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

Fudan University

Status and phase: Enrolling; Phase 3

Conditions: Multidrug Resistant Tuberculosis; Pre-XDR-TB; Rifampicin Resistant Tuberculosis

Treatments: Combination Product: A2c; Combination Product: A1; Combination Product: Bdq(Lzd)+Lfx(Mfx)+Cfz(Cs)+Pto+E+H+Z; Combination Product: A2a; Combination Product: B1; Combination Product: B-SOC; Combination Product: A3; Combination Product: A2b; Combination Product: A4; Combination Product: A5

Study type: Interventional

Funder types: Other

Identifiers

NCT05081401

INSPIRE-TB

Details and patient eligibility

About

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

Full 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.

Enrollment: 1,050 estimated patients

Sex: All

Ages: 16 to 75 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,050 participants in 10 patient groups

A-SOC

Active Comparator group

Description:

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.

Treatment:

Combination Product: Bdq(Lzd)+Lfx(Mfx)+Cfz(Cs)+Pto+E+H+Z

A1

Experimental group

Description:

The experimental A1 arm in fluroquinolones susceptible participants is a 9-month regimen consisted of bedaquiline, linezolid, fluroquinolones(moxifloxacin or levofloxacin), cycloserine, clofazimine.

Treatment:

Combination Product: A1

A2a

Experimental group

Description:

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.

Treatment:

Combination Product: A2a

A2b

Experimental group

Description:

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.

Treatment:

Combination Product: A2b

A2c

Experimental group

Description:

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.

Treatment:

Combination Product: A2c

A3

Experimental group

Description:

The experimental A3 arm in fluroquinolones susceptible participants is a 9-month regimen consisted of bedaquiline, linezolid, fluroquinolones(moxifloxacin or levofloxacin), clofazimide, pyrazinamide.

Treatment:

Combination Product: A3

A4

Experimental group

Description:

The experimental A4 arm in fluroquinolones susceptible participants is a 9-month regimen consisted of bedaquiline, fluroquinolones(moxifloxacin or levofloxacin), clofazimide, cycloserine, pyrazinamide.

Treatment:

Combination Product: A4

A5

Experimental group

Description:

The experimental A4 arm in fluroquinolones susceptible participants is a 9-month regimen consisted of fluroquinolones(moxifloxacin or levofloxacin), linezolid, clofazimide, cycloserine, pyrazinamide.

Treatment:

Combination Product: A5

B-SOC

Active Comparator group

Description:

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.

Treatment:

Combination Product: B-SOC

B1

Experimental group

Description:

In fluroquinolones resistant participants, the arm B1 is a 9-month treatment regimen with a combination of five drugs: bedaquiline, cycloserine, clofazimine, linezolid, pyrazinamide.

Treatment:

Combination Product: B1