Platform Assessing Regimens and Durations In a Global Multisite Consortium for TB

NCT06114628 | Recruiting Phase 2 DMC

• 1 other identifier: UNITE4TB-01
• Study Type: interventional
• Target: 2,500
• Locations: 5 countries
• Sites: 11

Brief Summary

The UNITE4TB consortium is a group of universities and pharmaceutical companies funded by the European Union. This consortium are carrying out a trial to find better and faster ways to treat tuberculosis (TB). The standard treatment for TB takes 24 weeks and uses four drugs. The consortium want to find new treatments that are faster but just as safe and effective. In the trial, two new drugs will be used, BTZ-043 and GSK3036656, along with the drugs that are already used to treat TB in a variety of combinations (11 different combinations initially). These new drugs have worked well in tests with animals and have reduced the amount of TB bacteria in people's sputum/phlegm when used alone for two weeks. These new drugs will be used in combination with other TB drugs for a longer time (up to 16 weeks) in people with TB. The UNITE4TB consortium want to see if they work well and are safe. This trial will take place at sites across the world and will involve people with TB of the lungs that would usually respond well to the standard treatment. But the new treatments being tested might also work for people with drug resistant TB, that's harder to treat. The trial has two parts. In the first part, different combinations of drugs will be tried on up to 700 people for 16 weeks. These combinations will be compared to the standard 24-week treatment to see which ones work the best and are safe. In the second part, the best combinations from the first part will be taken to try to find out what the best length of time is to give the treatment for. These combinations will be tried on up to 1800 people giving them either 8, 10, 12, 14 or 16 weeks treatment. The investigators will follow these people for a total of 72 weeks to make sure the treatment is working. The UNITE4TB consortium hope that this trial will find new treatments that are fast, safe, and effective for both regular TB and resistant TB. If it works, it can then be tested again in a bigger trial to be sure.

Conditions

Pulmonary Tuberculosis

Outcome Measures

Primary Outcomes (2)

• Rate of change in log10(Time to Positivity of MGIT culture) (Phase 2B)

  Primary Efficacy Outcome in Phase 2B, rate of change in log10(Time to positivity)

  Over 0-12 weeks

• Favourable/Unfavourable outcome (Phase 2C)

  Primary Efficacy Outcome in Phase 2C, the proportion of participants with a favourable outcome status

  at 48 weeks from randomisation

Secondary Outcomes (21)

• Grade 3/4/5 adverse events (Phase 2B)

  Up to 26 weeks from randomisation

• Grade 3/4/5 adverse events (Phase 2C)

  Up to 26 weeks from randomisation

• Serious adverse events (Phase 2B)

  Up to 26 weeks from randomisation

• Serious adverse events (Phase 2C)

  Up to 26 weeks from randomisation

• Adverse events of special interest (Phase 2B)

  Up to 26 weeks from randomisation

Study Arms (17)

A. Standard TB Regimen. 2HRZE/4HR

ACTIVE COMPARATOR

24 weeks treatment in both Phase 2B and 2C - 8 weeks Rifampicin, Isoniazid, Pyrazinamide, Ethambutol followed by 16 weeks Rifampicin and Isoniazid.

Drug: Pyrazinamide (Z); Drug: Rifampicin (R); Drug: Isoniazid (H); Drug: Ethambutol (E)

Arm B. BDM

EXPERIMENTAL

Bedaquiline, Delamanid, Moxifloxacin for 16 weeks in Phase 2B

Drug: Bedaquiline (B); Drug: Delamanid (D); Drug: Moxifloxacin (M)

Arm C. BDM + Gan

EXPERIMENTAL

Bedaquiline, Delamanid, Moxifloxacin and Ganfeborole for 16 weeks in Phase 2B Bedaquiline, Delamanid, Moxifloxacin and Ganfeborole for 8-16 weeks in phase 2C

Drug: Ganfeborole; Drug: Bedaquiline (B); Drug: Delamanid (D); Drug: Moxifloxacin (M)

Arm D. BDZ + Gan

EXPERIMENTAL

Bedaquiline, Delamanid, Pyrazinamide and Ganfeborole for 16 weeks in Phase 2B Bedaquiline, Delamanid, Pyrazinamide and Ganfeborole for 8-16 weeks in phase 2C

