A Phase 3, Randomized, Open-label, Multicenter Trial to Evaluate the Efficacy, Safety, and Tolerability of 4-month and 6-month Quabodepistat-containing Regimens for Rifampicin-resistant/Multidrug-resistant Pulmonary Tuberculosis
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 532
- 试验地点
- 68
- 主要终点
- Proportion of participants with unfavorable outcome.
研究概览
简要总结
This study aims to assess quabodepistat-based treatment regimens for RR/MDR-TB. The study will enroll adults and adolescents with rifampicin-resistant or multidrug-resistant pulmonary TB. The main goal is to see if a new drug called quabodepistat, when combined with other TB drugs, can shorten treatment duration to 4 months and be as effective and safer than current WHO endorsed treatment regimen given for 6-months. The study will compare different drug combinations in two groups of patients: those whose TB is sensitive to fluoroquinolones and those whose TB is resistant to fluoroquinolones. Participants will be randomly assigned to receive either the new treatment or the standard treatment. The study will last for 16 months for each participant and will measure how well the treatments work and how safe they are.
详细描述
This is a Phase 3, randomized, open-label, multicenter trial evaluating quabodepistat-containing regimens for rifampicin-resistant/multidrug-resistant (RR/MDR) pulmonary tuberculosis (TB).
The study aims to enroll 532 participants aged 14 years and older.
The study has two main cohorts:
Fluoroquinolone-sensitive RR/MDR-TB (432 participants):
- Experimental arm: BPaQM (bedaquiline, pretomanid, quabodepistat, moxifloxacin) for 4 months
- Control arm: BPaLM (bedaquiline, pretomanid, linezolid, moxifloxacin) for 6 months
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 study with blinded endpoint adjudication of the primary efficacy outcome. Certain sponsor team members will be blinded to treatment assignments to minimize potential bias as much as possible
入排标准
- 年龄范围
- 14 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥14 years
- •Body weight ≥30.0 kg
- •Able to provide written informed consent (if under 18, requires both participant assent and parent/guardian consent)
- •Documented pulmonary TB: Mtb confirmed by Xpert MTB/RIF Ultra (semi-quantitative result of 'low', 'medium', or 'high')
- •Rifampicin resistance confirmed by Xpert MTB/RIF Ultra test
- •Chest radiograph consistent with active TB disease
- •Able to provide sputum sample
- •Participants of childbearing potential must use 2 different approved birth control methods during treatment and for 12 weeks after last dose
- •Willing to have HIV test (unless previous positive result confirmed)
- •For HIV-positive participants: On stable antiretroviral regimen (dolutegravir, lamivudine/emtricitabine, tenofovir) for ≥3 months, Viral load <200 copies/mL, and CD4 count >100 cells/mL
排除标准
- •Known/suspected resistance to BDQ, PMD, LZD, or QBS
- •Prior treatment with BDQ, PMD, LZD, DLM, QBS, or DprE1 inhibitors for ≥1 month within past 3 months
- •Severe extrapulmonary TB
- •Abnormal laboratory values: ALT/AST >2.5×ULN, Total bilirubin >1.5×ULN, eGFR <60 mL/min/1.73m², Hemoglobin <8 g/dL, Platelets <100,000 cells/mm³, WBC <2.0×10⁹/L, ANC <1000 cells/μL, and HbA1c >9.0%
- •Pre-existing peripheral neuropathy (≥Grade 1), optic neuritis, or visual impairment
- •Co-enrollment in other therapeutic trials
- •QTcF >450 msec (males) or >470 msec (females)
- •Clinically significant cardiovascular disorders
- •Bleeding disorders
- •Conditions interfering with X-ray or sputum assessment
- •Drug allergies/hypersensitivity to study medications
- •Pregnancy or breastfeeding
- •Positive drug screen (case-by-case assessment for some substances)
- •Serious mental disorders
- •Karnofsky score <60
- •BMI <16.0 kg/m²
- •Significant comorbidities (metabolic, renal, gastrointestinal, neurological, psychiatric, endocrine, liver)
- •Pulmonary conditions other than TB (silicosis, fibrosis)
- •Active SARS-CoV-2 infection
- •Use of prohibited medications
- •Blood/plasma donation within 30 days
- •Current use of herbal remedies or traditional medicines
研究组 & 干预措施
BPaQM for Fluoroquinolone-sensitive RR/MDR-TB
Bedaquiline 400 mg once daily for 2 weeks then 100 mg once daily for 15 weeks + Pretomanid 200 mg QD for 17 weeks + Quabodepistat 30 mg once daily for 17 weeks + Moxifloxacin 400 mg once daily for 17 weeks
干预措施: BPaQM (Drug)
BPaLM for Fluoroquinolone-sensitive RR/MDR-TB
Bedaquiline 400 mg once daily for 2 weeks then 200 mg thrice a week for 24 weeks + Pretomanid 200 mg QD for 26 weeks + Linezolid 600 mg once daily for 26 weeks + Moxifloxacin 400 mg once daily for 26 weeks
干预措施: BPaLM (Drug)
BPaQ for Fluoroquinolone-resistant RR/MDR-TB
Bedaquiline 400 mg once daily for 2 weeks then 100 mg once daily for 24 weeks + Pretomanid 200 mg QD for 26 weeks + Quabodepistat 30 mg once daily for 26 weeks
干预措施: BPaQ (Drug)
BPaL for Fluoroquinolone-resistant RR/MDR-TB
Bedaquiline 400 mg once daily for 2 weeks then 200 mg thrice a week for 24 weeks + Pretomanid 200 mg QD for 26 weeks + Linezolid 600 mg once daily for 26 weeks
干预措施: BPaL (Drug)
结局指标
主要结局
Proportion of participants with unfavorable outcome.
时间窗: From randomization to Month 12
Unfavorable outcome is defined as a participant experiencing at least one of the following: death, treatment failure, change in regimen, or sputum culture with growth of Mycobacterium tuberculosis at certain timepoints as follows: Failure to achieve SCC at the end of the treatment period that results in a change in anti-mycobacterial therapy or Relapse during the follow-up period (i.e., the period from end of treatment to Month 12 post-randomization.
Incidence of Grade ≥3 Treatment-Emergent Adverse Events, Serious Adverse Events, or Adverse Events Leading to Dose Reduction or Discontinuation (Safety and Tolerability).
时间窗: From first dose to 2 weeks after end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL)
A participant experiencing at least one of the following: Grade 3 toxicity or higher treatment-emergent adverse events (TEAEs), serious TEAEs, or TEAEs leading to dose reduction or discontinuation.
次要结局
- Proportion of participants with sputum culture conversion.(At Week 8 and at end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL))
- Proportion of participants with adverse events of special interest (AESIs).(From first dose to 2 weeks after end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL))
- Time to first occurrence of any event meeting the unfavorable outcome definition.(From randomization to Month 12)
- Time to sputum culture conversion.(From randomization to end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL))
- Proportion of participants with microbiological relapse.(From end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL) to Month 12 post-randomization)
- Proportion of participants with treatment-emergent adverse events (TEAEs).(From randomization through Week 68)
- Proportion of time during treatment spent without adverse events.(From randomization to end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL))
- Proportion of participants who are lost to follow-up.(From randomization through Week 68)
- Plasma concentrations of each analyte at scheduled visits.(From randomization through Week 17 (BPaQM and BPaQ only))
- Proportion of participants with TB-related death.(From randomization through Week 68)