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

• ClinicalTrials.gov Identifier: NCT05971602
• Recruitment Status: Recruiting
• First Posted: August 2, 2023
• Sponsor: Bill & Melinda Gates Medical Research Institute
• Collaborators: Global Alliance for TB Drug Development; Janssen Pharmaceutica; Otsuka Pharmaceutical Co., Ltd.
• Information provided by (Responsible Party): Bill & Melinda Gates Medical Research Institute

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Pulmonary Tuberculosis	Drug: Delamanid, Bedaquiline, OPC-167832, and Sutezolid (DBOS); Drug: Pretomanid, Bedaquiline, OPC-167832, and Sutezolid (PBOS); Drug: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE); Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS); Drug: Isoniazid and Rifampicin (HR)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 514 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2b/c, Multi-Arm, 2-Stage, Duration Randomized Trial of the Efficacy and Safety of Two to Four Months Treatment With Regimens Containing Bedaquiline, OPC-167832, and Sutezolid, Plus Either Pretomanid or Delamanid, in Adults With Pulmonary Tuberculosis
• Actual Study Start Date: July 26, 2023
• Estimated Primary Completion Date: October 2027
• Estimated Study Completion Date: October 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Stage 1: Arm 1: DS-TB Participants receiving DBOS for 4 months (17 Weeks)	Drug: Delamanid, Bedaquiline, OPC-167832, and Sutezolid (DBOS); 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
Experimental: Stage 1: Arm 2: DS-TB Participants receiving PBOS for 4 months (17 Weeks)	Drug: Pretomanid, Bedaquiline, OPC-167832, and Sutezolid (PBOS); 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
Experimental: Stage 1: Arm 3: DS-TB Participants receiving 2HRZE/4HR for 6 months (26 weeks); 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); 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.; Drug: Isoniazid and Rifampicin (HR); 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.
Experimental: Stage 2: Arm 1: DS-TB Participants receiving XBOS for 2 months (9 Weeks); 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); 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
Experimental: Stage 2: Arm 2: DS-TB Participants receiving XBOS for 2.5 months (11 Weeks)	Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS); 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
Experimental: Stage 2: Arm 3: DS-TB Participants receiving XBOS for 3 months (13 Weeks)	Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS); 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
Experimental: Stage 2: Arm 4: DS-TB Participants receiving XBOS for 3.5 months (15 Weeks)	Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS); 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
Experimental: Stage 2: Arm 5: DS-TB Participants receiving XBOS for 4 months (17 Weeks)	Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS); 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
Experimental: Stage 2: Arm 6: DS-TB Participants receiving 2HRZE/4HR for 6 months (26 Weeks)	Drug: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE); 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.; Drug: Isoniazid and Rifampicin (HR); 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.
Experimental: Observational cohort: RR/MDR-TB Participants receiving XBOS for 4 months (17 Weeks)	Drug: Pretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS); 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

Outcome Measures

Primary Outcome Measures :

1. Stage 1: Percentage of participants with DS-TB reporting severe Adverse events (AEs) (≥ Grade 3) and/or Serious adverse events (SAEs), by treatment group [ Time Frame: Up to Week 19 for DBOS and PBOS; up to Week 28 for 2HRZE/4HR ]
2. Stage 1: Percentage of participants with pulmonary DS-TB with unfavorable outcome, by treatment group [ Time Frame: At Week 17 for DBOS and PBOS; at Week 26 for 2HRZE/4HR ]
   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.
3. Stage 2: Percentage of participants with DS-TB reporting severe AEs (≥ Grade 3) and/or SAEs, by treatment group [ Time Frame: Up to Week 19 for XBOS treatment groups; up to Week 28 for 2HRZE/4HR ]
4. Stage 2: Percentage of participants with pulmonary DS-TB reporting unfavorable outcome, by treatment group [ Time Frame: At 12 months post-randomization ]
   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.

