Innovating(IN) Shorter(S), All- Oral, Precised(P), Individualized(I) Treatment Regimen(RE) for Rifampicin Resistant Tuberculosis(INSPIRE-TB)

Обзор

The INSPIRE-TB study is a pragmatic, multicentre, randomised, controlled, non-inferiority open-label trial to evaluate the efficacy and safety of seven 9-month oral regimens compared to a 9-month standard of care (SOC) regimen in RR-TB participants susceptible to fluoroquinolones, and a bedaquiline-containing 9-month oral regimen compared to a 20-month conventional regimen in RR-TB participants resistant to fluoroquinolones

Подробное описание

RR-TB patients susceptible to fluoroquinolones are identified with the Xpert MTB/XDR assay (Cepheid; Sunnyvale, CA, USA). Experimental arms are seven oral regimens with a five-drug combination of the following: bedaquiline, linezolid, a fluoroquinolone (moxifloxacin or levofloxacin), cycloserine, clofazimine, and pyrazinamide.To minimize potential toxicity, each regimen includes no more than two major QT-prolonging drugs (bedaquiline, clofazimine, and moxifloxacin). Treatment duration of the experimental regimens is 9 months. A 2-month extension of treatment is allowed with the presence of cavities at month 9 or in case of a positive culture at month 2. Baseline molecular drug susceptibility test (DST) of pyrazinamide will be performed using whole gene sequencing (WGS) technique. The result of molecular DST of pyrazinamide will be interpreted by technical staff at central laboratory of Huashan Hospital, Fudan University. Once a participant is proved resistant to pyrazinamide by WGS results at baseline, pyrazinamide will be discontinued with no need for extra drug replacement. The control regimen for RR-TB patients susceptible to fluoroquinolones is the current SOC oral regimen recommended by the national guidelines.

Pre-XDR TB patients are identified with the Xpert MTB/XDR assay. The experimental arm is a 9-month regimen consisting of bedaquiline, cycloserine, clofazimine, linezolid, and pyrazinamide. Treatment extension to 11 months is allowed with the presence of cavities at month 9 or in case of a positive culture at month 2. Pyrazinamide will be discontinued from the study regimen if baseline molecular DST results reveal pyrazinamide resistance. The comparator is a conventional longer regimen (20 months) consistent with the national guidelines.

Вмешательства

• Комбинированный продукт Bdq(Lzd)+Lfx(Mfx)+Cfz(Cs)+Pto+E+H+Z
  A-SOC: 4Bdq(Lzd)+Lfx(Mfx)+Cfz(Cs)+Pto+E+H+Z/5Lfx(Mfx)+Cfz(Cs)+E+Z During the intensive phase: Bedaquiline(Linezolid);Levofloxacin(Moxifloxacin) All treatment is taken orally
• Комбинированный продукт A1
  9Bdq(6m)+Fq+Lzd+Cs+Cfz
• Комбинированный продукт A2a
  9Bdq(6m)+Fq+Lzd(600mg)+Cs+Z
• Комбинированный продукт A2b
  9Bdq(6m)+Fq+Lzd(2m)+Cs+Z
• Комбинированный продукт A2c
  9Bdq(6m)+Fq+Lzd(600mg-300mg)+Cs+Z
• Комбинированный продукт A3
  9Bdq(6m)+Fq+Lzd+Cfz+Z
• Комбинированный продукт A4
  9Bdq(6m)+Fq+Cfz+Cs+Z
• Комбинированный продукт A5
  9Fq+Lzd+Cfz+Cs+Z
• Комбинированный продукт B-SOC
  6Bdq+Lzd+Cs+Cfz/14Lzd+Cfz+Cs
• Комбинированный продукт B1
  9Bdq(6m)+Lzd+Cs+Cfz+Z

Первичные конечные точки

• a favorable outcome at the end of study [Срок оценки: at 21 months after randomization]

Вторичные конечные точки (6)

• The median time to sputum culture conversion [Срок оценки: at 21 months after randomization]
• The proportion of participants with grade 3 or higher AEs, SAEs [Срок оценки: at 21 months after randomization]
• All-cause mortality and treatment relevant mortality [Срок оценки: at 21 months after randomization]
• The proportion of participants with treatment relevant SAEs [Срок оценки: at 21 months post-randomization]
• The proportion of participants with grade 3 or higher QTc prolongation [Срок оценки: at 21 months after randomization]
• The proportion of participants experiencing permanent drug discontinuation or replacement due to QTc prolongation [Срок оценки: at 21 months after randomization]

Критерии участия

Критерии включения

• Male or female patients aged 16-75 years with weight over 30kg, regardless of HIV status;
• Pulmonary TB with rifampicin resistance diagnosed with either WHO-approved rapid molecular diagnostic test or phenotype drug susceptibility test (within 60 days prior to randomisation) ;
• Signed informed consent form (ICF).

Критерии исключения

• Known allergies, hypersensitivity, or contraindication to any of the study drugs as described in additional material;
• Participants combined with central nervous system TB, tuberculous osteomyelitis or arthritis, hematogenous disseminated pulmonary TB;
• Patients known to be pregnant or breastfeeding at the time of enrollment;
• Patients who have received second-line MDR-TB treatment for 14 days or more prior to enrollment;
• Patients in critical condition and expected survival is estimated by physician to be less than 12 weeks.

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

Китай · 5 центров

• Guiyang Public Health Treatment Center — Guiyang
• People's Hospital of Qiandongnan — Kaili
• The Third People's Hospital of Liupanshui — Liupanshui
• Affiliated Hospital of Zunyi Medical University — Zunyi
• Huashan Hospital of Fudan University — Шанхай

Идентификаторы

NCT: NCT05081401 · INSPIRE-TB

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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