treatment episode;
- •Prior exposure of 1 month or longer, unless protocol-defined exceptions are met;
- •Absolute contraindications to the relevant study drugs;
- •Use of prohibited concomitant medications within 14 days prior to enrolment.
- •Ongoing treatment for rifampicin-resistant tuberculosis for more than 10 days in the current tuberculosis episode.
- •Isolated extrapulmonary tuberculosis without pulmonary involvement.
- •Extrapulmonary tuberculosis, with or without concurrent pulmonary tuberculosis, involving the central nervous system, osteoarticular sites, pericardium, or disseminated/miliary disease.
- •Any of the following laboratory or ECG abnormalities:
- •A. Alanine transaminase or aspartate transaminase >120 U/L; B. Total bilirubin >2.4 mg/dL; C. Estimated glomerular filtration rate by the CKD-EPI equation <30 mL/min/1.73 m²; D. Serum potassium <3.2 mmol/L; E. QTcF >480 msec.
- •Atrioventricular block, second or third degree; current or previous history of clinically significant ventricular arrhythmias or long QT syndrome; or family history of long QT syndrome or sudden cardiac death.
- •Any condition or circumstance which, in the opinion of the investigator, based on information available at the time of screening, raises concerns regarding the participant's safety or ability to participate in the trial or the integrity of the study data.
结局指标
主要结局
Favourable outcome at 12 months after treatment discontinuation
时间窗: 12 months after treatment discontinuation
Proportion of evaluable participants with a favourable outcome at 12 months after treatment discontinuation in the investigational arm compared with the control arm. The primary efficacy analysis will assess whether the MDR-END Plus regimen is non-inferior to SoC regimens.
Composite safety and tolerability endpoint
时间窗: During treatment and up to 90 days after treatment discontinuation
Proportion of evaluable participants meeting the predefined composite safety and tolerability endpoint during treatment and up to 90 days after treatment discontinuation in the investigational arm compared with the control arm. The co-primary safety and tolerability analysis will assess whether the MDR-END Plus regimen is superior to SoC regimens, contingent upon demonstration of efficacy non-inferiority. The composite endpoint includes protocol-defined adverse events, serious adverse events, adverse events of special interest, and adverse events leading to permanent discontinuation of any study drug.
次要结局
- Model-derived delpazolid AUC0-24(Sparse PK sampling at Weeks 2, 8, and 26 after randomisation; intensive PK sampling at Week 2, pre-dose and 1, 2, 4, 8, and 24 hours post-dose.)
- Model-derived delpazolid Cmax(Sparse PK sampling at Weeks 2, 8, and 26 after randomisation; intensive PK sampling at Week 2, pre-dose and 1, 2, 4, 8, and 24 hours post-dose.)
研究者
Jae-Joon Yim
professor
Seoul National University Hospital