Secondary Outcome Measures :

1. Stage 1: Percentage of participants reporting all-cause trial treatment discontinuation, by treatment group [ Time Frame: Through 12 months post-randomization ]
2. Stage 1: Percentage of participants reporting severe AEs (≥ Grade 3) and/or SAEs, by treatment group [ Time Frame: Through 12 months post-randomization ]
3. 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 [ Time Frame: Up to Week 19 for DBOS and PBOS; up to Week 28 for 2HRZE/4HR ]
4. Stage 1: Percentage of participants with pulmonary DS-TB and HIV co-infection reporting severe AEs (≥ Grade 3) and/or SAEs, by treatment group [ Time Frame: Through 12 months post-randomization ]
5. Stage 1: Percentage of participants with pulmonary DS-TB and HIV co-infection reporting all-cause trial treatment discontinuation, by treatment group [ Time Frame: Through 12 months post-randomization ]
6. Stage 1: Percentage of participants with pulmonary DS-TB reporting unfavorable outcome, by treatment group [ Time Frame: At 12 months post-randomization ]
   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.
7. Stage 1: Percentage of participants with DS-TB and HIV co-infection reporting unfavorable outcome, by treatment group [ Time Frame: At Week 17 for DBOS and PBOS; at Week 26 for 2HRZE/4HR ]
   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.
8. Stage 1: Percentage of participants reporting unfavorable outcome, by treatment group [ Time Frame: At 6 months post-randomization ]
   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.
9. Stage 1: Time to sustained sputum culture conversion to negative for Mtb growth in Mycobacteria Growth Indicator Tube (MGIT) culture in participants receiving combination of DBOS and PBOS relative to 2HRZE/4HR [ Time Frame: Up to Week 28 ]
   Hazard ratio for time to sustained sputum culture conversion to negative will be assessed
10. Stage 1: Mean change from Baseline in sputum MGIT culture time to detection (TTD) in participants receiving combination of DBOS and PBOS relative to 2HRZE/4HR [ Time Frame: Baseline and at Weeks 4, 8, 9, 13, and 17 ]
    Mean change from Baseline in sputum MGIT culture time to detection (TTD) will be assessed
11. Stage 1: Percentage of participants with sustained sputum culture conversion in MGIT culture through Week 26, by treatment group [ Time Frame: Through Week 26 post-randomization ]
12. Stage 1: Time to sustained sputum culture conversion to negative in solid culture, by treatment group [ Time Frame: Up to Week 19 for DBOS and PBOS; up to Week 28 for 2HRZE/4HR ]
13. Stage 1: Percentage of participants with sustained sputum culture conversion in solid culture, by treatment group [ Time Frame: Up to Week 19 for DBOS and PBOS; up to Week 28 for 2HRZE/4HR ]
14. Stage 1: Percentage of participants developing resistance against each drug [ Time Frame: Up to 12 months post-randomization ]
15. Stage 1: Geometric mean concentration of DBOS in participants with pulmonary DS-TB [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
16. Stage 1: Geometric mean concentration of PBOS in participants with pulmonary DS-TB [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
17. Stage 1: Geometric mean concentration of DBOS in participants with DS-TB and HIV co-infection [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
18. Stage 1: Geometric mean concentration of PBOS in participants with DS-TB and HIV co-infection [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
19. Stage 1: Geometric coefficient of variation of DBOS in participants with pulmonary DS-TB [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
20. Stage 1: Geometric coefficient of variation of PBOS in participants with pulmonary DS-TB [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
21. Stage 1: Geometric coefficient of variation of DBOS in participants with DS-TB and HIV co-infection [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
22. Stage 1: Geometric coefficient of variation of PBOS in participants with DS-TB and HIV co-infection [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
23. Stage 2: Percentage of participants with DS-TB receiving XBOS reporting all-cause trial treatment discontinuation [ Time Frame: Week 9 through 17 ]
24. Stage 2: Percentage of participants with DS-TB receiving 2HRZE/4HR reporting all-cause trial treatment discontinuation [ Time Frame: Up to week 26 ]
