Safety and Efficacy Evaluation of 4-month Regimen of OPC-167832, Delamanid and Bedaquiline in Participants With Drug-Susceptible Pulmonary TB

A Multicenter, Phase 2b/c, Open-label, Randomized, Dose-finding Trial to Evaluate the Safety and Efficacy of a 4 Month Regimen of OPC-167832 in Combination With Delamanid and Bedaquiline in Subjects With Drug-susceptible Pulmonary Tuberculosis in Comparison With Standard Treatment

This trial will assess the safety and efficacy of OPC-167832 combined with delamanid and bedaquiline in participants with drug-susceptible tuberculosis (DS-TB) administered for 17 weeks compared to rifampin, isoniazid, ethambutol, pyrazinamide (RHEZ) administered for 26 weeks.

Study Overview

• Status: Completed
• Conditions: Pulmonary TB
• Intervention / Treatment: Drug: Delamanid; Drug: Bedaquiline; Drug: OPC-167832; Drug: RHEZ; Drug: Rifampin; Drug: Isoniazid

Detailed Description

Eligible participants for this study have a diagnosis of pulmonary DS-TB.

This is a Phase 2b/c multicenter, open-label, randomized, dose-finding study, consisting of up to 26 weeks of treatment period.

Following a screening period of up to 14 days, eligible participants will be randomized in the study.

Randomization will be stratified by presence of bilateral cavitation on screening chest x-ray (yes or no). After the end of the treatment period, participants will be followed until 12 months post randomization.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Cape Town, South Africa, 7100
    • TASK Applied Science, Brooklyn Chest Hospital Premises
  • Cape Town, South Africa, 7700
    • University of CapeTown Lung Center Institute
  • Johannesburg, South Africa, 2092
    • Themba Lethu Clinic Clinical HIV Research Unit (CHRU)
  • Klerksdorp, South Africa, 2574
    • Perinatal HIV Research Unit Tshepong Hospital Complex
  • Pretoria, South Africa, 0152
    • Setshaba Research Center
  • Gauteng
    • Tembisa, Gauteng, South Africa, 1632
      • Aurum Institute - Tembisa Clinical Research Centre

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

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.
2. Male or female participants between 18 and 65 years of age (inclusive) at the screening visit.
3. Body weight ≥ 35.0 kg at the screening visit.
4. Newly diagnosed, rifampin and isoniazid susceptible (on the screening sample) pulmonary TB.
5. Able to spontaneously produce sputum.
6. Females of childbearing potential (FOCBP) must agree to use 2 different approved methods of birth control or remain abstinent throughout their participation in the trial and for 12 weeks after the last dose of IMP or dose of RHEZ.
7. Male participants must agree to use 2 different approved methods of birth control or remain abstinent throughout their participation in the trial and for 12 weeks after the last dose of IMP or RHEZ.

Exclusion Criteria:

