Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis

NCT06192160 | Recruiting Phase 2 FDA Drug

• 2 other identifiers: A5409DOH-27-032024-5399
• Study Type: interventional
• Target: 315
• Locations: 14 countries
• Sites: 29

Brief Summary

A5409/RAD-TB is an adaptive Phase 2 randomized, controlled, open-label, dose-ranging, platform protocol to evaluate the safety and efficacy of multidrug regimens for the treatment of adults with drug-susceptible pulmonary tuberculosis (TB). A5409 hypothesizes that novel regimens for the treatment of pulmonary tuberculosis will result in superior early efficacy, as determined by longitudinal mycobacteria growth indicator tube (MGIT) liquid culture time to positivity (TTP) measurements over the first 6 weeks of treatment, and will have acceptable safety and tolerability over 8 weeks of treatment relative to standard of care \[(SOC) isoniazid/rifampicin/pyrazinamide/ethambutol (HRZE)\]. The study will run for 52 weeks, inclusive of 26 weeks of TB treatment comprised of 8 weeks of study treatment (experimental or SOC, based on treatment arm assignment) followed by 18 weeks of SOC continuation phase treatment with 45 participants in each experimental treatment arm and at least 90 participants in the SOC arm.

Conditions

Pulmonary Tuberculosis

Outcome Measures

Primary Outcomes (2)

• Difference in mean log10 (Time to positivity (TTP)) slope from longitudinal mycobacteria growth indicator tube (MGIT) liquid culture measurements over the first 6 weeks of treatment

  for each experimental treatment arm compared to the SOC treatment arm.

  Weeks 0, 1, 2, 3, 4 and 6

• Difference in the cumulative proportion of participants having at least one new Grade 3 or higher adverse event (AE) by week 8 of treatment

  for each experimental treatment arm compared to the SOC treatment arm.

  8 weeks

Secondary Outcomes (8)

• Cumulative proportion of participants with stable sputum culture conversion by week 8 as measured by culture-negative status via MGIT liquid culture at two consecutive measurements.

  8 weeks

• Mean log10 TTP slope from longitudinal MGIT liquid culture measurements over the first 8 weeks of treatment.

  Weeks 0, 1, 2, 3, 4, 6 and 8

• Cumulative proportion of participants with a new Grade 3 or higher AE by week 26 of treatment.

  26 weeks

• Cumulative proportion of participants with permanent discontinuation of study-provided anti-TB drugs due to any reason prior to Week 8 of treatment.

  8 weeks

• Cumulative proportion of participants with permanent discontinuation or temporary discontinuation for ≥3 days of at least one anti-TB drug due to any reason prior to week 8 of treatment.

  8 weeks

Study Arms (6)

Arm 1: Standard of Care (SOC)

ACTIVE COMPARATOR

* Weeks 1-8: INH 300 mg, RIF 600 mg, PZA weight-based, EMB weight-based * Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)

Drug: Isoniazid; Drug: Rifampicin; Drug: Pyrazinamide; Drug: Ethambutol

Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD)

EXPERIMENTAL

* Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, LZD 600 mg * Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)

Drug: Isoniazid; Drug: Rifampicin; Drug: Bedaquiline; Drug: Pretomanid; Drug: Linezolid

Arm 3A: BDQ, Pa and TBI-223 (1200 mg)

EXPERIMENTAL

* Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 1200 mg * Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)

Drug: Isoniazid; Drug: Rifampicin; Drug: Bedaquiline; Drug: Pretomanid; Drug: TBI-223

Arm 3B: BDQ, Pa and TBI-223 (2400 mg)

EXPERIMENTAL

* Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, TBI-223 2400 mg * Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)

Drug: Isoniazid; Drug: Rifampicin; Drug: Bedaquiline; Drug: Pretomanid; Drug: TBI-223

Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg)

EXPERIMENTAL

* Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 800 mg * Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)

Drug: Isoniazid; Drug: Rifampicin; Drug: Bedaquiline; Drug: Pretomanid; Drug: Sutezolid

Arm 4B: BDQ, Pa and SZD (1600 mg)

EXPERIMENTAL

* Weeks 1-8: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks, Pa 200 mg, SZD 1600 mg * Weeks 9-26: INH 300 mg, RIF 600 mg (or weight-based dosing following WHO guidance)

Drug: Isoniazid; Drug: Rifampicin; Drug: Bedaquiline; Drug: Pretomanid; Drug: Sutezolid

Interventions

Isoniazid DRUG

INH 300 mg will be administered as one tablet orally once daily.

