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

Pulmonary Tuberculosis Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06058299
• Other study ID #: NC-009
• Status: Recruiting
• Phase: Phase 2
• Start date: October 24, 2023
• Est. completion date: June 2026

Study information

• Verified date: March 2024
• Source: Global Alliance for TB Drug Development
• Contact: Leandra Lombard
• Phone: +27 83 307 6784
• Email: leandra.lombard[@]tballiance.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: June 2026
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Drug Sensitive Tuberculosis
• Hypersensitivity
• Pulmonary TB
• Pulmonary Tuberculosis
• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• TBAJ-876
tablet
• Pretomanid
200 mg
• Linezolid
600 mg
• Bedaquiline
200 mg for 8 weeks followed by 100 mg for 18 weeks
• HRZE
Isoniazid (H) + rifampicin (R) + pyrazinamide (Z) plus ethambutol (E) fixed dose combination tablets dosed by weight
• HR
Isoniazid (H) + rifampicin (R) fixed dose combination tablets dosed by weight

Locations

Country	Name	City	State
Georgia	National Center for Tuberculosis and Lung Diseases	Tbilisi
Philippines	De La Salle Medical and Health Sciences Institute	Dasmariñas
Philippines	Tropical Disease Foundation	Makati City
Philippines	Lung Center of the Philippines	Quezon City
South Africa	Madibeng Centre for Research	Brits
South Africa	Desmond Tutu Health Foundation	Cape Town
South Africa	TASK Brooklyn	Cape Town
South Africa	University of Cape Town Lung Institute (UCTLI)	Cape Town
South Africa	Setshaba Research Centre	City Of Tshwane
South Africa	Enhancing Care Foundation	Durban
South Africa	Synergy Biomed Research Institute (SBRI)	East London
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
Tanzania	NIMR-MBEYA Medical Research Center	Mbeya
Tanzania	Kilimanjaro Christian Medical Centre	Moshi
Tanzania	National Institute for Medical Research (NIMR)	Mwanza
Uganda	Case Western Reserve University- Research collaboration Uganda	Kampala
Uganda	Joint Clinical Research Centre (JCRC)	Kampala

Sponsors (1)

Lead Sponsor	Collaborator
Global Alliance for TB Drug Development

Countries where clinical trial is conducted

Georgia,  Philippines,  South Africa,  Tanzania,  Uganda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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