25. Stage 2: Percentage of participants with DS-TB reporting Severe AEs (≥ Grade 3) and/or SAEs, by treatment group [ Time Frame: Through 12 months post-randomization ]
26. Stage 2: Percentage of participants with pulmonary DS-TB and HIV co-infection reporting severe AEs (≥ Grade 3) and/or SAEs, by treatment group [ Time Frame: Up to Week 11, Week 13, Week 15, Week 17, and Week 19 for XBOS treatment groups; up to Week 28 for 2HRZE/4HR ]
27. Stage 2: Percentage of participants with pulmonary DS-TB and HIV co-infection reporting severe AEs (≥ Grade 3) and/or SAEs, by treatment group [ Time Frame: Through 12 months post-randomization ]
28. Stage 2: Percentage of participants with pulmonary DS-TB and HIV co-infection reporting all-cause trial treatment discontinuation, by treatment group [ Time Frame: Up to Week 9, Week 11, Week 13, Week 15, and Week 17 for XBOS treatment groups; up to Week 26 for 2HRZE/4HR ]
29. Stage 2: Percentage of participants with RR/MDR-TB reporting severe AEs (≥ Grade 3) and/or SAEs in participants who receive XBOS for four months [ Time Frame: Up to 19 weeks ]
30. Stage 2: Percentage of participants with RR/MDR-TB reporting severe AEs (≥ Grade 3) and/or SAEs in participants who receive XBOS for four months [ Time Frame: Through 12 months post-randomization ]
31. Stage 2: Percentage of participants with RR/MDR-TB reporting all-cause trial treatment discontinuation in participants who receive XBOS for four months [ Time Frame: Up to 17 weeks ]
32. Stage 2: Percentage of participants with pulmonary DS-TB reporting unfavorable outcome, by treatment group [ Time Frame: Week 9, Week 11, Week 13, Week 15, and Week 17 for XBOS treatment groups; at Week 26 for 2HRZE/4HR ]
    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.
33. Stage 2: Percentage of participants with pulmonary DS-TB and HIV co-infection reporting unfavorable outcome, by treatment group [ Time Frame: Through 12 months post-randomization ]
    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.
34. Stage 2: Percentage of participants reporting unfavorable outcome, by treatment group [ Time Frame: At 6 months post-treatment after randomized duration of treatment ]
    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.
35. Stage 2: Time to sustained sputum culture conversion to negative for Mtb growth in MGIT culture in participants receiving combination of XBOS relative to 2HRZE/4HR [ Time Frame: Up to Week 28 ]
36. Stage 2: Mean change from Baseline in sputum MGIT culture TTD in participants receiving combination of XBOS relative to 2HRZE/4HR [ Time Frame: Baseline and at Weeks 4, 8, 9, 11, 13, 15, and 17 ]
37. Stage 2: Percentage of participants with sustained sputum culture conversion to negative at Week 8 and end of treatment, by treatment group [ Time Frame: At Week 8 for all treatment groups; at Week 9, Week 11, Week 13, Week 15, and Week 17 for all XBOS treatment groups; at Week 26 for 2HRZE/4HR ]
38. Stage 2: Time to sustained sputum culture conversion to negative in solid culture in participants receiving combination of XBOS relative to 2HRZE/4HR [ Time Frame: Up to Week 28 ]
39. Stage 2: Percentage of participants with sustained sputum culture conversion in solid culture, by treatment group [ Time Frame: Up to Week 11, Week 13, Week 15, Week 17, and Week 19 for XBOS treatment groups; up to Week 28 for 2HRZE/4HR ]
40. Stage 2: Percentage of participants developing resistance against each drug [ Time Frame: Up to 12 months post-randomization ]
41. Stage 2: Geometric mean concentration of XBOS in participants with pulmonary DS-TB and RR/MDR-TB [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
42. Stage 2: Geometric mean concentration of XBOS in participants with DS-TB and HIV co-infection [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
43. Stage 2: Geometric coefficient of variation of XBOS in participants with pulmonary DS-TB and RR/MDR-TB [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]
44. Stage 2: Geometric coefficient of variation of XBOS in participants with DS-TB and HIV co-infection [ Time Frame: Pre-dose, post-dose at Weeks 1, 2, 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 26 and at Months 9, 12 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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 3 weeks prior to informed consent, untreated (≤4 days of treatment), drug-susceptible pulmonary TB, as defined by all of the following:

