Efficacy and Safety Evaluation of Two to Four Months of Treatment With the Combination Regimens of DBOS and PBOS in Adults With Pulmonary Tuberculosis

NCT05971602 | Terminated Phase 2 DMC

• 1 other identifier: Gates MRI-TBD06-201
• Study Type: interventional
• Target: 93
• Locations: 2 countries
• Sites: 13

Brief Summary

This multicenter, two-stage, open-label, randomized trial will aim to assess the efficacy, safety, optimal duration, and pharmacokinetics (PK) of Delamanid, Bedaquiline, OPC-167832, and Sutezolid (DBOS) and Pretomanid, Bedaquiline, OPC-167832, and Sutezolid (PBOS) in adult participants with drug sensitive tuberculosis (DS-TB) and rifampicin or multi-drug resistant TB (RR/MDR-TB).

Conditions

Pulmonary Tuberculosis

Keywords

Delamanid, Bedaquiline, OPC-167832, and Sutezolid (DBOS); Pretomanid, Bedaquiline, OPC-167832, and Sutezolid (PBOS); Drug sensitive tuberculosis; Rifampicin-resistant tuberculosis (RR-TB); Multi-drug resistant tuberculosis (MDR-TB)

Outcome Measures

Primary Outcomes (4)

• Stage 1: Percentage of participants with DS-TB reporting severe Adverse events (AEs) (≥ Grade 3) and/or Serious adverse events (SAEs), by treatment group

  Up to Week 19 for DBOS and PBOS; up to Week 28 for 2HRZE/4HR

• Stage 1: Percentage of participants with pulmonary DS-TB with unfavorable outcome, by treatment group

  Participants that experience one or more of the following events following randomization will be categorized as having an unfavorable outcome status: Absence of microbiological cure (positive sputum culture); Death from any cause; Permanent discontinuation of trial treatment before the end of the assigned treatment duration ; Extension of TB treatment by the Investigator more than 5 days beyond the end of the assigned treatment duration for any reason; Positive culture for Mtb at last visit excluding documented TB re-infection with a different Mtb strain than Baseline.

  At Week 17 for DBOS and PBOS; at Week 26 for 2HRZE/4HR

• Stage 2: Percentage of participants with DS-TB reporting severe AEs (≥ Grade 3) and/or SAEs, by treatment group

  Up to Week 19 for XBOS treatment groups; up to Week 28 for 2HRZE/4HR

• Stage 2: Percentage of participants with pulmonary DS-TB reporting unfavorable outcome, by treatment group

  Participants that experience one or more of the following events following randomization will be categorized as having an unfavorable outcome status: Absence of microbiological cure (positive sputum culture); Death from any cause; Permanent discontinuation of trial treatment before the end of the assigned treatment duration; Extension of TB treatment by the Investigator more than 5 days beyond the end of the assigned treatment duration for any reason; Re-start of TB treatment by the Investigator during the post-treatment follow-up period excluding documented TB re-infection with a different Mtb strain than Baseline; Positive culture for Mtb at last visit excluding documented TB re-infection with a different Mtb strain than Baseline.

  At 12 months post-randomization

Secondary Outcomes (47)

• Stage 1: Percentage of participants reporting all-cause trial treatment discontinuation, by treatment group

  Through 12 months post-randomization

• Stage 1: Percentage of participants reporting severe AEs (≥ Grade 3) and/or SAEs, by treatment group

  Through 12 months post-randomization

• Stage 1: Percentage of participants with pulmonary DS-TB and Human immunodeficiency virus (HIV) co-infection reporting severe AEs (≥ Grade 3) and/or SAEs, by treatment group

  Up to Week 19 for DBOS and PBOS; up to Week 28 for 2HRZE/4HR

• Stage 1: Percentage of participants with pulmonary DS-TB and HIV co-infection reporting severe AEs (≥ Grade 3) and/or SAEs, by treatment group

