A Phase 1/2 Trial of Multiple Oral Doses of OPC-167832 for Uncomplicated Pulmonary Tuberculosis

NCT ID: NCT03678688

Last Updated: 2023-11-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 122 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-18
• Study Completion Date: 2022-03-11

Brief Summary

This trial will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of multiple oral doses of OPC-167832 in participants with uncomplicated, smear-positive, drug-susceptible pulmonary tuberculosis (TB).

Conditions

Pulmonary TB

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Stage 1: RHEZ

Participants received a single dose of RHEZ (each tablet containing 150 milligrams (mg) rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol), orally, once daily (QD) from Day 1 through Day 20.

Group Type: ACTIVE_COMPARATOR

RHEZ

Intervention Type: DRUG

RHEZ was used in both Stage 1 and Stage 2. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Participants received a single-dose from Day 1 through Day 20. The total number of tablets per day was based on the pretreatment body weight:

• Participants weighing 30 to 37 kg received 2 tablets per day
• Participants weighing 38 to 54 kg received 3 tablets per day
• Participants weighing 55 to 70 kg received 4 tablets per day
• Participants weighing > 70 kg received 5 tablets per day

Stage 1: 10 mg OPC-167832

Participants received OPC-167832, 10 mg, orally, QD, from Day 1 through Day 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.

Group Type: EXPERIMENTAL

10 mg OPC-167832

Intervention Type: DRUG

Once daily oral dose of 10 mg OPC-167832 from Day 1 through Day 14.

Stage 1: 30 mg OPC-167832

Participants received OPC-167832, 30 mg, orally, QD from Day 1 through Day 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.

Group Type: EXPERIMENTAL

30 mg OPC-167832

Intervention Type: DRUG

Once daily oral dose of 30 mg OPC-167832 from Day 1 through Day 14.

Stage 1: 90 mg OPC-167832

Participants received OPC-167832, 90 mg, orally, QD from Day 1 through Day 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.

Group Type: EXPERIMENTAL

90 mg OPC-167832

Intervention Type: DRUG

Once daily oral dose of 90 mg OPC-167832 from Day 1 through Day 14.

Stage 1: 3 mg OPC-167832

Participants received OPC-167832, 3 mg, orally, QD from Day 1 through Day 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.

Group Type: EXPERIMENTAL

3 mg OPC-167832

Intervention Type: DRUG

Once daily oral dose of 3 mg OPC-167832 from Day 1 through Day 14.

Stage 2: 30 mg OPC-167832 + 300 mg Delamanid

Participants received OPC-167832, 30 mg, in combination with delamanid, 300 mg, orally, QD from Day 1 through Day 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.

Group Type: EXPERIMENTAL

30 mg OPC-167832 + 300 mg delamanid

Intervention Type: DRUG

Once daily oral dose of 30 mg OPC-167832 plus 300 mg delamanid from Day 1 through Day 14.

Stage 2: 30 mg OPC-167832 + 400 mg Bedaquiline (BDQ)

Participants received OPC-167832, 30 mg, in combination with BDQ, orally, QD, from Day 1 through Day 14. Participants received a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. BDQ was then administered at a dose of 400 mg, QD, orally from Days 3 to 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.

Group Type: EXPERIMENTAL

30 mg OPC-167832 + 400 mg BDQ

Intervention Type: DRUG

Once daily oral dose of 30 mg OPC-167832 plus 400 mg BDQ from Day 1 through Day 14. Participants received a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. The dose of BDQ was 400 mg QD for Days 3 to 14.

Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ

Participants received OPC-167832, 30 mg, in combination with delamanid, 300 mg and BDQ, 400 mg, orally, QD, from Day 1 through Day 14. Participants received a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. BDQ was then administered at a dose of 400 mg, orally, QD from Days 3 to 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.

Group Type: EXPERIMENTAL

30 mg OPC-167832 + 300 mg delamanid + 400 mg BDQ

Intervention Type: DRUG

Once daily oral dose of 30 mg OPC-167832 plus 300 mg delamanid plus 400 mg BDQ from Day 1 through Day 14. Participants received a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. The dose of BDQ was 400 mg QD for Days 3 to 14.

