Phase 2 Trial Assessing TBAJ876 or Bedaquiline, With Pretomanid and Linezolid in Adults With Drug-sensitive Pulmonary Tuberculosis
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| ClinicalTrials.gov Identifier: NCT06058299 |
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Recruitment Status :
Recruiting
First Posted : September 28, 2023
Last Update Posted : March 7, 2024
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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
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Pulmonary TB Pulmonary Tuberculosis Drug Sensitive Tuberculosis | Drug: TBAJ-876 Drug: Pretomanid Drug: Linezolid Drug: Bedaquiline Drug: HRZE Drug: HR | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 300 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Masking Description: | TBAJ-876 and the first 8 weeks of bedaquiline will be blinded. Participants randomized to TBAJ-876 or bedaquiline arms will received active TBAJ-876 (and placebo TBAJ876 to blind the dose) and placebo bedaquiline or placebo TBAJ-876 and active bedaquiline |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 2, Partially-blinded, Randomised Trial Assessing the Safety and Efficacy of TBAJ-876 or Bedaquiline, in Combination With Pretomanid and Linezolid in Adult Participants With Newly Diagnosed, Drug-sensitive, Smear-positive Pulmonary Tuberculosis |
| Actual Study Start Date : | October 24, 2023 |
| Estimated Primary Completion Date : | February 2025 |
| Estimated Study Completion Date : | June 2026 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: TBAJ876 25 mg
TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
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Drug: TBAJ-876
tablet Drug: Pretomanid 200 mg
Other Names:
Drug: Linezolid 600 mg
Other Name: Zyvox Drug: HR Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight |
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Experimental: TBAJ876 50 mg
TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
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Drug: TBAJ-876
tablet Drug: Pretomanid 200 mg
Other Names:
Drug: Linezolid 600 mg
Other Name: Zyvox Drug: HR Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight |
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Experimental: TBAJ876 100 mg
TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
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Drug: TBAJ-876
tablet Drug: Pretomanid 200 mg
Other Names:
Drug: Linezolid 600 mg
Other Name: Zyvox Drug: HR Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight |
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Active Comparator: BPaL
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
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Drug: Pretomanid
200 mg
Other Names:
Drug: Linezolid 600 mg
Other Name: Zyvox Drug: Bedaquiline 200 mg for 8 weeks followed by 100 mg for 18 weeks
Other Names:
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Active Comparator: 2HRZE/4HR
Isoniazid (H) + rifampicin (R) + pyrazinamide (Z), ethambutol (E) for 8 weeks followed by HR for 18 weeks (dose based on participant's weight).
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Drug: HRZE
Isoniazid (H) + rifampicin (R) + pyrazinamide (Z) plus ethambutol (E) fixed dose combination tablets dosed by weight Drug: HR Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight |
- Time to stable sputum conversion [ Time Frame: Through 8 weeks of treatment ]Time to stable sputum culture conversion to negative status using data from weekly cultures through 8 weeks of treatment.
- Favorable Outcome 26 Weeks after End of Treatment [ Time Frame: 26 weeks after end of treatment ]Proportion of participants with a favourable outcome at 26 weeks after the end of treatment.
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| Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06058299
| Contact: Leandra Lombard | +27 83 307 6784 | leandra.lombard@tballiance.org | |
| Contact: Morounfolu Olugbosi, MD | +27 79 045 4917 | morounfolu.olugbosi@tballiance.org |
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| Study Director: | Morounfolu Olugbosi, MD | TB Alliance |
| Responsible Party: | Global Alliance for TB Drug Development |
| ClinicalTrials.gov Identifier: | NCT06058299 |
| Other Study ID Numbers: |
NC-009 |
| First Posted: | September 28, 2023 Key Record Dates |
| Last Update Posted: | March 7, 2024 |
| Last Verified: | March 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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TBAJ-876 Tuberculosis pretomanid bedaquiline linezolid |
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Tuberculosis Tuberculosis, Pulmonary Hypersensitivity Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Immune System Diseases Respiratory Tract Infections |
Lung Diseases Respiratory Tract Diseases Linezolid Bedaquiline Anti-Bacterial Agents Anti-Infective Agents Protein Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antitubercular Agents |