Multidrug Resistant Tuberculosis, Rifampicin Resistant Tuberculosis, Pre-XDR-TB
Conditions
Keywords
multidrug resistant tuberculosis, shorter treatment, all-oral regimen, PZA sensitivity
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.
Interventions
COMBINATION_PRODUCTBdq(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
COMBINATION_PRODUCTA1
9Bdq(6m)+Fq+Lzd+Cs+Cfz
COMBINATION_PRODUCTA2a
9Bdq(6m)+Fq+Lzd(600mg)+Cs+Z
COMBINATION_PRODUCTA2b
9Bdq(6m)+Fq+Lzd(2m)+Cs+Z
COMBINATION_PRODUCTA2c
9Bdq(6m)+Fq+Lzd(600mg-300mg)+Cs+Z
COMBINATION_PRODUCTA3
9Bdq(6m)+Fq+Lzd+Cfz+Z
COMBINATION_PRODUCTA4
9Bdq(6m)+Fq+Cfz+Cs+Z
COMBINATION_PRODUCTA5
9Fq+Lzd+Cfz+Cs+Z
COMBINATION_PRODUCTB-SOC
6Bdq+Lzd+Cs+Cfz/14Lzd+Cfz+Cs
COMBINATION_PRODUCTB1
9Bdq(6m)+Lzd+Cs+Cfz+Z
Sponsors
Huashan Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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. |
| 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. |
Countries
China
Contacts
Primary ContactFeng Sun, Dr.
Backup ContactYang Li, Dr.
Outcome results
None listed