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

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

Study Overview

• Status: Recruiting
• Conditions: Rifampicin Resistant Tuberculosis; Multidrug Resistant Tuberculosis; Pre-XDR-TB
• Intervention / Treatment: Combination product: Bdq(Lzd)+Lfx(Mfx)+Cfz(Cs)+Pto+E+H+Z; Combination product: A1; Combination product: A2a; Combination product: A2b; Combination product: A2c; Combination product: A3; Combination product: A4; Combination product: A5; Combination product: B-SOC; Combination product: B1

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.

• Study Type: Interventional
• Enrollment (Estimated): 1050
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yang Li, Dr.; Phone Number: (086)18817583793; Email: lalaliy@sina.com
• Study Contact Backup: Name: Feng Sun, Dr.; Phone Number: (086)15921403893; Email: feng.sun@nmcid.org.cn

Study Locations

• China
  • Guizhou
    • Guiyang, Guizhou, China
      • Recruiting
      • Guiyang Public Health Treatment Center
      • Contact: Zhongfeng Huang; Email: 1017899870@qq.com
    • Kaili, Guizhou, China
      • Recruiting
      • People's Hospital of Qiandongnan
      • Contact: Jing Wang
    • Liupanshui, Guizhou, China
      • Recruiting
      • The Third People's Hospital of Liupanshui
      • Contact: Chunlong Zhang
    • Zunyi, Guizhou, China
      • Recruiting
      • Affiliated Hospital of Zunyi Medical University
      • Contact: Jianyong Zhang
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Recruiting
      • Huashan Hospital of Fudan University
      • Contact: Yang Li
      • Contact: Wenhong Zhang, PhD, MD; Phone Number: 8123 +86 21 52889999; Email: zhangwenhong@fudan.edu.cn
      • Contact: Feng Sun
      • Contact: Yilin Zhang

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Study Population

All RR-TB patients started on an individually designed, shorter all-oral treatment regimen based on molecular drug sensitivity test and enrolled in clinical care within research sites.

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A-SOC; The control arm for fluroquinolones susceptible participants is the current standard of care oral regimen for RR-TB recommended by Chinese national guidelines. The SOC regimen comprise one or two group A drugs(bedaquiline or linezolid, moxifloxacin or levofloxacin) and one group B drug(clofazimine or cycloserine) along with other companion drugs.	Combination product: 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
Experimental: A1; The experimental A1 arm in fluroquinolones susceptible participants is a 9-month regimen consisted of bedaquiline, linezolid, fluroquinolones(moxifloxacin or levofloxacin), cycloserine, clofazimine.	Combination product: A1; 9Bdq(6m)+Fq+Lzd+Cs+Cfz
Experimental: A2a; The experimental A2a arm in fluroquinolones susceptible participants is a 9-month regimen consisted of bedaquiline, linezolid, fluroquinolones(moxifloxacin or levofloxacin), cycloserine, pyrazinamide. The dosage of linezolid is 600mg daily for 9 months.	Combination product: A2a; 9Bdq(6m)+Fq+Lzd(600mg)+Cs+Z
Experimental: A2b; The experimental A2b arm in fluroquinolones susceptible participants is a 9-month regimen consisted of bedaquiline, linezolid, fluroquinolones(moxifloxacin or levofloxacin), cycloserine, pyrazinamide. The dosage of linezolid is 600mg daily for 2 months.	Combination product: A2b; 9Bdq(6m)+Fq+Lzd(2m)+Cs+Z
Experimental: A2c; The experimental A2c arm in fluroquinolones susceptible participants is a 9-month regimen consisted of bedaquiline, linezolid, fluroquinolones(moxifloxacin or levofloxacin), cycloserine, pyrazinamide. The dosage of linezolid is 600mg daily for 2 months and then 300mg daily for 7 months.	Combination product: A2c; 9Bdq(6m)+Fq+Lzd(600mg-300mg)+Cs+Z
Experimental: A3; The experimental A3 arm in fluroquinolones susceptible participants is a 9-month regimen consisted of bedaquiline, linezolid, fluroquinolones(moxifloxacin or levofloxacin), clofazimide, pyrazinamide.	Combination product: A3; 9Bdq(6m)+Fq+Lzd+Cfz+Z
Experimental: A4; The experimental A4 arm in fluroquinolones susceptible participants is a 9-month regimen consisted of bedaquiline, fluroquinolones(moxifloxacin or levofloxacin), clofazimide, cycloserine, pyrazinamide.	Combination product: A4; 9Bdq(6m)+Fq+Cfz+Cs+Z
Experimental: A5; The experimental A4 arm in fluroquinolones susceptible participants is a 9-month regimen consisted of fluroquinolones(moxifloxacin or levofloxacin), linezolid, clofazimide, cycloserine, pyrazinamide.	Combination product: A5; 9Fq+Lzd+Cfz+Cs+Z
Active Comparator: B-SOC; In fluroquinolones resistant participants, the comparator is a locally approved standard of care long regimen which is consistent with local guidelines for treatment of RR-TB in China and WHO recommendations. The control arm contain bedaquiline, cycloserine, clofazimine, and linezolid. Treatment duration is 20 months, with a 6-month intensive phase and a 14-month continuation phase.	Combination product: B-SOC; 6Bdq+Lzd+Cs+Cfz/14Lzd+Cfz+Cs
Experimental: B1; In fluroquinolones resistant participants, the arm B1 is a 9-month treatment regimen with a combination of five drugs: bedaquiline, cycloserine, clofazimine, linezolid, pyrazinamide.	Combination product: B1; 9Bdq(6m)+Lzd+Cs+Cfz+Z

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
a favorable outcome at the end of study	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.	at 21 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The median time to sputum culture conversion	Time from treatment initiation to the first of two consecutive negative sputum culture conversion without an intervening positive culture.	at 21 months after randomization
The proportion of participants with grade 3 or higher AEs, SAEs	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.	at 21 months after randomization
All-cause mortality and treatment relevant mortality	To compare the death rate and treatment relevant death rate during treatment or follow-up in safety population.	at 21 months after randomization
The proportion of participants with treatment relevant SAEs	To compare the proportion of patients treatment relevant SAEs, during treatment or follow-up in safety population.	at 21 months post-randomization
The proportion of participants with grade 3 or higher QTc prolongation	To compare the proportion of patients treatment relevant SAEs, during treatment or follow-up in safety population.	at 21 months after randomization
The proportion of participants experiencing permanent drug discontinuation or replacement due to QTc prolongation	To compare the proportion of patients experiencing permanent drug discontinuation or replacement due to QTc prolongation, during treatment or follow-up in safety population.	at 21 months after randomization

Collaborators and Investigators

• Sponsor: Huashan Hospital
• Investigators: Principal Investigator: Wenhong Zhang, PHD, Huashan Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: October 5, 2021
• First Submitted That Met QC Criteria: October 5, 2021
• First Posted (Actual): October 18, 2021

Study Record Updates

• Last Update Posted (Actual): April 6, 2025
• Last Update Submitted That Met QC Criteria: April 1, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: shorter treatment; all-oral regimen; PZA sensitivity; multidrug resistant tuberculosis
• Additional Relevant MeSH Terms: Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Multidrug-Resistant
• Other Study ID Numbers: INSPIRE-TB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No