  Through 12 months post-randomization

• Stage 1: Percentage of participants with pulmonary DS-TB and HIV co-infection reporting all-cause trial treatment discontinuation, by treatment group

  Through 12 months post-randomization

Study Arms (10)

Stage 1: Arm 1: DS-TB Participants receiving DBOS for 4 months (17 Weeks)

EXPERIMENTAL

Drug: Delamanid, Bedaquiline, OPC-167832, and Sutezolid (DBOS)

Stage 1: Arm 2: DS-TB Participants receiving PBOS for 4 months (17 Weeks)

EXPERIMENTAL

Drug: Pretomanid, Bedaquiline, OPC-167832, and Sutezolid (PBOS)

Stage 1: Arm 3: DS-TB Participants receiving 2HRZE/4HR for 6 months (26 weeks)

EXPERIMENTAL

Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E) - refers to standard regimen of 8 weeks of HRZE followed by 18 weeks of HR (2HRZE/4HR)

Drug: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE); Drug: Isoniazid and Rifampicin (HR)

Stage 2: Arm 1: DS-TB Participants receiving XBOS for 2 months (9 Weeks)

EXPERIMENTAL

Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (Regimen from Stage 1 that advances to Stage 2 \[XBOS\])

Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS)

Stage 2: Arm 2: DS-TB Participants receiving XBOS for 2.5 months (11 Weeks)

EXPERIMENTAL

Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS)

Stage 2: Arm 3: DS-TB Participants receiving XBOS for 3 months (13 Weeks)

EXPERIMENTAL

Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS)

Stage 2: Arm 4: DS-TB Participants receiving XBOS for 3.5 months (15 Weeks)

EXPERIMENTAL

Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS)

Stage 2: Arm 5: DS-TB Participants receiving XBOS for 4 months (17 Weeks)

EXPERIMENTAL

Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS)

Stage 2: Arm 6: DS-TB Participants receiving 2HRZE/4HR for 6 months (26 Weeks)

EXPERIMENTAL

Drug: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE); Drug: Isoniazid and Rifampicin (HR)

Observational cohort: RR/MDR-TB Participants receiving XBOS for 4 months (17 Weeks)

EXPERIMENTAL

Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS)

Interventions

Delamanid, Bedaquiline, OPC-167832, and Sutezolid (DBOS) DRUG

D- 300 milligram (mg) once daily (QD) for treatment duration; B- 400 mg QD for 2 weeks, 200 mg thrice weekly for remaining treatment weeks; O- 30 mg QD for treatment duration and S- 1200 mg QD for treatment duration

Stage 1: Arm 1: DS-TB Participants receiving DBOS for 4 months (17 Weeks)

Pretomanid, Bedaquiline, OPC-167832, and Sutezolid (PBOS) DRUG

P- 200 mg QD for treatment duration; B- 400 mg QD for 2 weeks, 200 mg thrice weekly for remaining treatment weeks; O- 30 mg QD for treatment duration and S- 1200 mg QD for treatment duration

Stage 1: Arm 2: DS-TB Participants receiving PBOS for 4 months (17 Weeks)

Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE) DRUG

Fixed dose combination (FDC) of 75 mg of isoniazid, 150 mg of rifampicin, 400 mg of pyrazinamide, and 275 mg of ethambutol (HRZE) (Standard of Care \[SOC\]). All the doses administered will be weight-based.

Stage 1: Arm 3: DS-TB Participants receiving 2HRZE/4HR for 6 months (26 weeks); Stage 2: Arm 6: DS-TB Participants receiving 2HRZE/4HR for 6 months (26 Weeks)

Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS) DRUG

X - Pretomanid 200 mg QD for treatment duration OR Delamanid 300 mg QD for treatment duration; B - 400 mg QD for 2 weeks, 200 mg thrice weekly for remaining treatment weeks; O- 30 mg QD for treatment duration and S-1200 mg QD for treatment duration