  1. 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.
  2. 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.
  3. 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.
  4. Clinical signs and/or symptoms consistent with active TB in the opinion of the Investigator.
  5. 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 3 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:

1. Confirmation of Mtb infection: Mtb positivity on a molecular test (eg, Xpert Ultra, Hain LPA) conducted on a screening sputum specimen.
2. Evidence of non-paucibacillary disease: ≥1+ sputum smear positivity for acid-fast bacilli using fluorescent microscopy, as defined on the IUATLD/WHO scale, OR Xpert Ultra semi-quantitative result of 'medium' or 'high' on the sputum specimen for trial screening.
3. Resistance pattern:

i. For DS TB arm, isoniazid and rifampicin resistance not detected on a molecular test (eg, Hain LPA, Xpert Ultra, Xpert MTB/XDR) conducted on a screening sputum specimen, OR

ii. For RR/MDR TB arm, either rifampicin resistance (RR TB) OR rifampicin and isoniazid resistance (MDR TB) detected on a molecular test (eg, Hain LPA, Xpert Ultra, Xpert MTB/XDR) conducted on a screening sputum specimen.

• Participants with RR or MDR TB must also have fluoroquinolone resistance not detected, as determined by a molecular test (eg, Hain LPA second line, Xpert MTB/XDR) performed on the sputum specimen for trial screening.

d) Clinical signs and/or symptoms consistent with active TB in the opinion of the Investigator.

e) Chest radiograph consistent with active TB in the opinion of the Investigator.

The other inclusion criteria remain the same for Stage 2.

Exclusion Criteria:

• Suspected or documented extra-thoracic TB. Confirmed or suspected lymph node TB is not considered exclusionary. The presence of a pleural effusion considered not clinically significant together with pulmonary TB is not exclusionary.
• 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.
• Significant history of, or current evidence of an active clinically significant/poorly controlled pulmonary disease, such as asthma, Chronic obstructive Pulmonary disease (COPD), silicosis, or lung fibrosis (other than TB), considered as severe by the Investigator. In particular, any underlying pulmonary condition that could significantly interfere with the assessment of X-ray images, interpretation of sputum findings, or otherwise compromise the participant's participation in the trial is exclusionary based on the Investigator's judgement. Clinically significant post-Coronavirus disease-2019 (COVID-19) pulmonary sequelae should be considered exclusionary.

• If HIV-infected, having any of the following present:

  1. Not on antiretroviral treatment at time of screening or taking antiretroviral treatment for <3 months prior to screening, OR
  2. Cluster of differentiation (CD)4+ T-cell count <200 cells/microliter (μL) during the screening period, OR
  3. HIV viral load >200 copies/milliliter (mL) during the screening period, OR
  4. Evidence of a currently active opportunistic malignancy or infection related to HIV other than TB that requires treatment with a prohibited concomitant medication (oral candidiasis is not exclusionary).
• 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.
• Positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Polymerase chain reaction (PCR) result on nasopharyngeal sample taken during screening. Prior history of COVID-19/SARS-CoV-2 infection is not exclusionary if SARS-CoV-2 PCR performed on screening sample is negative.