Also known as: INH

Arm 1: Standard of Care (SOC); Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD); Arm 3A: BDQ, Pa and TBI-223 (1200 mg); Arm 3B: BDQ, Pa and TBI-223 (2400 mg); Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg); Arm 4B: BDQ, Pa and SZD (1600 mg)

Rifampicin DRUG

RIF 600 mg will be administered as two 300 mg capsules orally once daily on an empty stomach, 1 hour before or 2 hours after eating a meal.

Also known as: RIF

Arm 1: Standard of Care (SOC); Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD); Arm 3A: BDQ, Pa and TBI-223 (1200 mg); Arm 3B: BDQ, Pa and TBI-223 (2400 mg); Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg); Arm 4B: BDQ, Pa and SZD (1600 mg)

Pyrazinamide DRUG

PZA will be administered as 500 mg tablets, based on weight, orally once daily.

Also known as: PZA

Arm 1: Standard of Care (SOC)

Ethambutol DRUG

EMB will be administered as 400 mg tablets, based on weight, orally once daily.

Also known as: EMB

Arm 1: Standard of Care (SOC)

Bedaquiline DRUG

BDQ 400 mg will be administered as four 100 mg tablets orally once daily with a meal for the first 2 weeks followed by 200 mg (two 100 mg tablets) orally once daily with a meal for 6 weeks.

Also known as: BDQ

Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD); Arm 3A: BDQ, Pa and TBI-223 (1200 mg); Arm 3B: BDQ, Pa and TBI-223 (2400 mg); Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg); Arm 4B: BDQ, Pa and SZD (1600 mg)

Pretomanid DRUG

Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.

Also known as: Pa

Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD); Arm 3A: BDQ, Pa and TBI-223 (1200 mg); Arm 3B: BDQ, Pa and TBI-223 (2400 mg); Arm 4A: BDQ, Pa and Sutezolid (SZD) (800 mg); Arm 4B: BDQ, Pa and SZD (1600 mg)

Linezolid DRUG

LZD 600 mg will be administered as one 600 mg tablet orally once daily.

Also known as: LZD

Arm 2: Bedaquiline (BDQ), Pretomanid (Pa), and Linezolid (LZD)

TBI-223 DRUG

TBI-223 2400 mg once daily will be administered as four 600 mg tablets orally once daily with a meal.

Arm 3B: BDQ, Pa and TBI-223 (2400 mg)

Sutezolid DRUG

SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.

Also known as: SZD

Arm 4B: BDQ, Pa and SZD (1600 mg)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Pulmonary TB (among individuals either without history of prior TB treatment or with history of TB treatment completed more than 2 years prior to study entry), identified within 7 days prior to study entry by at least one sputum specimen positive for Mtb by Xpert. Semiquantitative Mtb results of "medium" or "high" from Xpert MTB/RIF Ultra are required.
• Pulmonary TB with documented INH susceptibility (by Line Probe Assay (LPA) or Xpert MTB/XDR or other validated molecular test) and with documented RIF susceptibility (by LPA or Xpert MTB/RIF or Xpert MTB/RIF Ultra or other validated molecular test) within 7 days prior to study entry.
• Documentation of HIV-1 infection status, as below:
• Presence or absence of HIV-1 infection, as documented by:
• Any licensed rapid HIV test or HIV-1 enzyme or chemiluminescence immunoassay (E/CIA) test kit, any time prior to study entry. AND for a positive result confirmation by one of the following:
• A second antibody test from different manufacturers or based on different principles and epitopes (combination antigen-antibody-based rapid tests may be used), or
• HIV-1 antigen, or
• Plasma HIV-1 RNA viral load, or
• A licensed Western blot
• For individuals with HIV: CD4+ cell count ≥100 cells/mm3 based on testing performed within 30 days prior to study entry.
• For individuals with HIV: Currently being treated with dolutegravir-based antiretroviral therapy (ART), or plan to initiate dolutegravir-based ART at or before study week 8.
• Individuals age ≥18 years.
• The following laboratory values obtained within 7 days prior to study entry at any network-approved non-U.S. laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs:
• Serum or plasma alanine aminotransferase (ALT) ≤3 times the upper limit of normal (ULN)
• Serum or plasma total bilirubin ≤2 times ULN

You may not qualify if:

• More than cumulative 7 days of treatment directed against active TB for the current TB episode in the 60 days preceding study entry.
• Current extrapulmonary TB, in the opinion of the investigator.
• QTcF interval \>450 ms within 7 days prior to study entry.
• History of or ongoing heart failure.
• Personal or family history of congenital QT prolongation.
• History of known, untreated, ongoing hypothyroidism.
• History of or ongoing bradyarrhythmia.
• History of torsades de pointes.
• Current Grade 2 or higher peripheral neuropathy.
• Other medical conditions (e.g., diabetes, liver or kidney disease, blood disorders, chronic diarrhea), in the opinion of the site investigator, in which the current clinical condition of the participant is likely to prejudice the response to, or assessment of, treatment.
• Pregnant or breastfeeding or planning to become pregnant within the next 12 months.
• Weight \<35 kg.
• Unable to take oral medications.
• Taking any of prohibited medications.
• Known allergy/sensitivity or any hypersensitivity to components of investigational agents or their formulation.

Sponsors & Collaborators

• TB Alliance: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (29)

12701, Gaborone CRS

Gaborone, 0000, Botswana

RECRUITING

12201, Instituto de Pesquisas em AIDS do Rio Grande do Sul - IPARGS CRS

Porto Alegre, 91350, Brazil

RECRUITING

12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS

Rio de Janeiro, 21040, Brazil

RECRUITING

30022, Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS

Port-au-Prince, 6110, Haiti

NOT YET RECRUITING

31730, GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS

Port-au-Prince, 6110, Haiti

NOT YET RECRUITING

31441, Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, 411001, India

NOT YET RECRUITING

12601, Moi University Clinical Research Center (MUCRC) CRS

Eldoret, 30100, Kenya

RECRUITING

12501, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS

Kericho, 20200, Kenya

RECRUITING

30301, Blantyre CRS

Blantyre, 265, Malawi

NOT YET RECRUITING

12001, Malawi CRS

Lilongwe, A-104, Malawi

NOT YET RECRUITING

32078, Nutrición-Mexico CRS

Mexico City, 14080, Mexico

NOT YET RECRUITING

11301, Barranco CRS

Lima, 1010, Peru

NOT YET RECRUITING

31985, Socios En Salud Sucursal Perú CRS

Lima, 15046, Peru

NOT YET RECRUITING

11302, San Miguel CRS San Miguel

Lima, Peru

NOT YET RECRUITING

31981, TB HIV Innovations and Clinical Research Foundation Corp.