Observational cohort: RR/MDR-TB Participants receiving XBOS for 4 months (17 Weeks); Stage 2: Arm 1: DS-TB Participants receiving XBOS for 2 months (9 Weeks); Stage 2: Arm 2: DS-TB Participants receiving XBOS for 2.5 months (11 Weeks); Stage 2: Arm 3: DS-TB Participants receiving XBOS for 3 months (13 Weeks); Stage 2: Arm 4: DS-TB Participants receiving XBOS for 3.5 months (15 Weeks); Stage 2: Arm 5: DS-TB Participants receiving XBOS for 4 months (17 Weeks)

Isoniazid and Rifampicin (HR) DRUG

Fixed dose combination (FDC) of 75 mg of isoniazid and 150 mg of rifampicin (HR) (Standard of Care \[SOC\]). All the doses administered will be weight-based.

Stage 1: Arm 3: DS-TB Participants receiving 2HRZE/4HR for 6 months (26 weeks); Stage 2: Arm 6: DS-TB Participants receiving 2HRZE/4HR for 6 months (26 Weeks)

Eligibility Criteria

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

You may qualify if:

• For Stage 1:
• Able to provide written, informed consent prior to initiation of any trial-related procedures or treatments, and able, in the opinion of the Investigator, to comply with all the requirements of the trial.
• Male or female participants between 18 and 65 years of age (inclusive) at the screening visit.
• Body weight ≥35.0 kilograms (kg) and body mass index (BMI) ≥16.0 at the screening visit.
• Newly diagnosed within the past 8 weeks prior to informed consent, untreated (≤4 days of treatment), drug-susceptible pulmonary TB, as defined by all of the following:
• Confirmation of Mtb infection: Mtb positivity on a molecular test (eg, Xpert Ultra, Hain Line probe assay \[LPA\]) conducted on a sputum specimen for trial screening.
• Evidence of non-paucibacillary disease: ≥1+ sputum smear positivity for acid-fast bacilli using fluorescent microscopy, as defined by the International Union Against Tuberculosis and Lung Disease (IUATLD)/World Health Organization (WHO) scale, OR a Xpert Ultra semi-quantitative result of 'medium' or 'high' on the sputum specimen for trial screening.
• Drug-susceptible TB: Isoniazid and rifampicin resistance not detected, as determined by a molecular test (eg, Hain LPA, Xpert Ultra, Xpert MTB/Extensively Drug Resistant \[XDR\]) conducted on a sputum specimen for trial screening.
• Clinical signs and/or symptoms consistent with active TB in the opinion of the Investigator.
• Chest radiograph consistent with active TB in the opinion of the Investigator. Note, the Investigator is permitted, but not required, to incorporate a radiologist's interpretation into their assessment of a participant's chest radiograph.
• Able to spontaneously produce sputum.
• Female participants of childbearing potential (FOCBP) must agree to use 2 approved methods of contraception with their male sexual partners or abstain from heterosexual intercourse throughout their participation in the trial.
• Male participants must agree to use an approved method of contraception with their female sexual partners of childbearing potential or abstain from heterosexual intercourse throughout their participation in the trial.
• For Stage 2:
• Newly diagnosed within the past 8 weeks of informed consent, untreated (≤4 days of treatment), drug-susceptible or rifampicin-/multi-drug resistant pulmonary TB, as defined by all of the following:

You may not qualify if:

