Phase 2 Trial Assessing TBAJ876 or Bedaquiline, With Pretomanid and Linezolid in Adults With Drug-sensitive Pulmonary Tuberculosis
- Conditions
- Pulmonary TBPulmonary TuberculosisDrug Sensitive Tuberculosis
- Interventions
- Registration Number
- NCT06058299
- Lead Sponsor
- Global Alliance for TB Drug Development
- Brief Summary
The goal of this clinical trial is to evaluate 3 dose levels of TBAJ876 for 8 weeks in combination with pretomanid and linezolid, compared to 8 weeks of Isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE), in adult participants with newly diagnosed, smear-positive, pulmonary drug sensitive tuberculosis (DS-TB).
The main questions the trial aims to answer are:
* What is the optimal dose of TBAJ876 to continue further in development.
* What is the bactericidal activity of bedaquiline with pretomanid and linezolid (B-Pa-L) compared to 2HRZE and TBAJ876-Pa-L over 8 weeks
* What is the efficacy and safety of the 26-week B-Pa-L regimen compared with the SOC (2HRZE/4HR) in participants with DS-TB.
Participants will be seen regularly during treatment (up to 26 weeks) and follow-up (52 weeks post treatment) for safety and efficacy assessments, including but not limited to:
* Safety labs, ECGs, vital signs, physical exams, PK sampling, neuropathy assessments and adverse event monitoring
* Sputum collection
- Detailed Description
Participants will be treated up to 26 weeks with either:
* TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
* TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
* TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
* Bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks
* Isoniazid (H) + rifampicin (R) + pyrazinamide (Z), ethambutol (E) for 8 weeks followed by HR for 18 weeks (dose based on participant's weight).
TBAJ876 and bedaquiline will be blinded during the first 8 weeks of trial treatment; participants randomised to the TBAJ876 or bedaquiline arms will receive open-label pretomanid and linezolid. Participants randomised to the 2HRZE/4HR arm will receive open-label HRZE.
After receiving 8 weeks of treatment, participants randomised to the TBAJ876-Pa-L treatment arms will receive open-label HR for at least 7 weeks. Treatment completion will be allowed at Week 15 in participants randomised to the TBAJ876-Pa-L arms, if the below criteria are met:
* Week 8 or EOT Make-up Period 1 sputum MGIT culture is negative, and
* The participant has no TB-related symptoms by Week 15. Participants with symptoms that have a more likely alternative explanation are eligible to complete treatment at Week 15.
If the MGIT result is MTB positive and/or there are still TB symptom(s), participants will continue to receive HR (in the 3 TBAJ876 arms) and will complete 18 weeks of treatment with HR, for a total of 26 weeks of treatment. After receiving 8 weeks of trial treatment, all participants randomised to the HRZE arm will receive open-label HR for 18 weeks, for a total of 26 weeks of treatment. After receiving 8 weeks of treatment, a participants randomised to the B-Pa-L arm will receive open-label bedaquiline 100 mg (a reduction from the 200 mg daily dose in the first 8 weeks), pretomanid 200 mg, and linezolid 600 mg daily for 18 weeks, for a total of 26 weeks of trial treatment.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 300
- Signed informed consent
- DS-TB as defined as sensitive to rifampicin and isoniazid by rapid sputum-based test AND either newly diagnosed for TB or have a history of being untreated for at least 3 years after cure from a previous episode of TB
- Of non-childbearing potential OR using effective birth control methods
- Body weight ≥ 35 kg
- Karnofsky score < 60 at screening
- Any evidence of extrapulmonary TB
- Cardiovascular or QT prolongation risk factors
- Pregnant or breast-feeding
Any of the following lab toxicities:
- Platelets <100,000/mm³
- Creatinine >1.3 x ULN
- Haemoglobin <9.5 g/dL or <95 g/L
- Absolute neutrophil count <800/mm³
- Serum potassium less than the lower limit of normal for the laboratory.