Stage 2: RHEZ

Participants received a single dose of RHEZ (each tablet containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol), orally, QD, from Day 1 through Day 20.

Group Type: ACTIVE_COMPARATOR

RHEZ

Intervention Type: DRUG

RHEZ was used in both Stage 1 and Stage 2. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Participants received a single-dose from Day 1 through Day 20. The total number of tablets per day was based on the pretreatment body weight:

• Participants weighing 30 to 37 kg received 2 tablets per day
• Participants weighing 38 to 54 kg received 3 tablets per day
• Participants weighing 55 to 70 kg received 4 tablets per day
• Participants weighing > 70 kg received 5 tablets per day

Interventions

10 mg OPC-167832

Once daily oral dose of 10 mg OPC-167832 from Day 1 through Day 14.

Intervention Type: DRUG

30 mg OPC-167832

Once daily oral dose of 30 mg OPC-167832 from Day 1 through Day 14.

Intervention Type: DRUG

90 mg OPC-167832

Once daily oral dose of 90 mg OPC-167832 from Day 1 through Day 14.

Intervention Type: DRUG

3 mg OPC-167832

Once daily oral dose of 3 mg OPC-167832 from Day 1 through Day 14.

Intervention Type: DRUG

RHEZ

RHEZ was used in both Stage 1 and Stage 2. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Participants received a single-dose from Day 1 through Day 20. The total number of tablets per day was based on the pretreatment body weight:

• Participants weighing 30 to 37 kg received 2 tablets per day
• Participants weighing 38 to 54 kg received 3 tablets per day
• Participants weighing 55 to 70 kg received 4 tablets per day
• Participants weighing > 70 kg received 5 tablets per day

Intervention Type: DRUG

30 mg OPC-167832 + 300 mg delamanid

Once daily oral dose of 30 mg OPC-167832 plus 300 mg delamanid from Day 1 through Day 14.

Intervention Type: DRUG

30 mg OPC-167832 + 400 mg BDQ

Once daily oral dose of 30 mg OPC-167832 plus 400 mg BDQ from Day 1 through Day 14. Participants received a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. The dose of BDQ was 400 mg QD for Days 3 to 14.

Intervention Type: DRUG

30 mg OPC-167832 + 300 mg delamanid + 400 mg BDQ

Once daily oral dose of 30 mg OPC-167832 plus 300 mg delamanid plus 400 mg BDQ from Day 1 through Day 14. Participants received a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. The dose of BDQ was 400 mg QD for Days 3 to 14.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Able to provide written, informed consent prior to initiation of any trial-related procedures, and able, in the opinion of the investigator, to comply with all the requirements of the trial.
• Male or female participants between 18 and 64 years of age (inclusive) at the screening visit.
• Body mass index ≥ 16.0 and ≤ 32.0 kilograms per meters squared (kg/m^2) (inclusive) at the screening visit.
• Newly diagnosed, uncomplicated, drug-susceptible pulmonary TB.
• Microscopy performed on a sputum smear at screening indicates presence of acid-fast bacilli (at least 1+).
• Able to produce an adequate volume of sputum (approximately 10 millilitres (mL) or more estimated overnight production).
• Female participants of childbearing potential must agree to use 2 different approved methods of birth control or remain abstinent throughout the participation in the trial and for 12 weeks after the last dose of trial treatment (investigational medicinal product (IMP) or RHEZ).
• Male participants must agree to use 2 different approved methods of birth control or remain abstinent throughout the participation in the trial and for 12 weeks after the last dose of trial treatment (IMP or RHEZ).