1. Participants are known or suspected of having resistance to rifampin, isoniazid, ethambutol, pyrazinamide, DLM, or BDQ either confirmed by the laboratory, or based on epidemiological history, at screening.
2. Evidence of clinically significant metabolic (for example, including ongoing or current hypokalemia [ie, potassium <3.5 mEq/dL at screening]), gastrointestinal, neurological, psychiatric, endocrine or liver (eg, hepatitis B and C) disease; malignancy; or other abnormalities (other than the indication being studied).
3. History of, or current, clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, uncontrolled hypertension, arrhythmia or symptom strongly suggestive of such a problem (for example, syncope or palpitations), tachyarrhythmia or status after myocardial infarction.
4. Known bleeding disorders or family history of bleeding disorders.
5. Any diseases or conditions in which the use of DLM, BDQ, OPC 167832, rifampin, isoniazid, pyrazinamide, or ethambutol is contraindicated.
6. Any prior treatment for M tuberculosis within the past 2 years.
7. Any treatment with a drug active against M tuberculosis (eg, quinolones) within the 3 months prior to screening.
8. Clinical evidence of severe extrapulmonary TB (eg, miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis).
9. Evidence of pulmonary silicosis, lung fibrosis, or other lung condition considered as severe by the investigator (other than TB). In particular, any underlying condition that could interfere with the assessment of x-ray images, sputum collection, or interpretation of sputum findings, or otherwise compromise the subject's participation in the trial.
10. Any renal impairment characterized by creatinine clearance/estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2, or hepatic impairment characterized by alanine transaminase or aspartate transaminase > 2.0 × upper limit of normal of the clinical laboratory reference range or bilirubin > 2.0 × upper limit of normal of the clinical laboratory reference range, at screening.
11. Screening glucose (nonfasting) ≥ 200 mg/dL or glycosylated hemoglobin (HbA1c) ≥ 6.5%.
12. QTcF > 450 msec in male participants (> 470 msec in female participants), atrioventricular block II or III, bi-fasicular block, at screening or current or history of clinically significant ventricular arrhythmias. Other ECG abnormalities, if considered clinically significant by the investigator.
13. Participants receiving any of the prohibited medications (see Section 6.5.1) within the specified periods or who would be likely to require prohibited concomitant therapy during the trial.
14. Female participants who are breast-feeding or who have a positive pregnancy test result prior to receiving the first dose of IMP or RHEZ on Day 1.
15. Current history of 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 well-being during the course of the trial.
16. History of current hepatitis or carriers of hepatitis B surface antigen (HBsAg) and/or anti hepatitis C virus (HCV).
17. Participants who test positive for cocaine or other drugs of abuse (excluding known prescription stimulants and other prescribed medications and marijuana) at screening are excluded. Detectable levels of alcohol, marijuana, barbiturates, or opiates in the drug screen are not exclusionary if, in the investigator's documented opinion, the participant does not meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for moderate to severe substance use disorder and the positive test does not signal a clinical condition that would impact the safety of the participant or interpretation of the trial results, and participation is agreed to by the medical monitor prior to treatment.
18. History of having taken an investigational drug within 30 days preceding trial entry.
19. A history of difficulty in donating blood.
20. Donation of blood or plasma within 30 days prior to dosing.
21. History of serious mental disorders that, in the opinion of the investigator, would exclude the participant from participating in this trial.
22. Any known prior exposure to OPC-167832, DLM, or BDQ.
23. Participants with significant medical comorbidities that in the opinion of the investigator, should not participate in the trial.
24. Participants with Karnofsky score < 60 will be excluded from the trial.
25. Participants testing positive for active severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection at screening.
26. Participants with HIV co infection not on a stable anti-retroviral regimen consisting of tenofovir, emtricitabine/ lamivudine, dolutegravir (ie > 3 months), or who have a detectable viral load, or who have a CD4 count < 350 cells/mm3 will be excluded from the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Delamanid + Bedaquiline + OPC-167832 10 mg; Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, once daily (QD), bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, thrice weekly (TIW) and OPC-167832, 10 mg, oral tablets, QD for a total of 17 weeks.	Drug: Delamanid; Delamanid (300 mg QD) for 17 weeks; Drug: Bedaquiline; Bedaquiline (400 mg QD x 2 weeks, then 200 mg TIW) for 17 weeks; Drug: OPC-167832; OPC-167832 at a dose of either 10 mg, 30 mg, or 90 mg for 17 weeks
Experimental: Delamanid + Bedaquiline + OPC-167832 30 mg; Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, QD, bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, TIW and OPC-167832, 30 mg, oral tablets, QD for a total of 17 weeks.	Drug: Delamanid; Delamanid (300 mg QD) for 17 weeks; Drug: Bedaquiline; Bedaquiline (400 mg QD x 2 weeks, then 200 mg TIW) for 17 weeks; Drug: OPC-167832; OPC-167832 at a dose of either 10 mg, 30 mg, or 90 mg for 17 weeks
Experimental: Delamanid + Bedaquiline + OPC-167832 90 mg; Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, QD, bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, TIW and OPC-167832, 90 mg, oral tablets, QD for a total of 17 weeks.	Drug: Delamanid; Delamanid (300 mg QD) for 17 weeks; Drug: Bedaquiline; Bedaquiline (400 mg QD x 2 weeks, then 200 mg TIW) for 17 weeks; Drug: OPC-167832; OPC-167832 at a dose of either 10 mg, 30 mg, or 90 mg for 17 weeks