Drug: Ganfeborole; Drug: Bedaquiline (B); Drug: Delamanid (D); Drug: Pyrazinamide (Z)

Arm E. BDL + 656

EXPERIMENTAL

Bedaquiline, Delamanid, Linezolid and Ganfeborole for 8 weeks followed by 8 weeks Bedaquiline, Delamanid and Ganfeborole in Phase 2B Bedaquiline, Delamanid, Linezolid and Ganfeborole for 8 weeks followed by 0-8 weeks Bedaquiline, Delamanid and Ganfeborole in Phase 2C

Drug: Ganfeborole; Drug: Bedaquiline (B); Drug: Delamanid (D); Drug: Linezolid (L)

Arm F. BPaM + Gan

EXPERIMENTAL

Bedaquiline, Pretomanid, Moxifloxacin and Ganfeborole for 16 weeks in Phase 2B Bedaquiline, Pretomanid, Moxifloxacin and Ganfeborolefor 8-16 weeks in Phase 2C

Drug: Ganfeborole; Drug: Bedaquiline (B); Drug: Pretomanid (Pa); Drug: Moxifloxacin (M)

Arm G. BDM + BTZ-043

EXPERIMENTAL

Bedaquiline, Delamanid, Moxifloxacin and BTZ-043 for 16 weeks in Phase 2B Bedaquiline, Delamanid, Moxifloxacin and BTZ-043 for 8-16 weeks in phase 2C

Drug: BTZ-043; Drug: Bedaquiline (B); Drug: Delamanid (D); Drug: Moxifloxacin (M)

Arm H. BDZ + BTZ-043

EXPERIMENTAL

Bedaquiline, Delamanid, Pyrazinamide and BTZ-043 for 16 weeks in Phase 2B Bedaquiline, Delamanid, Pyrazinamide and BTZ-043 for 8-16 weeks in phase 2C

Drug: BTZ-043; Drug: Bedaquiline (B); Drug: Delamanid (D); Drug: Pyrazinamide (Z)

Arm I. BDL + BTZ-043

EXPERIMENTAL

Bedaquiline, Delamanid, Linezolid and BTZ-043 for 8 weeks followed by 8 weeks Bedaquiline, Delamanid and BTZ-043 in Phase 2B Bedaquiline, Delamanid, Linezolid and BTZ-043 for 8 weeks followed by 0-8 weeks Bedaquiline, Delamanid and BTZ-043 in Phase 2C

Drug: BTZ-043; Drug: Bedaquiline (B); Drug: Delamanid (D); Drug: Linezolid (L)

Arm J. BPaM + BTZ-043

EXPERIMENTAL

Bedaquiline, Pretomanid, Moxifloxacin and BTZ-043 for 16 weeks in Phase 2B Bedaquiline, Pretomanid, Moxifloxacin and BTZ-043 for 8-16 weeks in Phase 2C

Drug: BTZ-043; Drug: Bedaquiline (B); Drug: Pretomanid (Pa); Drug: Moxifloxacin (M)

Arm K. BMZ + BTZ-043

EXPERIMENTAL

Bedaquiline, Moxifloxacin, Pyrazinamide and BTZ-043 for 16 weeks in Phase 2B Bedaquiline, Moxifloxacin, Pyrazinamide and BTZ-043 for 8-16 weeks in phase 2C

Drug: BTZ-043; Drug: Bedaquiline (B); Drug: Moxifloxacin (M); Drug: Pyrazinamide (Z)

Arm L. BD + Gan + BTZ-043

EXPERIMENTAL

Bedaquiline, Delamanid, Ganfeborole and BTZ-043 for 16 weeks in Phase 2B Bedaquiline, Delamanid, Ganfeborole and BTZ-043 for 8-16 weeks in phase 2C

Drug: Ganfeborole; Drug: BTZ-043; Drug: Bedaquiline (B); Drug: Delamanid (D)

Arm M: BDM + Q

EXPERIMENTAL

Bedaquiline, delamanid, moxifloxacin, quabodepistat for 16 weeks in Phase 2B

Drug: Bedaquiline (B); Drug: Delamanid (D); Drug: Moxifloxacin (M); Drug: Quabodepistat (Q)

Arm N: BPAM + Q

EXPERIMENTAL

Bedaquiline, pretomanid, moxifloxacin, quabodepistat for 16 weeks in Phase 2B

Drug: Bedaquiline (B); Drug: Pretomanid (Pa); Drug: Moxifloxacin (M); Drug: Quabodepistat (Q)

Arm O: BD + Gan + Q

EXPERIMENTAL

Bedaquiline, delamanid, ganfeborole, quabodepistat for 16 weeks in Phase 2B

Drug: Ganfeborole; Drug: Bedaquiline (B); Drug: Delamanid (D); Drug: Quabodepistat (Q)

Arm P: BPa + Gan +Q

EXPERIMENTAL

Bedaquiline, pretomanid, ganfeborole, quabodepistat for 16 weeks in Phase 2B

Drug: Ganfeborole; Drug: Bedaquiline (B); Drug: Pretomanid (Pa); Drug: Quabodepistat (Q)

Arm Q: BPa + DZD + BTZ-043

EXPERIMENTAL

Bedaquiline, pretomanid, delpazolid, BTZ-043 for 16 weeks in Phase 2B

Drug: BTZ-043; Drug: Bedaquiline (B); Drug: Pretomanid (Pa); Drug: Delpazolid (DZD)

Interventions

Ganfeborole DRUG

Oral daily dosage of 20mg.

Also known as: GSK3036656

Arm C. BDM + Gan; Arm D. BDZ + Gan; Arm E. BDL + 656; Arm F. BPaM + Gan; Arm L. BD + Gan + BTZ-043; Arm O: BD + Gan + Q; Arm P: BPa + Gan +Q

BTZ-043 DRUG

Oral daily dosage of 1000mg.

Arm G. BDM + BTZ-043; Arm H. BDZ + BTZ-043; Arm I. BDL + BTZ-043; Arm J. BPaM + BTZ-043; Arm K. BMZ + BTZ-043; Arm L. BD + Gan + BTZ-043; Arm Q: BPa + DZD + BTZ-043

Bedaquiline (B) DRUG

Oral daily dosage of 400mg for the first 2 weeks, thereafter 100mg daily until end of treatment.

Arm B. BDM; Arm C. BDM + Gan; Arm D. BDZ + Gan; Arm E. BDL + 656; Arm F. BPaM + Gan; Arm G. BDM + BTZ-043; Arm H. BDZ + BTZ-043; Arm I. BDL + BTZ-043; Arm J. BPaM + BTZ-043; Arm K. BMZ + BTZ-043; Arm L. BD + Gan + BTZ-043; Arm M: BDM + Q; Arm N: BPAM + Q; Arm O: BD + Gan + Q; Arm P: BPa + Gan +Q; Arm Q: BPa + DZD + BTZ-043

Delamanid (D) DRUG

Oral daily dosage of 300mg.

Arm B. BDM; Arm C. BDM + Gan; Arm D. BDZ + Gan; Arm E. BDL + 656; Arm G. BDM + BTZ-043; Arm H. BDZ + BTZ-043; Arm I. BDL + BTZ-043; Arm L. BD + Gan + BTZ-043; Arm M: BDM + Q; Arm O: BD + Gan + Q

Pretomanid (Pa) DRUG

Oral daily dosage of 200mg.

Arm F. BPaM + Gan; Arm J. BPaM + BTZ-043; Arm N: BPAM + Q; Arm P: BPa + Gan +Q; Arm Q: BPa + DZD + BTZ-043

Moxifloxacin (M) DRUG

Oral daily dosage of 400mg.

Arm B. BDM; Arm C. BDM + Gan; Arm F. BPaM + Gan; Arm G. BDM + BTZ-043; Arm J. BPaM + BTZ-043; Arm K. BMZ + BTZ-043; Arm M: BDM + Q; Arm N: BPAM + Q

Linezolid (L) DRUG

Oral daily dosage of 600mg for the first 8 weeks.

Arm E. BDL + 656; Arm I. BDL + BTZ-043

Pyrazinamide (Z) DRUG

Oral daily dosage of 1200mg-2000mg depending on weight.

A. Standard TB Regimen. 2HRZE/4HR; Arm D. BDZ + Gan; Arm H. BDZ + BTZ-043; Arm K. BMZ + BTZ-043

Rifampicin (R) DRUG

Oral daily dosage of 450mg-750mg depending on weight.

A. Standard TB Regimen. 2HRZE/4HR

Isoniazid (H) DRUG

Oral daily dosage of 225mg-375mg depending on weight.

