Pulmonary TB
Conditions
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).
Interventions
DRUG10 mg OPC-167832
Once daily oral dose of 10 mg OPC-167832 from Day 1 through Day 14.
DRUG30 mg OPC-167832
Once daily oral dose of 30 mg OPC-167832 from Day 1 through Day 14.
DRUG90 mg OPC-167832
Once daily oral dose of 90 mg OPC-167832 from Day 1 through Day 14.
DRUG3 mg OPC-167832
Once daily oral dose of 3 mg OPC-167832 from Day 1 through Day 14.
DRUGRHEZ
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
DRUG30 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.
DRUG30 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.
DRUG30 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.
Sponsors
Bill and Melinda Gates Foundation
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This will be a multiple-dose trial of OPC-167832 with 2 stages. Stage 1 is a multiple ascending dose trial planned to be conducted in 4 sequential cohorts of 18 participants each. There will be 2 arms (OPC-167832, combination of rifampicin, isoniazid, ethambutol, and pyrazinamide (RHEZ)) in each cohort. Stage 2 will be a parallel group comparison of 4 treatment regimens: 1) OPC-167832 plus Delamanid 2) OPC-167832 plus Bedaquiline 3) OPC-167832 plus Delamanid plus Bedaquiline 4) RHEZ.
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | — |
| 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 | 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 | 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. |
| 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: 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 | 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 | 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. |
| 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) | From first dose of study drug to end of follow up period (up to 34 days) | 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. |
| 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 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 1: Change From Baseline in TB Bacterial Load in Sputum as a Measure of Early Bactericidal Activity (EBA) | Baseline to Day 14 | 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. |
| 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) | 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 | 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. |
| 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: 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: AUC0-24 of Delamanid | Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Baseline to Day 14 | 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. |
| Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System | Day 1 to Day 14 of treatment period + 42 days of inoculation period (up to 56 days) | 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. |
| Stage 2: Change From Baseline in TB Bacterial Load in Sputum as a Measure of EBA | Baseline to Day 14 | 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. |
| 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 | Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1 | DM-6705 is a metabolite of delamanid. |
| Stage 2: Cmax,ss of DM-6705 | 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 | DM-6705 is a metabolite of delamanid. |
| Stage 2: Tmax of DM-6705 | 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 | DM-6705 is a metabolite of delamanid. |
| Stage 2: AUC0-24 for DM-6705 | 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 | DM-6705 is a metabolite of delamanid. |
| Stage 2: T1/2,z of DM-6705 | 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 | 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. |
| Stage 2: Cmax of N-Desmethyl Bedaquiline | Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1 | N-Desmethyl Bedaquiline is a metabolite of BDQ. |
| Stage 2: Cmax,ss of N-Desmethyl 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 | N-Desmethyl Bedaquiline is a metabolite of BDQ. |
| Stage 2: Tmax of N-Desmethyl Bedaquiline | 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 | N-Desmethyl Bedaquiline is a metabolite of BDQ. |
| Stage 2: AUC0-24 for N-Desmethyl Bedaquiline | 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 | N-Desmethyl Bedaquiline is a metabolite of BDQ. |
| Stage 2: Number of Participants With TEAEs 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) | 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. |
| 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
| Measure | Time frame |
|---|---|
| Correlation of QT Interval and Plasma Concentrations of OPC-167832 and/or Delamanid and/or Bedaquiline | Day 1 and Day 14 |
Countries
South Africa
Participant flow
Recruitment details
Participants took part in this study at two investigative sites in South Africa from 18 October 2018 to 11 March 2022.