Active Comparator: Rifampin, Isoniazid, Ethambutol, and Pyrazinamide (RHEZ); Participants will receive RHEZ, orally, QD for 8 weeks followed by 18 weeks of rifampin and isoniazid for a total of 26 weeks.	Drug: RHEZ; RHEZ (RIFAFOUR single dose combination tablets) for 8 weeks; Other Names: RIFAFOUR; Drug: Rifampin; Rifampin tablets for 18 weeks; Drug: Isoniazid; Isoniazid tablets for 18 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment Emergent Adverse Events	Incidence of TEAEs: all TEAEs, TEAEs by severity, TEAEs potentially causally related to the IMP or trial medication, TEAEs with an outcome of death or trial medication, Serious TEAEs, TEAEs leading to discontinuation of the IMP or trial medication	Baseline to 12 months post randomization
Incidence of potentially clinically significant changes of laboratory tests from baseline and abnormalities in the vital signs, physical examinations, electrocardiograms (ECGs) at each visit were assessed and at end of study.	Incidence of potentially clinically significant changes from baseline and abnormalities in the parameters below, at each visit were assessed and at end of study: Lab Tests: Hematology, Clinical Chemistry, CD4 Count, Urinalysis Vital Signs: systolic and diastolic blood pressure (mmHg), heart rate (beats/min), respiratory rate (breaths/min), body temperature (C), weight (kg) and body mass index (kg/m2) Physical exam include examination of the abdomen; extremities; head, eyes, ears, nose (HEENT); neurological; skin and mucosae; thorax; urogenital; audiometry assessment and visual assessment. ECGs: ECG PR interval (msec) ECG QTc interval (msec) ECG arrhythmia	Baseline to 12 months post randomization
Number of participants with a grade 3 or higher AE	The proportion of subjects with a grade 3 or higher AE	Baseline to 12 months post randomization
Number of all cause Treatment Discontinuation	Rate of All Cause Treatment Discontinuation	Baseline to 12 months post randomization
Sputum culture conversion (SCC) in Mycobacteria Growth Indicator Tube® (MGIT)	The proportion of subjects achieving sputum culture conversion (SCC) in Mycobacteria Growth Indicator Tube® (MGIT) (Sputum culture conversion occurs when a subject has the first of 2 visits of at least 1 week apart (±4 days) with sputum cultures negative and without a positive sputum culture result in between).	Baseline to End of Treatment Period - Week 17 and Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants who achieve SCC in MGIT by 8 weeks of treatment	Proportion of subjects who achieve SCC.	Baseline to Week 8
Time to detection of MGIT cultures	Change in time to detection, in days, of MGIT liquid culture results	Baseline to 12 months post randomization
Proportion of participants who convert sputum LAM to negative by 8 weeks of treatment and by end of treatment	The proportion of subjects who convert sputum LAM concentrations from positive to negative by 8 weeks of treatment and by end of treatment	End of Treatment Period - Week 17 and Week 26
Proportion of participants who develop drug resistance	Proportion of subjects whose sputum cultures test "resistant" to any drugs in the treatment regimens during the treatment period.	Baseline to 12 months post randomization
Time to Sputum Culture Conversion (SCC) of each treatment group.	To compare time to SCC, in days, of each treatment group.	Baseline to 12 months post randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the positron emission tomography/computerized axial tomography (PET/CT) imaging response over the course of treatment	Positron emission tomography/computerized axial tomography (PET/CT) imaging changes over the course of treatment, using quantitative scan assessment.	Baseline to Week 26
Evaluate the ribosomal ribonucleic acid synthesis ratio (RS ratio) decline in sputum	The decline of ribosomal ribonucleic acid synthesis ratio (RS ratio - a ratio of spacers between the mRNA) in sputum over the course of trial.	Baseline to 12 months post randomization
Assess whole blood transcriptomic signatures previously associated with TB cure from serum	The change in whole blood transcriptomic signatures over the course of treatment will be evaluated using ROC curves for association with microbiological and clinical response.	Screening to 12 months post randomization
The proportion of participants with favorable outcome at 12 months post randomization	The proportion of subjects with favorable outcome as compared to the 6 months post end of treatment and at 12 months post randomization.	Baseline to 12 months post randomization
Number of participants with relapse at 12 months post randomization	Proportion of participants with relapse at 12 months post randomization.	Baseline to 12 months post randomization

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Collaborators: Bill and Melinda Gates Foundation

Publications and helpful links

General Publications

• Dawson R, Diacon AH, Takuva S, Liu Y, Zheng B, Karwe V, Hafkin J. Quabodepistat in combination with delamanid and bedaquiline in participants with drug-susceptible pulmonary tuberculosis: protocol for a multicenter, phase 2b/c, open-label, randomized, dose-finding trial to evaluate safety and efficacy. Trials. 2024 Jan 19;25(1):70. doi: 10.1186/s13063-024-07912-5.

Helpful Links

• Otsuka Clinical Trial Website:
• Otsuka Clinical Trial Transparency:

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2022
• Primary Completion (Actual): April 8, 2024
• Study Completion (Actual): May 19, 2024

Study Registration Dates

• First Submitted: August 20, 2021
• First Submitted That Met QC Criteria: January 21, 2022
• First Posted (Actual): February 3, 2022

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Polycyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Rifamycins; Lactams, Macrocyclic; Macrocyclic Compounds; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Rifampin; Isoniazid; bedaquiline; OPC-67683
• Other Study ID Numbers: 323-201-00006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
• IPD Sharing Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• IPD Sharing Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No