A. Standard TB Regimen. 2HRZE/4HR

Ethambutol (E) DRUG

Oral daily dosage of 825mg-1375mg depending on weight.

A. Standard TB Regimen. 2HRZE/4HR

Delpazolid (DZD) DRUG

Oral daily dosage of 1200mg

Arm Q: BPa + DZD + BTZ-043

Quabodepistat (Q) DRUG

Oral daily dosage of 30mg

Arm M: BDM + Q; Arm N: BPAM + Q; Arm O: BD + Gan + Q; Arm P: BPa + Gan +Q

Eligibility Criteria

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

You may qualify if:

• Age 18 years or above at screening (or above age of legal consent at screening, if this is higher than 18 years in the jurisdiction in which the study is taking place)
• Clinical evidence of active TB disease, meeting either or both of the following criteria:
• Symptoms consistent with pulmonary TB at screening AND/OR
• Imaging findings consistent with active pulmonary TB on chest X-ray performed at screening or within 7 days prior to screening
• At least one sputum specimen produced at screening tested on Xpert MTB/RIF Ultra that has:
• a semi-quantitative result of 'medium' or 'high' AND
• does not show rifampicin resistance
• Body weight within the range of 30 to 100kg and body mass index within the range of 15 to 40kg/m2
• Willing to comply with study visits, all study procedures and treatment observation
• Resident at a fixed address that is readily accessible for visiting, within feasible travelling distance to the site and likely to remain resident there for the duration of trial follow-up
• Has provided written informed consent

You may not qualify if:

• Taken more than 1 daily dose of medication with anti-tuberculous activity during the 14 days prior to randomisation (isoniazid, rifampicin, pyrazinamide, ethambutol; linezolid, moxifloxacin, levofloxacin or amikacin) (for Phase 2b and Phase 2c)
• Known isoniazid resistance (at sites where national isoniazid monoresistance is greater than 10% rapid testing at screening is mandated; at other sites rapid testing at screening is optional)
• Severe clinical pulmonary TB e.g. respiratory failure or complications likely to require hospital admission in the opinion of the investigator
• Poor general condition (Karnofsky score ≤50) OR where any delay in treatment cannot be tolerated in the opinion of the investigator
• Active malignancy requiring systemic therapy, radiotherapy or palliative therapy
• History of myocardial infarction, coronary heart disease or congestive cardiac failure; long QT syndrome or clinically significant arrhythmias; pulmonary hypertension; any known congenital cardiac problems; family history of long QT syndrome or sudden death from unknown or cardiac related cause; uncontrolled arterial hypertension (not excluded if this is corrected prior to randomisation)
• Vitiligo
• History of seizure(s)
• Current tendinitis (any cause) or history of tendinopathy associated with fluoroquinolone use
• History of vascular aneurysm
• Symptomatic peripheral neuropathy causing greater than minimal interference with usual social and functional activities
• Current alcohol or illicit drug use sufficient to compromise the safety of the participant or research staff or compromise adherence to study procedures, in the opinion of the investigator
• Any current or recent use of amphetamines or methamphetamines, either reported or evident on toxicity screen, if performed
• Any other medically or socially significant condition (e.g. psychiatric illness, chronic diarrhoeal disease, metabolic condition, other cardiovascular disease not listed under criterion 7), that would, in the opinion of the investigator, compromise the participant's safety or outcome in the trial; or lead to poor compliance with study visits and protocol requirements; or compromise the interpretation of trial safety and efficacy endpoints
• Women who are currently pregnant or breast-feeding

Sponsors & Collaborators

• University College, London: lead
• Radboud University Medical Center: collaborator
• London School of Hygiene and Tropical Medicine: collaborator
• University of Oxford: collaborator
• Research Center Borstel: collaborator
• Lygature: collaborator
• TASK Applied Science: collaborator
• Vita-Salute San Raffaele University: collaborator
• Helmholtz Zentrum Munchen: collaborator
• KNCV Tuberculosis Foundation: collaborator
• Critical Path Institute: collaborator
• European Lung Foundation: collaborator
• Instituto de Saude Publica da Universidade do Porto: collaborator
• University of Liverpool: collaborator
• Institut de Recherche pour le Developpement: collaborator
• University of Hamburg-Eppendorf: collaborator
• University of California, San Francisco: collaborator
• TB Alliance: collaborator
• Find: collaborator
• University of Milano: collaborator
• University of St Andrews: collaborator
• Uppsala University: collaborator
• European Respiratory Society: collaborator
• Tuberculosis Network European Trialsgroup: collaborator
• Janssen, LP: collaborator
• Otsuka Pharmaceutical Development & Commercialization, Inc.: collaborator
• German Center for Infection Research: collaborator
• LMU University Hospital Munich: collaborator
• University of Cambridge: collaborator
• GlaxoSmithKline: collaborator