Cavite, 4114, Philippines

NOT YET RECRUITING

31793, South African Tuberculosis Vaccine Initiative (SATVI) CRS

Cape Town, 6850, South Africa

RECRUITING

31792, University of Cape Town Lung Institute (UCTLI) CRS

Cape Town, 7700, South Africa

RECRUITING

31422, CAPRISA eThekwini CRS

Durban, 40001, South Africa

RECRUITING

11201, Durban International CRS

Durban, 4091, South Africa

RECRUITING

12301, Soweto ACTG CRS

Johannesburg, 1864, South Africa

RECRUITING

11101, University of the Witwatersrand Helen Joseph (WITS HJH) CRS

Johannesburg, 2193, South Africa

NOT YET RECRUITING

31684, Rustenburg CRS

Rustenburg, South Africa

RECRUITING

31784, Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS

Chiang Mai, 50200, Thailand

RECRUITING

5116 Chiangrai Prachanukroh Hospital NICHD CRS

Chiang Rai, 57000, Thailand

RECRUITING

31802, Thai Red Cross AIDS Research Centre (TRC-ARC) CRS

Pathum Wan, 10330, Thailand

RECRUITING

12401, Joint Clinical Research Centre (JCRC)/Kampala CRS

Kampala, 10005, Uganda

RECRUITING

30293 MU-JHU Research Collaboration (MUJHU CARE LTD) CRS

Kampala, 23491, Uganda

NOT YET RECRUITING

32483 National Lung Hospital CRS

Hanoi, 100000, Vietnam

RECRUITING

30313, Milton Park CRS

Harare, 30313, Zimbabwe

NOT YET RECRUITING

Related Publications (2)

• Harrison LJ, Velasquez GE, Kempker RR, Imperial MZ, Nuermberger E, Dorman SE, Ignatius E, Granche J, Phillips PPJ, Furin J, Yang E, Foley C, Chiambah S, Rogers R, Van Grack A, Roa J, Shenje J, Nerette S, Kanyama C, Kyeyune RB, Mendoza-Ticona A, Murtaugh W, Foraida S, Goth M, Vernon A, Dooley KE, Savic RM. ACTG A5409 (RAD-TB): Study protocol for a phase 2 randomized, adaptive, dose-ranging, open-label trial of novel regimens for the treatment of pulmonary tuberculosis. Trials. 2025 Aug 15;26(1):291. doi: 10.1186/s13063-025-08973-w.

  PMID: 40817073 DERIVED

• Harrison L, Velasquez GE, Kempker RR, Imperial MZ, Nuermberger E, Dorman SE, Ignatius E, Granche J, Phillips PP, Furin J, Yang E, Foley C, Chiambah S, Rogers R, Van Grack A, Roa J, Shenje J, Nerette S, Kanyama C, Kyeyune RB, Mendoza-Ticona A, Murtaugh W, Foraida S, Goth M, Vernon A, Dooley KE, Savic RM. ACTG A5409 (RAD-TB): Study Protocol for a Phase 2 Randomized, Adaptive, Dose-Ranging, Open-Label Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis. Res Sq [Preprint]. 2025 Mar 26:rs.3.rs-5931694. doi: 10.21203/rs.3.rs-5931694/v1.

  PMID: 40195983 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Isoniazid; Rifampin; Pyrazinamide; Ethambutol; bedaquiline; pretomanid; Linezolid; PNU-100480

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines; Acetamides; Amides; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles

Study Officials

• Radojka Savic, PharmD, PhD

  University of California

  STUDY CHAIR

• Kelly Dooley, MD, PhD

  Vanderbilt University Medical Center

  STUDY CHAIR

• Gustavo Velásquez, MD, MPH

  University of California

  STUDY CHAIR

Central Study Contacts

Radojka Savic, PharmD, PhD

CONTACT

415-502-0640; rada.savic@ucsf.edu

Kelly Dooley, MD, PhD

CONTACT

615-322-8972; kelly.e.dooley@vumc.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2023
• First Posted: January 5, 2024
• Study Start: March 11, 2025
• Primary Completion (Estimated): November 11, 2026
• Study Completion (Estimated): August 11, 2027
• Last Updated: May 19, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
• Access Criteria: * With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group. * For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group. * By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/submit-a-proposal/. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

Locations

BO (1); BR (2); PH (1); ZA (7); UG (2); ME (1); TH (3); MA (2); IN (1); ZI (1); HA (2); PE (3); VN (1); KE (2)