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

Otsuka

Status and phase: Completed; Phase 2; Phase 1

Conditions: Pulmonary TB

Treatments: Drug: 30 mg OPC-167832 + 300 mg delamanid; Drug: 30 mg OPC-167832 + 300 mg delamanid + 400 mg BDQ; Drug: 30 mg OPC-167832; Drug: 90 mg OPC-167832; Drug: 30 mg OPC-167832 + 400 mg BDQ; Drug: 10 mg OPC-167832; Drug: RHEZ; Drug: 3 mg OPC-167832

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03678688

OPP1178898 (Other Grant/Funding Number)

323-201-00003

Details and patient eligibility

About

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).

Enrollment: 122 patients

Sex: All

Ages: 18 to 64 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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122 participants in 9 patient groups

Stage 1: RHEZ

Active Comparator group

Description:

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.

Treatment:

Drug: RHEZ

Stage 1: 10 mg OPC-167832

Experimental group

Description:

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.

Treatment:

Drug: 10 mg OPC-167832

Stage 1: 30 mg OPC-167832

Experimental group

Description:

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.

Treatment:

Drug: 30 mg OPC-167832

Stage 1: 90 mg OPC-167832

Experimental group

Description:

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.

Treatment:

Drug: 90 mg OPC-167832

Stage 1: 3 mg OPC-167832

Experimental group

Description:

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.

Treatment:

Drug: 3 mg OPC-167832

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

Experimental group

Description:

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.

Treatment:

Drug: 30 mg OPC-167832 + 300 mg delamanid

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

Experimental group

Description:

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.

Treatment:

Drug: 30 mg OPC-167832 + 400 mg BDQ

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

Experimental group

Description:

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.

Treatment:

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

Stage 2: RHEZ

Active Comparator group

Description:

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.

Treatment:

Drug: RHEZ