Clinical trial NCT05081401: Innovating(IN) Shorter(S), All- Oral, Precised(P), Individualized(I) Treatment Regimen(RE) for Rifampicin Resistant Tuberculosis(INSPIRE-TB)
Official title: Innovating(IN) Shorter(S), All- Oral, Precised(P), Individualized(I) Treatment Regimen(RE) for Rifampicin Resistant Tuberculosis(INSPIRE-TB)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Multidrug Resistant Tuberculosis
Rifampicin Resistant Tuberculosis
Pre-XDR-TB
Keywords: multidrug resistant tuberculosis
shorter treatment
all-oral regimen
PZA sensitivity
Lead sponsor: Huashan Hospital
Sponsor class: OTHER
First posted: 2021-10-18
Enrollment: 1050
Sex: ALL
Minimum age (years): 16
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Male or female patients aged 16-75 years with weight over 30kg, regardless of HIV status;
2. 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) ;
3. Signed informed consent form (ICF).

Exclusion Criteria:

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

Primary outcomes:
measure: a favorable outcome at the end of study
timeFrame: at 21 months after randomization
Secondary outcomes:
measure: The median time to sputum culture conversion
timeFrame: at 21 months after randomization
measure: The proportion of participants with grade 3 or higher AEs, SAEs
timeFrame: at 21 months after randomization
measure: All-cause mortality and treatment relevant mortality
timeFrame: at 21 months after randomization
measure: The proportion of participants with treatment relevant SAEs
timeFrame: at 21 months post-randomization
measure: The proportion of participants with grade 3 or higher QTc prolongation
timeFrame: at 21 months after randomization
measure: The proportion of participants experiencing permanent drug discontinuation or replacement due to QTc prolongation
timeFrame: at 21 months after randomization
Other outcomes:
Locations:
city: Guiyang
country: China
facility: Guiyang Public Health Treatment Center
state: Guizhou
city: Kaili
country: China
facility: People's Hospital of Qiandongnan
state: Guizhou
city: Liupanshui
country: China
facility: The Third People's Hospital of Liupanshui
state: Guizhou
city: Zunyi
country: China
facility: Affiliated Hospital of Zunyi Medical University
state: Guizhou
city: Shanghai
country: China
facility: Huashan Hospital of Fudan University
state: Shanghai
Study officials:
affiliation: Huashan Hospital
name: Wenhong Zhang, PHD
role: PRINCIPAL_INVESTIGATOR
References: