Phase 2 Trial Assessing TBAJ876 or Bedaquiline, With Pretomanid and Linezolid in Adults With Drug-sensitive Pulmonary Tuberculosis

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2, Partially-blinded, Randomised Trial Assessing the Safety and Efficacy of TBAJ876 or Bedaquiline, in Combination With Pretomanid and Linezolid in Adult Participants With Newly Diagnosed, Drug-sensitive, Smear-positive Pulmonary Tuberculosis

Conditions
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Pulmonary TB, Pulmonary Tuberculosis, Drug Sensitive Tuberculosis

Intervention / Treatment
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* Drug: TBAJ-876
* Drug: Pretomanid
* Drug: Linezolid
* Drug: Bedaquiline
* Drug: HRZE
* Drug: HR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants who meet all of the inclusion criteria and none of the exclusion criteria will be randomised in a 1:1:1:1:1 ratio using an interactive response technology that stratifies based on country and severity of disease (AFB 3+ and/or bilateral cavitation) to 1 of the 5 treatment arms:
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TBAJ876 25 mg<br>TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks | Drug: TBAJ-876<br>* tablet<br>Drug: Pretomanid<br>* 200 mg<br>* Other names: Dovprela;Drug: Linezolid<br>* 600 mg<br>* Other names: Zyvox;Drug: HR<br>* Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight<br>|
| Experimental: TBAJ876 50 mg<br>TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks | Drug: TBAJ-876<br>* tablet<br>Drug: Pretomanid<br>* 200 mg<br>* Other names: Dovprela;Drug: Linezolid<br>* 600 mg<br>* Other names: Zyvox;Drug: HR<br>* Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight<br>|
| Experimental: TBAJ876 100 mg<br>TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks | Drug: TBAJ-876<br>* tablet<br>Drug: Pretomanid<br>* 200 mg<br>* Other names: Dovprela;Drug: Linezolid<br>* 600 mg<br>* Other names: Zyvox;Drug: HR<br>* Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight<br>|
| Active Comparator: BPaL<br>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 | Drug: Pretomanid<br>* 200 mg<br>* Other names: Dovprela;Drug: Linezolid<br>* 600 mg<br>* Other names: Zyvox;Drug: Bedaquiline<br>* 200 mg for 8 weeks followed by 100 mg for 18 weeks<br>* Other names: TMC207;|
| Active Comparator: 2HRZE/4HR<br>Isoniazid (H) + rifampicin (R) + pyrazinamide (Z), ethambutol (E) for 8 weeks followed by HR for 18 weeks (dose based on participant's weight). | Drug: HRZE<br>* Isoniazid (H) + rifampicin (R) + pyrazinamide (Z) plus ethambutol (E) fixed dose combination tablets dosed by weight<br>Drug: HR<br>* Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to stable sputum conversion | Time to stable sputum culture conversion to negative status using data from weekly cultures through 8 weeks of treatment. | Through 8 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Favorable Outcome 26 Weeks after End of Treatment | Proportion of participants with a favourable outcome at 26 weeks after the end of treatment. | 26 weeks after end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TBAJ-876, Tuberculosis, pretomanid, bedaquiline, linezolid