Clinical trial NCT06058299: Phase 2 Trial Assessing TBAJ876 or Bedaquiline, with Pretomanid and Linezolid in Adults with Drug-sensitive Pulmonary Tuberculosis
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Pulmonary TB
Pulmonary Tuberculosis
Drug Sensitive Tuberculosis
Keywords: TBAJ-876
Tuberculosis
pretomanid
bedaquiline
linezolid
Lead sponsor: Global Alliance for TB Drug Development
Sponsor class: OTHER
First posted: 2023-09-28
Enrollment: 309
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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:
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time to stable sputum conversion
timeFrame: Through 8 weeks of treatment
Secondary outcomes:
measure: Favorable Outcome 26 Weeks after End of Treatment
timeFrame: 26 weeks after end of treatment
Other outcomes:
Locations:
city: Tbilisi
country: Georgia
facility: National Center for Tuberculosis and Lung Diseases
city: Dasmariñas
country: Philippines
facility: Care Clinical Trial Group Inc.
city: Makati City
country: Philippines
facility: Tropical Disease Foundation
city: Quezon City
country: Philippines
facility: Lung Center of the Philippines
city: Soshanguve
country: South Africa
facility: Setshaba Research Centre
state: Gauteng
city: Brits
country: South Africa
facility: Madibeng Centre for Research
city: Cape Town
country: South Africa
facility: TASK Brooklyn
city: Cape Town
country: South Africa
facility: University of Cape Town Lung Institute (UCTLI)
city: Cape Town
country: South Africa
facility: Desmond Tutu Health Foundation
city: Durban
country: South Africa
facility: Enhancing Care Foundation
city: East London
country: South Africa
facility: Synergy Biomed Research Institute (SBRI)
city: George
country: South Africa
facility: TASK Eden
city: Hillcrest
country: South Africa
facility: TB and HIV Investigative Network (THINK)
city: Johannesburg
country: South Africa
facility: WITS, Clinical HIV Research Unit (CHRU) Themba Lethu Clinic, Helen Joseph Hospital
city: Klerksdorp
country: South Africa
facility: Perinatal HIV Research Unit (PHRU)
city: Port Elizabeth
country: South Africa
facility: Isango Lethemba TB Research Unit
city: Rustenburg
country: South Africa
facility: The Aurum Institute
city: Mbeya
country: Tanzania
facility: NIMR-MBEYA Medical Research Center
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical Centre
city: Mwanza
country: Tanzania
facility: National Institute for Medical Research (NIMR)
city: Kampala
country: Uganda
facility: Case Western Reserve University- Research collaboration Uganda
city: Kampala
country: Uganda
facility: Joint Clinical Research Centre (JCRC)
Study officials:
affiliation: TB Alliance
name: Morounfolu Olugbosi, MD
role: STUDY_DIRECTOR
References: