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

A Phase 1/2, Active-controlled, Randomized, Open-label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Multiple Oral Doses of OPC-167832 Tablets in Subjects With Uncomplicated, Smear-positive, Drug-susceptible Pulmonary Tuberculosis

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).

Study Overview

• Status: Completed
• Conditions: Pulmonary TB
• Intervention / Treatment: Drug: 10 mg OPC-167832; Drug: 30 mg OPC-167832; Drug: 90 mg OPC-167832; Drug: 3 mg OPC-167832; Drug: RHEZ; Drug: 30 mg OPC-167832 + 300 mg delamanid; Drug: 30 mg OPC-167832 + 400 mg BDQ; Drug: 30 mg OPC-167832 + 300 mg delamanid + 400 mg BDQ

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• South Africa
  • Cape Town, South Africa, 7405
    • Satellite Site: Task at Brooklyn Chest Hospital
  • Cape Town, South Africa, 7530
    • Task Clinical Research Centre
  • Mowbray
    • Cape Town, Mowbray, South Africa, 7700
      • University of Cape Town (Pty) Ltd.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	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
Experimental: 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.	Drug: 10 mg OPC-167832; Once daily oral dose of 10 mg OPC-167832 from Day 1 through Day 14.
Experimental: 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.	Drug: 30 mg OPC-167832; Once daily oral dose of 30 mg OPC-167832 from Day 1 through Day 14.
Experimental: 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.	Drug: 90 mg OPC-167832; Once daily oral dose of 90 mg OPC-167832 from Day 1 through Day 14.
Experimental: 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.	Drug: 3 mg OPC-167832; Once daily oral dose of 3 mg OPC-167832 from Day 1 through Day 14.
Experimental: 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.	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.
Experimental: 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.	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.
Experimental: 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.	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.
Active Comparator: 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.	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1: Change From Baseline in TB Bacterial Load in Sputum as a Measure of Early Bactericidal Activity (EBA)	Bacterial load in sputum at each collection time point was measured by CFU counts on agar media culture. EBA was determined by the rate of decline per day in log10CFU/mL during the first 14 days of treatment. Change from baseline in log 10 CFU was calculated as post-baseline minus baseline. A larger EBA in positive direction indicates a better drug effect.	Baseline to Day 14
Stage 1 and Stage 2: Maximum (Peak) Plasma Concentration (Cmax) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 1 and Stage 2: Cmax at Steady-state (Cmax,ss) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Time to Cmax (Tmax) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Area Under the Concentration-Time Curve (AUC) From Time Zero to Time t (the Last Observable Concentration, Here t=24) (AUC0-24), for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 1 and Stage 2: AUC Calculated Over the Dosing Interval at Steady-state (AUCτ) for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Terminal-phase Elimination Half-life (t1/2,z) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)	T1/2,z is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose. Half-life (T1/2) is determined in the terminal phase after drug administration, which is calculated from the relationship T1/2 = ln2/λz where λz is the terminal-phase slope obtainable from non-compartmental analysis (NCA). The values reported for this outcome measure (OM) are estimates and not actual observed data.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Apparent Clearance From Plasma at Steady-state (CLss/F) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Accumulation Ratio of Cmax (RCmax) for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Accumulation Ratio of AUC (RAUC) for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Cmax Normalized to Dose (Cmax/Dose) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUCτ Normalized to Dose (AUCτ/Dose) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Cmax of Delamanid		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: Cmax,ss of Delamanid		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Tmax of Delamanid		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: Tmax of Delamanid		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUC0-24 of Delamanid		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: AUCτ of Delamanid		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: T1/2,z of Delamanid	T1/2,z is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose. Half-life (T1/2) is determined in the terminal phase after drug administration, which is calculated from the relationship T1/2 = ln2/λz where λz is the terminal-phase slope obtainable using the NCA method. The values reported for this OM are estimates and not actual observed data.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: CLss/F of Delamanid From Plasma		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: RCmax of Delamanid		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: RAUC of Delamanid		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Cmax/Dose of Delamanid		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUCτ/Dose of Delamanid		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Cmax of Bedaquiline		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: Cmax,ss of Bedaquiline		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Tmax of Bedaquiline		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: Tmax of Bedaquiline		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUC0-24 of Bedaquiline		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: AUCτ of Bedaquiline		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: T1/2,z of Bedaquiline	T1/2,z is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose. Half-life (T1/2) is determined in the terminal phase after drug administration, which is calculated from the relationship T1/2 = ln2/λz where λz is the terminal-phase slope obtainable using the NCA method. The values reported for this OM are estimates and not actual observed data. Hence, the value might not lie within the sampling timepoints provided in the timeframe.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: CLss/F of BDQ From Plasma		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Cmax/Dose of Bedaquiline		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUCτ/Dose of Bedaquiline		Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs)	An AE is defined as any untoward medical occurrence in a clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAEs were all AEs which started after the start of randomized study drug treatment or if the event was continuous from baseline and was serious, study drug-related, or resulted in death, discontinuation, interruption, or reduction of study therapy.	From first dose of study drug to end of follow up period (up to 34 days)
Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values		From first dose of study drug to end of follow up period (up to 34 days)
Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters		From first dose of study drug to end of follow up period (up to 34 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System	LAM is a key component of the M. tuberculosis cell wall and the decline of sputum LAM concentrations has been shown to correlate closely with CFU decreases in sputum counted on agar media during the first 14 days of TB treatment. Sputum LAM concentration at each collection time point was measured using MGIT system. Baseline LAM was calculated as the log 10 of the average from Day -2 and Day -1 and the change from baseline in log10 was calculated as post-baseline minus baseline for each parameter.	Baseline to Day 14
Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System	TTD is the time from start of inoculation of a sputum sample until a MGIT machine detects a positive signal during the 42-day incubation period. One TTD measurement, reported in days and hours was taken at each of the visits at Days -2, -1, 2, 4, 6, 8, 10, 12 and 14. TTD values were then calculated as "days + hours/24" to be used in deriving the analysis values of TTD. Each sample collected from Day -2 to Day 14 were inoculated for 42 days. Baseline TTD was derived using Day -2 and Day -1 MGIT culture with a pure positive result for Mycobacterium tuberculosis. Postbaseline TTD analysis values from Day 1 were derived based on the MGIT culture result as follows: If MGIT culture result was negative for MTB complex, TTD was set to 42 days; If the MGIT culture was pure positive for MTB, but the TTD took longer than 42 days, TTD was capped at 42 days.	Day 1 to Day 14 of treatment period + 42 days of inoculation period (up to 56 days)
Stage 2: Change From Baseline in TB Bacterial Load in Sputum as a Measure of EBA	Bacterial load in sputum at each collection time point was measured by CFU counts on agar media culture. EBA was determined by the rate of decline per day in log10CFU/mL during the first 14 days of treatment. Change from baseline in log 10 CFU was calculated as post-baseline minus baseline. A larger EBA in positive direction indicates a better drug effect.	Baseline to Day 14
Stage 2: Plasma Concentration of Rifampin		2 hours and 6 hours post-dose on Day 14
Stage 1: Plasma Concentration of Isoniazid		2 hours and 6 hours post-dose on Day 14
Stage 2: Cmax of DM-6705	DM-6705 is a metabolite of delamanid.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: Cmax,ss of DM-6705	DM-6705 is a metabolite of delamanid.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Tmax of DM-6705	DM-6705 is a metabolite of delamanid.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUC0-24 for DM-6705	DM-6705 is a metabolite of delamanid.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: T1/2,z of DM-6705	T1/2,z is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose. Half-life (T1/2) was determined in the terminal phase after drug administration, which was calculated from the relationship T1/2 = ln2/λz where λz is the terminal-phase slope obtainable using the NCA method. The values reported for this OM are estimates and not actual observed data. Hence, the value might not lie within the sampling timepoints provided in the timeframe.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Cmax of N-Desmethyl Bedaquiline	N-Desmethyl Bedaquiline is a metabolite of BDQ.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: Cmax,ss of N-Desmethyl Bedaquiline	N-Desmethyl Bedaquiline is a metabolite of BDQ.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Tmax of N-Desmethyl Bedaquiline	N-Desmethyl Bedaquiline is a metabolite of BDQ.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours (±15 minutes) postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUC0-24 for N-Desmethyl Bedaquiline	N-Desmethyl Bedaquiline is a metabolite of BDQ.	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Number of Participants With TEAEs on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline	An AE is defined as any untoward medical occurrence in a clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAEs were all adverse events which started after the start of randomized study drug treatment or if the event was continuous from baseline and was serious, study drug-related, or resulted in death, discontinuation, interruption, or reduction of study therapy.	From first dose of study drug to end of follow up period (up to 34 days)
Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline		From first dose of study drug to end of follow up period (up to 34 days)
Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline		From first dose of study drug to end of follow up period (up to 34 days)

Other Outcome Measures

Outcome Measure	Time Frame
Correlation of QT Interval and Plasma Concentrations of OPC-167832 and/or Delamanid and/or Bedaquiline	Day 1 and Day 14

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Collaborators: Bill and Melinda Gates Foundation
• Investigators: Principal Investigator: Veronique R de Jager, MD, Task Clinical Research Centre; Principal Investigator: Prof. Rodney Dawson, MD, University of Cape Town (Pty) Ltd.; Principal Investigator: Prof. Andreas Diacon, TASK Clinical Research Centre (TCRC)

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2018
• Primary Completion (Actual): February 14, 2022
• Study Completion (Actual): March 11, 2022

Study Registration Dates

• First Submitted: September 18, 2018
• First Submitted That Met QC Criteria: September 19, 2018
• First Posted (Actual): September 20, 2018

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: October 27, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Anti-Infective Agents; Anti-Bacterial Agents; Antitubercular Agents; Bedaquiline; Diarylquinolines
• Other Study ID Numbers: 323-201-00003; OPP1178898 (Other Grant/Funding Number: Bill and Melinda Gates Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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