• Any of the following laboratory results during screening:

  1. Estimated creatinine clearance <60 mL/minute
  2. Alanine transaminase (ALT) or aspartate transaminase (AST) >2.5 × upper limit of normal of the clinical laboratory reference range
  3. Total bilirubin >2x upper limit of normal of the clinical laboratory reference range, at screening
  4. Hemoglobin <8.0 grams per deciliter (g/dL)
  5. Platelet count <100 x 10^9/liter (L)
  6. White blood cell count <2.0 x 10^9/L
  7. Screening glycosylated hemoglobin (HbA1c) ≥10.0%
  8. Positive hepatitis B surface antigen
  9. Positive hepatitis C antibody.
• Moderate to severe substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria (substances of concern may include cocaine, amphetamines, opiates, barbiturates, benzodiazepines, or alcohol).
• A clinically significant Electrocardiogram (ECG) abnormality at screening as confirmed by a central ECG reading service. Examples of such include, but are not limited to, second- or third-degree atrioventricular block, complete right bundle branch block, left bundle branch block, QRS duration ≥120 millisecond (msec), QT interval corrected using Fridericia's formula (QTcF) interval >450 msec in males or >470 msec in females, atrial fibrillation or flutter, supraventricular tachycardia, and ventricular tachycardia or multiple multifocal premature ventricular complexes. The following ECG findings are not considered clinically significant: sinus tachycardia, mild first-degree atrioventricular block (P-R interval <0.23 sec), right or left axis deviation, incomplete right bundle branch block, and isolated left anterior fascicular block (left anterior hemiblock) in young otherwise healthy participants.
• Participants receiving any of the prohibited medications within the specified periods or who would be likely to require prohibited concomitant therapy during the trial.
• History of having taken another investigational drug within 30 days preceding trial entry or participates in another clinical study during the duration of this trial.

Contacts and Locations

Contacts

Contact: Gates MRI; +1 857 702 2108; clinical.trials@gatesmri.org

Contact: Gates MRI (Toll Free Number); +1 866 789 5767

Locations

Philippines

Tropical Disease Foundation; Recruiting

Makati, Philippines

Lung Center of the Philippines; Recruiting

Quezon City, Philippines

Silang Specialist Medical Center; Recruiting

Silang, Philippines

South Africa

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

Cape Town, South Africa

TASK - Central (Brooklyn); Recruiting

Cape Town, South Africa

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

Cape Town, South Africa

UCT South African Tuberculosis Vaccine Initiative (SATVI); Recruiting

Cape Town, South Africa

University of Cape Town (UCT) Lung Institute; Recruiting

Cape Town, South Africa

CHRU - Durban; Not yet recruiting

Durban, South Africa

Synergy Biomed Research Institute; Recruiting

East London, South Africa

Clinical HIV Research Unit (CHRU) - Johannesburg; Not yet recruiting

Johannesburg, South Africa

The Aurum Institute (Tembisa CRS); Not yet recruiting

Johannesburg, South Africa

Perinatal HIV Research Unit (PHRU); Recruiting

Klerksdorp, South Africa

Sponsors and Collaborators

Bill & Melinda Gates Medical Research Institute

Global Alliance for TB Drug Development

Janssen Pharmaceutica

Otsuka Pharmaceutical Co., Ltd.

Investigators

• Study Director: Gates MRI; Bill & Melinda Gates Medical Research Institute

More Information

• Responsible Party: Bill & Melinda Gates Medical Research Institute
• ClinicalTrials.gov Identifier: NCT05971602
• Other Study ID Numbers: Gates MRI-TBD06-201
• First Posted: August 2, 2023
• Last Update Posted: May 9, 2024
• Last Verified: May 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Bill & Melinda Gates Medical Research Institute:

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)

Additional relevant MeSH terms:

Tuberculosis; Tuberculosis, Pulmonary; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Rifampin; Isoniazid; Pyrazinamide; Ethambutol; Bedaquiline; Diarylquinolines; Oxazolidinones; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Leprostatic Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers