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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Drug Sensitive Tuberculosis; Pulmonary Tuberculosis; Pulmonary TB
• Intervention / Treatment: Drug: Linezolid; Drug: TBAJ-876; Drug: Pretomanid; Drug: HR; Drug: Bedaquiline; Drug: HRZE

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.

• Study Type: Interventional
• Enrollment (Actual): 309
• Phase: Phase 2

Contacts and Locations

Study Locations

• Georgia
  • Tbilisi, Georgia, 0101
    • National Center for Tuberculosis and Lung Diseases
• Philippines
  • Dasmariñas, Philippines, 4114
    • CARE Clinical Trial Group Inc.
  • Makati City, Philippines, 1230
    • Tropical Disease Foundation
  • Quezon City, Philippines, 1104
    • Lung Center Of The Philippines
• South Africa
  • Brits, South Africa, 0250
    • Madibeng Centre for Research
  • Cape Town, South Africa, 7700
    • University of Cape Town Lung Institute (UCTLI)
  • Cape Town, South Africa, 7405
    • TASK Brooklyn
  • Cape Town, South Africa, 7750
    • Desmond Tutu Health Foundation
  • Durban, South Africa, 4052
    • Enhancing Care Foundation
  • East London, South Africa, 5201
    • Synergy Biomed Research Institute (SBRI)
  • George, South Africa, 6529
    • TASK Eden
  • Hillcrest, South Africa, 3610
    • TB and HIV Investigative Network (THINK)
  • Johannesburg, South Africa, 2092
    • WITS, Clinical HIV Research Unit (CHRU) Themba Lethu Clinic, Helen Joseph Hospital
  • Klerksdorp, South Africa, 2571
    • Perinatal HIV Research Unit (PHRU)
  • Port Elizabeth, South Africa, 6200
    • Isango Lethemba TB Research Unit
  • Rustenburg, South Africa, 2999
    • The Aurum Institute
  • Gauteng
    • Soshanguve, Gauteng, South Africa, 0152
      • Setshaba Research Centre
• Tanzania
  • Mbeya, Tanzania
    • NIMR-Mbeya Medical Research Center
  • Moshi, Tanzania
    • Kilimanjaro Christian Medical Centre
  • Mwanza, Tanzania
    • National Institute for Medical Research (NIMR)
• Uganda
  • Kampala, Uganda
    • Joint Clinical Research Centre (JCRC)
  • Kampala, Uganda
    • Case Western Reserve University- Research collaboration Uganda

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TBAJ876 25 mg; TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks	Drug: Linezolid; 600 mg; Other Names: Zyvox; Drug: TBAJ-876; tablet; Drug: Pretomanid; 200 mg; Other Names: PA-824; Dovprela; Drug: HR; Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight
Experimental: TBAJ876 50 mg; TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks	Drug: Linezolid; 600 mg; Other Names: Zyvox; Drug: TBAJ-876; tablet; Drug: Pretomanid; 200 mg; Other Names: PA-824; Dovprela; Drug: HR; Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight
Experimental: TBAJ876 100 mg; TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks	Drug: Linezolid; 600 mg; Other Names: Zyvox; Drug: TBAJ-876; tablet; Drug: Pretomanid; 200 mg; Other Names: PA-824; Dovprela; Drug: HR; Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight
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	Drug: Linezolid; 600 mg; Other Names: Zyvox; Drug: Pretomanid; 200 mg; Other Names: PA-824; Dovprela; Drug: Bedaquiline; 200 mg for 8 weeks followed by 100 mg for 18 weeks; Other Names: Sirturo; TMC207
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).	Drug: HR; Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight; Drug: HRZE; Isoniazid (H) + rifampicin (R) + pyrazinamide (Z) plus ethambutol (E) fixed dose combination tablets dosed by weight

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Global Alliance for TB Drug Development
• Investigators: Study Director: Morounfolu Olugbosi, MD, TB Alliance

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2023
• Primary Completion (Actual): December 27, 2024
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: September 22, 2023
• First Submitted That Met QC Criteria: September 22, 2023
• First Posted (Actual): September 28, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 13, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: TBAJ-876; Tuberculosis; pretomanid; linezolid; bedaquiline
• Additional Relevant MeSH Terms: Immune System Diseases; Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Hypersensitivity; Tuberculosis; Tuberculosis, Pulmonary; Anti-Bacterial Agents; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Synthesis Inhibitors; Antitubercular Agents; Linezolid; Bedaquiline
• Other Study ID Numbers: NC-009

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

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