A Study of Quabodepistat-containing Regimens for the Treatment of Drug-resistant Pulmonary Tuberculosis

Официальное название

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

Обзор

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.

Подробное описание

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

Fluoroquinolone-resistant RR/MDR-TB (100 participants):

* Experimental arm: BPaQ (bedaquiline, pretomanid, quabodepistat) for 6 months * Control arm: BPaL (bedaquiline, pretomanid, linezolid) for 6 months

The primary efficacy endpoint is an unfavorable outcome by 12 months post-randomization.

Secondary endpoints include time to unfavorable outcome, time to sputum culture conversion, and safety/tolerability assessments. Participants will be followed for 16 months post-randomization.

The study will be conducted at approximately 40 sites in up to 12 countries.

An independent Data Monitoring Committee and Endpoint Adjudication Committee will be used in the study.

The trial aims to evaluate if quabodepistat-containing regimens can shorten treatment duration to 4 months for fluoroquinolone-sensitive RR/MDR-TB and provide a safer alternative to linezolid-containing regimens for both fluoroquinolone-sensitive and fluoroquinolone-resistant RR/MDR-TB.

Вмешательства

• Препарат BPaQM
  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
• Препарат BPaLM
  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
• Препарат BPaQ
  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
• Препарат BPaL
  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

Первичные конечные точки

• Proportion of participants with unfavorable outcome. [Срок оценки: From randomization to Month 12]
• Incidence of Grade ≥3 Treatment-Emergent Adverse Events, Serious Adverse Events, or Adverse Events Leading to Dose Reduction or Discontinuation (Safety and Tolerability). [Срок оценки: From first dose to 2 weeks after end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL)]

Вторичные конечные точки (10)

• Time to first occurrence of any event meeting the unfavorable outcome definition. [Срок оценки: From randomization to Month 12]
• Time to sputum culture conversion. [Срок оценки: From randomization to end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL)]
• Proportion of participants with sputum culture conversion. [Срок оценки: At Week 8 and at end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL)]
• Proportion of participants with microbiological relapse. [Срок оценки: From end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL) to Month 12 post-randomization]
• Proportion of participants with adverse events of special interest (AESIs). [Срок оценки: From first dose to 2 weeks after end of treatment (Week 17 for BPaQM; Week 26 for BPaLM, BPaQ, BPaL)]
• Proportion of participants with treatment-emergent adverse events (TEAEs). [Срок оценки: From randomization through Week 68]
• Proportion of time during treatment spent without adverse events. [Срок оценки: 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. [Срок оценки: From randomization through Week 68]
• Proportion of participants with TB-related death. [Срок оценки: From randomization through Week 68]
• Plasma concentrations of each analyte at scheduled visits. [Срок оценки: From randomization through Week 17 (BPaQM and BPaQ only)]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

ЮАР · 13 центров

• Synergy Biomed Research Institute — East London
• Isango Lethemba TB Res Unit (CHRU) - Jose Pearson TB Hospital — Port Elizabeth
• The Aurum Institute - Tembisa Hospital Clinical Research Centre — Johannesburg
• Clinical HIV Research Unit (CHRU) - Helen Joseph Hospital — Johannesburg
• Sizwe Clinical Research Site (CHRU) - Sizwe Tropical Disease Hospital, — Johannesburg
• Setshaba Research Center — Pretoria
• Perinatal HIV Research Unit (PHRU) - Chris Hani Baragwanath Academic Hospital — Soweto
• Centre for the AIDS Programme of Research in South Africa (CAPRISA) — Durban
• … и ещё 5 центров

Китай · 9 центров

• Capital Medical University - Beijing Chest Hospital — Пекин
• Fuzhou Tuberculosis Prevention and Control Hospital of Fujian Province — Фучжоу
• The Third People's Hospital of Shenzhen — Шэньчжэнь
• Wuhan Institute of Tuberculosis Control (Wuhan Pulmonary Hospital) — Ухань
• The Second Hospital of Nanjing — Нанкин
• Shandong Public Health Clinical Center — Цзинань
• Huashan Hospital Fudan University — Шанхай
• Shanghai Pulmonary Hospital - Pneumology — Шанхай
• … и ещё 1 центр

Филиппины · 4 центра

• Silang Specialist Medical Center — Silang
• Jose B. Lingad Memorial Regional Hospital — San Fernando City
• Tropical Disease Foundation — Makati City
• Lung Center Of The Philippines — Quezon City

Перу · 3 центра

• Socios en Salud Sucursal Peru — La Molina
• Centro de Investigación del Hospital de Emergencias de Villa el Salvador — Villa El Salvador
• Hospital Sergio E. Bernales — Lima

South Korea · 3 центра

• The Catholic University of Korea, Incheon St. Mary's Hospital — Incheon
• Pusan National University Hospital — Busan
• Asan Medical Center - Pulmonology — Seoul

Грузия · 1 центр

• National Center for Tuberculosis and Lung Disease — Tbilisi

Япония · 1 центр

• Japan Anti-Tuberculosis Association Fukujuji Hospital — Kiyose

Moldova · 1 центр

• IMSP Institutul de Ftiziopneumologie Chiril Draganiuc - Phthisiopneumology — Chisinau

Идентификаторы

NCT: NCT07209761 · 323-201-00013 · jRCT2031260045

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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