Exclusion Criteria

• Participants are known or suspected of having resistance to rifampicin, isoniazid, ethambutol, or pyrazinamide using any combination of Xpert Mycobacterium tuberculosis/Rifampin (MTB/RIF), line probe assay, culture, and/or epidemiologic history at screening.
• Poor general condition where no delay in treatment can be tolerated or where immediate hospital admission is warranted.
• Evidence of clinically significant metabolic (including ongoing or current hypokalemia), gastrointestinal, neurological, psychiatric, endocrine or liver (e.g., hepatitis B and C) disease; malignancy; or other abnormalities (other than the indication being studied).
• History of or current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, hypertension, arrhythmia or symptom strongly suggestive of such a problem (for example, syncope or palpitations), tachyarrhythmia or status after myocardial infarction.
• Known bleeding disorders or family history of bleeding disorders.
• Any diseases or conditions in which the use of delamanid, rifampicin, isoniazid, pyrazinamide, ethambutol, or Bedaquiline is contraindicated.
• Any prior treatment for M. tuberculosis within the past 3 years.
• Any treatment with a drug active against M. tuberculosis (e.g., quinolones) within the 3 months prior to screening.
• Clinical evidence of severe extrapulmonary TB (e.g., miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis).
• 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.
• Any renal impairment characterized by serum creatinine clearance of <60 millilitres per minute (mL/min), or hepatic impairment characterized by alanine transaminase, aspartate transaminase, or total bilirubin >1.5 x upper limit of normal (ULN) of the clinical laboratory reference range at screening.
• For Stage 1, participants who are human immunodeficiency virus (HIV) positive are excluded. For Stage 2, participants with HIV co-infection who are on antiretroviral drugs during screening or with CD4 cell count <500/ millimeters cubed (mm^3) are excluded.
• Changes in the electrocardiogram (ECG) such as QTcF >450 milliseconds (msec), atrioventricular block II or III, bi-fasicular block, at screening or current history of clinically significant ventricular arrhythmias. Other ECG changes if considered clinically significant by the investigator.
• Participants receiving any of the prohibited medications within the specified periods or who would be likely to require prohibited concomitant therapy during the trial.
• 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.
• History of significant drug and/or alcohol abuse within 2 years prior to screening.
• History of or current hepatitis or carriers of HBsAg and/or anti-HCV.
• Positive urine or blood alcohol test and/or urine drug screen for substance abuse at screening (not including cannabinoids).
• History of having taken an investigational drug within 30 days preceding trial entry (ie, prior to screening).
• A history of difficulty in donating blood.
• Donation of blood or plasma within 30 days prior to dosing.
• Consumption of alcohol and/or grapefruit, grapefruit juice, Seville oranges, or Seville orange juice and related products within 72 hours prior to the first dose of IMP or RHEZ on Day 1.
• History of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial.
• Any known prior exposure to OPC-167832, delamanid or Bedaquiline.
• Participants with significant medical comorbidities that in the opinion of the investigator, should not participate in the trial.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bill and Melinda Gates Foundation

OTHER

Sponsor Role: collaborator

Otsuka Pharmaceutical Development & Commercialization, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Veronique R de Jager, MD

Role: PRINCIPAL_INVESTIGATOR

TASK Clinical Research Centre

Prof. Rodney Dawson, MD

Role: PRINCIPAL_INVESTIGATOR

University of Cape Town (Pty) Ltd.

Prof. Andreas Diacon

Role: PRINCIPAL_INVESTIGATOR

TASK Clinical Research Centre (TCRC)

Locations

University of Cape Town (Pty) Ltd.

Cape Town, Mowbray, South Africa

Satellite Site: Task at Brooklyn Chest Hospital

Cape Town, , South Africa

TASK Clinical Research Centre

Cape Town, , South Africa

Countries

South Africa

References

Dawson R, Diacon AH, De Jager V, Narunsky K, Moodley VM, Stinson KW, Liu Y, Zheng B, Hafkin J. Safety, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both in adults with pulmonary tuberculosis: a randomised, active-controlled, open-label trial. Lancet Infect Dis. 2025 Apr;25(4):435-444. doi: 10.1016/S1473-3099(24)00601-7. Epub 2024 Nov 26.

Reference Type: DERIVED

PMID: 39612928 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

OPP1178898

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

323-201-00003

Identifier Type: -

Identifier Source: org_study_id