Innovating(IN) Shorter(S), All- Oral, Precised(P), Individualized(I) Treatment Regimen(RE) for Rifampicin Resistant Tuberculosis(INSPIRE-TB)
- Conditions
- Multidrug Resistant TuberculosisRifampicin Resistant TuberculosisPre-XDR-TB
- Interventions
- Other: This is a non-intervention observational study.
- Registration Number
- NCT05081401
- Lead Sponsor
- Huashan Hospital
- Brief Summary
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
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1050
- 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).
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Individualized 9-12 month all-oral regimen This is a non-intervention observational study. Treatment regimen is individually designed in this trial by responsible physicians at study sites based on radiological, clinical, bacteriological as well as drug sensitivity test results. RIF resistance was confirmed with phenotypic or molecular drug sensitivity test. Drug resistance to FQs, SLIDs, INH and Eto was evaluated by GeneXpert MTB/XDR. PZA resistance was confirmed by whole genome sequencing. Candidate anti-TB drugs are BDQ, LZD, FQs, Cs, Cfz, Z, Dlm and INH.
- Primary Outcome Measures
Name Time Method a favorable outcome at the end of study at 21 months after randomization A favorable outcome is defined by the absence of previous unfavorable, and the last two culture results are negative. These two cultures must be taken from respiratory samples collected on separate visits at least 7 days apart. The latest culture sample should be collected between month 21 and 23.
- Secondary Outcome Measures
Name Time Method The median time to sputum culture conversion at 21 months after randomization Time from treatment initiation to the first of two consecutive negative sputum culture conversion without an intervening positive culture.
The proportion of participants with grade 3 or higher AEs, SAEs at 21 months after randomization To compare the proportion of patients who experience grade 3 or greater adverse events (AE graded according to the Common terminology criteria for adverse events, version 5.0), during treatment or follow-up in safety population.
All-cause mortality and treatment relevant mortality at 21 months after randomization To compare the death rate and treatment relevant death rate during treatment or follow-up in safety population.
The proportion of participants with treatment relevant SAEs at 21 months post-randomization To compare the proportion of patients treatment relevant SAEs, during treatment or follow-up in safety population.
The proportion of participants with grade 3 or higher QTc prolongation at 21 months after randomization To compare the proportion of patients treatment relevant SAEs, during treatment or follow-up in safety population.
The proportion of participants experiencing permanent drug discontinuation or replacement due to QTc prolongation at 21 months after randomization To compare the proportion of patients experiencing permanent drug discontinuation or replacement due to QTc prolongation, during treatment or follow-up in safety population.
Trial Locations
- Locations (5)
Guiyang Public Health Treatment Center
🇨🇳Guiyang, Guizhou, China
People's Hospital of Qiandongnan
🇨🇳Kaili, Guizhou, China
The Third People's Hospital of Liupanshui
🇨🇳Liupanshui, Guizhou, China
Affiliated Hospital of Zunyi Medical University
🇨🇳Zunyi, Guizhou, China
Huashan Hospital of Fudan University
🇨🇳Shanghai, Shanghai, China