Study Sites (11)

PMSI Institute of Pneumology "Chiril Draganiuc"

Chisinau, Moldova

ACTIVE NOT RECRUITING

TASK Brooklyn

Cape Town, South Africa

RECRUITING

University of Cape Town Lung Institute

Cape Town, South Africa

RECRUITING

TASK Eden

George, South Africa

RECRUITING

NIMR Mbeya

Mbeya, Tanzania

RECRUITING

Kibong'oto Infectious Diseases Hospital

Moshi, Tanzania

RECRUITING

NIMR Mwanza

Mwanza, Tanzania

RECRUITING

Joint Clinical Research Centre

Kampala, Uganda

RECRUITING

Makerere University Lung Institute

Kampala, Uganda

RECRUITING

National Lung Hospital

Hanoi, Vietnam

ACTIVE NOT RECRUITING

Pnth/Oucru

Ho Chi Minh City, Vietnam

ACTIVE NOT RECRUITING

Related Publications (3)

• Eckhardt E, Li Y, Mamerow S, Schinkothe J, Sehl-Ewert J, Dreisbach J, Corleis B, Dorhoi A, Teifke J, Menge C, Kloss F, Bastian M. Pharmacokinetics and Efficacy of the Benzothiazinone BTZ-043 against Tuberculous Mycobacteria inside Granulomas in the Guinea Pig Model. Antimicrob Agents Chemother. 2023 Apr 18;67(4):e0143822. doi: 10.1128/aac.01438-22. Epub 2023 Mar 28.

  PMID: 36975792 BACKGROUND

• Tenero D, Derimanov G, Carlton A, Tonkyn J, Davies M, Cozens S, Gresham S, Gaudion A, Puri A, Muliaditan M, Rullas-Trincado J, Mendoza-Losana A, Skingsley A, Barros-Aguirre D. First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment. Antimicrob Agents Chemother. 2019 Jul 25;63(8):e00240-19. doi: 10.1128/AAC.00240-19. Print 2019 Aug.

  PMID: 31182528 BACKGROUND

• Li X, Hernandez V, Rock FL, Choi W, Mak YSL, Mohan M, Mao W, Zhou Y, Easom EE, Plattner JJ, Zou W, Perez-Herran E, Giordano I, Mendoza-Losana A, Alemparte C, Rullas J, Angulo-Barturen I, Crouch S, Ortega F, Barros D, Alley MRK. Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656). J Med Chem. 2017 Oct 12;60(19):8011-8026. doi: 10.1021/acs.jmedchem.7b00631. Epub 2017 Sep 27.

  PMID: 28953378 BACKGROUND

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

GSK656; 2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; bedaquiline; OPC-67683; Fumigant 93; pretomanid; Moxifloxacin; Linezolid; Pyrazinamide; Rifampin; Isoniazid; Protons; Ethambutol; delpazolid

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)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Pyrazines; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Cations, Monovalent; Cations; Ions; Electrolytes; Inorganic Chemicals; Hydrogen; Elements; Gases; Nucleons; Elementary Particles; Physical Phenomena; Ethylenediamines; Diamines; Polyamines; Amines

Central Study Contacts

Susie Slater

CONTACT

20 7670 4789; mrcctu.paradigm4tb@ucl.ac.uk

Karen Sanders

CONTACT

2076704826; karen.sanders@ucl.ac.uk

Study Design

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

Study Record Dates

• First Submitted: October 17, 2023
• First Posted: November 2, 2023
• Study Start: January 9, 2024
• Primary Completion (Estimated): February 24, 2027
• Study Completion (Estimated): August 11, 2027
• Last Updated: October 6, 2025

Record last verified: 2025-09

Locations

TA (3); UG (2); MO (1); ZA (3); VN (2)