• Known, or suspected of having, resistance to a rifamycin, isoniazid, ethambutol, pyrazinamide, delamanid, pretomanid, bedaquiline, linezolid, tedizolid, or sutezolid either confirmed by the laboratory, or based on epidemiological history, such as a known source case with said resistance.
• Received any prior treatment for active Mtb disease (\>4 days) within the past 1 year of informed consent.
• Received any treatment with a fluoroquinolone active against Mtb (ie, levofloxacin, moxifloxacin, ciprofloxacin) or an aminoglycoside for more than 14 days within the 3 months prior to informed consent even if the medication was given for a different indication than TB treatment.
• Any known prior exposure to delamanid, pretomanid, bedaquiline, OPC-167832, or any oxazolidinone (linezolid, tedizolid, delpazolid, or sutezolid).
• Evidence of an active clinically significant/uncontrolled metabolic, gastrointestinal, neurological (including peripheral neuropathy), psychiatric, endocrine (including uncontrolled diabetes), hematologic, ophthalmologic (particularly optic neuritis), or liver disease; active malignancy; or other medical co-morbidity considered significant enough by the Investigator that the participant should not enter the trial.
• Significant history of, or current clinically relevant cardiovascular disorder, such as heart failure, coronary artery disease, uncontrolled hypertension, arrhythmia, tachyarrhythmia, prolonged QT syndrome, or presence of symptom(s) strongly suggestive of such a problem, such as exertional chest pressure/pain or unexplained syncope.
• If HIV-infected, having any of the following present:
• Not on antiretroviral treatment at time of screening or taking antiretroviral treatment for \<3 months prior to screening, OR
• Cluster of differentiation (CD)4+ T-cell count \<200 cells/microliter (μL) during the screening period, OR
• HIV viral load \>200 copies/milliliter (mL) during the screening period, OR
• HIV-infected participants enrolling at a trial site in Peru will not be eligible due to the requirement for longer TB treatment courses than the standard 6-month HRZE regimen for patients with HIV/TB co-infection as per the Peruvian national TB treatment guidelines.
• If female, currently pregnant or breastfeeding, OR having a positive serum or urine pregnancy test during the screening period, OR planning to become pregnant within the 12-month period after the screening period.
• Current significant drug and/or alcohol abuse that is likely to result in poor adherence to trial requirements or that would pose a risk to the participant's wellbeing during the trial.
• Karnofsky Performance Status scale score at screening of \<60.
• Having a disease or condition where the use of delamanid, pretomanid, bedaquiline, OPC-167832, sutezolid, rifampicin, isoniazid, pyrazinamide, or ethambutol is contraindicated.

Sponsors & Collaborators

• Gates Medical Research Institute: lead
• Global Alliance for TB Drug Development: collaborator
• Janssen Pharmaceuticals: collaborator
• Otsuka Pharmaceutical Co., Ltd.: collaborator

Study Sites (13)

Tropical Disease Foundation

Makati, Philippines

Location

Lung Center of the Philippines

Quezon City, Philippines

Location

Silang Specialist Medical Center

Silang, Philippines

Location

Bio-Medical Research Institute; Faculty of Medicine and Health Sciences, Stellenbosch University; Tygerberg Medical Campus

Cape Town, South Africa

Location

TASK - Central (Brooklyn)

Cape Town, South Africa

Location

UCT (Cape Town); General Medicine & Global Health (GMGH); Hatter Heart Research Institute

Cape Town, South Africa

Location

UCT South African Tuberculosis Vaccine Initiative (SATVI)

Cape Town, South Africa

Location

University of Cape Town (UCT) Lung Institute

Cape Town, South Africa

Location

CHRU - Durban

Durban, South Africa

Location

Synergy Biomed Research Institute

East London, South Africa

Location

Clinical HIV Research Unit (CHRU) - Johannesburg

Johannesburg, South Africa

Location

The Aurum Institute (Tembisa CRS)

Johannesburg, South Africa

Location

Perinatal HIV Research Unit (PHRU)

Klerksdorp, South Africa

Location

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant

Interventions

OPC-67683; bedaquiline; PNU-100480; pretomanid; Isoniazid; Rifampin; Pyrazinamide; Ethambutol

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

Study Officials

• Gates MRI

  Gates Medical Research Institute

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: June 14, 2023
• First Posted: August 2, 2023
• Study Start: July 26, 2023
• Primary Completion: February 6, 2025
• Study Completion: February 6, 2025
• Last Updated: February 25, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share

Locations

PH (3); ZA (10)