- ALT and/or AST ≥2.5 x ULN
- Total bilirubin ≥1.6 x ULN
- Direct bilirubin >1 x ULN
- Haemoglobin A1c ≥8.0%
- Total lipase ≥1.5 x ULN
- Total amylase ≥1.5 x ULN
- CPK >3 x ULN (if >3 x ULN, enquire about the participant's recent strenuous activity and consider repeating the test within the screening window)
- TSH >1 x ULN
- Positive results at screening for HBsAg, HAV IgM, or hepatitis C antibodies
For participants living with HIV only:
- CD4+ count<200 cells/μL.
- WHO Clinical Stage 4 HIV disease
- Participant does not agree to use DTG/TFV/3TC during trial if ARV therapy is indicated, and randomised to the TBAJ876 or the B-Pa-L regimen
- If initiation of ARV therapy is indicate, participants who are known to be intolerant, non-responsive to DTG/TFV/3TC or have DTG/TFV/3TC as a contraindication.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description TBAJ876 100 mg TBAJ-876 TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 25 mg TBAJ-876 TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 25 mg Pretomanid TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 25 mg Linezolid TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 25 mg HR TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 50 mg TBAJ-876 TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 50 mg Pretomanid TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 100 mg Pretomanid TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 50 mg Linezolid TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 50 mg HR TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks TBAJ876 100 mg Linezolid TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks 2HRZE/4HR HR Isoniazid (H) + rifampicin (R) + pyrazinamide (Z), ethambutol (E) for 8 weeks followed by HR for 18 weeks (dose based on participant's weight). TBAJ876 100 mg HR TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks BPaL Bedaquiline Bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks 2HRZE/4HR HRZE Isoniazid (H) + rifampicin (R) + pyrazinamide (Z), ethambutol (E) for 8 weeks followed by HR for 18 weeks (dose based on participant's weight). BPaL Linezolid Bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks BPaL Pretomanid Bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks
- Primary Outcome Measures
Name Time Method Time to stable sputum conversion Through 8 weeks of treatment Time to stable sputum culture conversion to negative status using data from weekly cultures through 8 weeks of treatment.
- Secondary Outcome Measures
Name Time Method Favorable Outcome 26 Weeks after End of Treatment 26 weeks after end of treatment Proportion of participants with a favourable outcome at 26 weeks after the end of treatment.
Trial Locations
- Locations (22)
Care Clinical Trial Group Inc.
🇵🇭Dasmariñas, Philippines
National Center for Tuberculosis and Lung Diseases
🇬🇪Tbilisi, Georgia
Tropical Disease Foundation
🇵🇭Makati City, Philippines
Lung Center of the Philippines
🇵🇭Quezon City, Philippines
Setshaba Research Centre
🇿🇦Soshanguve, Gauteng, South Africa
Madibeng Centre for Research
🇿🇦Brits, South Africa
TASK Brooklyn
🇿🇦Cape Town, South Africa
University of Cape Town Lung Institute (UCTLI)
🇿🇦Cape Town, South Africa
Desmond Tutu Health Foundation
🇿🇦Cape Town, South Africa
Enhancing Care Foundation
🇿🇦Durban, South Africa
Synergy Biomed Research Institute (SBRI)
🇿🇦East London, South Africa
TASK Eden
🇿🇦George, South Africa
TB and HIV Investigative Network (THINK)
🇿🇦Hillcrest, South Africa
WITS, Clinical HIV Research Unit (CHRU) Themba Lethu Clinic, Helen Joseph Hospital
🇿🇦Johannesburg, South Africa
Perinatal HIV Research Unit (PHRU)
🇿🇦Klerksdorp, South Africa
Isango Lethemba TB Research Unit
🇿🇦Port Elizabeth, South Africa
The Aurum Institute
🇿🇦Rustenburg, South Africa
NIMR-MBEYA Medical Research Center
🇹🇿Mbeya, Tanzania
Kilimanjaro Christian Medical Centre
🇹🇿Moshi, Tanzania
National Institute for Medical Research (NIMR)
🇹🇿Mwanza, Tanzania
Case Western Reserve University- Research collaboration Uganda
🇺🇬Kampala, Uganda
Joint Clinical Research Centre (JCRC)
🇺🇬Kampala, Uganda