Pre-assignment details
Participants with uncomplicated, smear-positive, drug-susceptible pulmonary tuberculosis were enrolled in two stages. Stage 1: A total of 76 participants were randomized in 4 cohorts to receive either OPC-167832 10 milligrams (mg), 30 mg, 90 mg & 3 mg or a combination of rifampicin, isoniazid, ethambutol, and pyrazinamide (RHEZ). Stage 2: A total of 46 participants were randomized in 4 groups to receive OPC-167832+delamanid, OPC-167832+bedaquilline (BDQ), OPC-167832+delamanid+BDQ or RHEZ.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 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. | 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. | 17 |
| 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. | 14 |
| Stage 1: 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. | 17 |
| 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. | 14 |
| Stage 2: 30 mg OPC-167832 + 400 mg 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. | 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. | 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. | 4 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Covid Related Adverse Event | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 1 | 0 |
| Overall Study | Non-Covid Related Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Reason not Specified | 0 | 0 | 3 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Stage 1: 10 mg OPC-167832 | Total | Stage 2: RHEZ | Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 2: 30 mg OPC-167832 + 300 mg Delamanid | Stage 1: RHEZ | Stage 1: 3 mg OPC-167832 | Stage 1: 90 mg OPC-167832 | Stage 1: 30 mg OPC-167832 |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 31.7 years STANDARD_DEVIATION 14.6 | 33.4 years STANDARD_DEVIATION 11.9 | 31.3 years STANDARD_DEVIATION 9.5 | 30.1 years STANDARD_DEVIATION 8.2 | 29.8 years STANDARD_DEVIATION 8.9 | 34.1 years STANDARD_DEVIATION 9.9 | 33.4 years STANDARD_DEVIATION 10.9 | 37.2 years STANDARD_DEVIATION 15.6 | 36.2 years STANDARD_DEVIATION 13.3 | 34.9 years STANDARD_DEVIATION 12.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 118 Participants | 4 Participants | 14 Participants | 14 Participants | 14 Participants | 15 Participants | 14 Participants | 17 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants | 69 Participants | 3 Participants | 9 Participants | 10 Participants | 7 Participants | 8 Participants | 6 Participants | 11 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 6 Participants | 52 Participants | 1 Participants | 5 Participants | 4 Participants | 7 Participants | 9 Participants | 8 Participants | 5 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 4 Participants | 38 Participants | 1 Participants | 4 Participants | 2 Participants | 2 Participants | 5 Participants | 4 Participants | 8 Participants | 8 Participants |
| Sex: Female, Male Male | 10 Participants | 84 Participants | 3 Participants | 10 Participants | 12 Participants | 12 Participants | 12 Participants | 10 Participants | 9 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 17 | 0 / 14 | 0 / 16 | 0 / 13 | 0 / 13 | 0 / 14 | 0 / 4 |
| other Total, other adverse events | 10 / 14 | 13 / 14 | 13 / 17 | 10 / 14 | 15 / 16 | 9 / 13 | 11 / 13 | 9 / 14 | 3 / 4 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 17 | 1 / 14 | 0 / 16 | 0 / 13 | 2 / 13 | 0 / 14 | 0 / 4 |
Outcome results
Primary
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)
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 1.99 ratio | Standard Deviation 0.55 |
| Stage 1: 30 mg OPC-167832 | 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) | 1.60 ratio | Standard Deviation 0.289 |
| Stage 1: 90 mg OPC-167832 | 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) | 2.01 ratio | Standard Deviation 0.565 |
| Stage 1: 3 mg OPC-167832 | 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) | 1.55 ratio | Standard Deviation 0.416 |
| Stage 1: RHEZ | 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) | 1.70 ratio | Standard Deviation 0.378 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 1.47 ratio | Standard Deviation 0.314 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 1.36 ratio | Standard Deviation 0.237 |
Primary
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)
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 1.39 ratio | Standard Deviation 0.381 |
| Stage 1: 30 mg OPC-167832 | 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) | 1.26 ratio | Standard Deviation 0.167 |
| Stage 1: 90 mg OPC-167832 | 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) | 1.56 ratio | Standard Deviation 0.399 |
| Stage 1: 3 mg OPC-167832 | 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) | 1.36 ratio | Standard Deviation 0.362 |
| Stage 1: RHEZ | 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) | 1.34 ratio | Standard Deviation 0.349 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 1.23 ratio | Standard Deviation 0.191 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 1.30 ratio | Standard Deviation 0.244 |
Primary
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)
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 164 mL/minute (min) | Standard Deviation 62.6 |
| Stage 1: 30 mg OPC-167832 | 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) | 195 mL/minute (min) | Standard Deviation 28.8 |
| Stage 1: 90 mg OPC-167832 | 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) | 231 mL/minute (min) | Standard Deviation 91.8 |
| Stage 1: 3 mg OPC-167832 | 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) | 272 mL/minute (min) | Standard Deviation 53.8 |
| Stage 1: RHEZ | 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) | 215 mL/minute (min) | Standard Deviation 61 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 269 mL/minute (min) | Standard Deviation 88.5 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 283 mL/minute (min) | Standard Deviation 103 |
Primary
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)
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 178 nanogram.hour per milliliter (ng*h/mL) | Standard Deviation 65.1 |
| Stage 1: 30 mg OPC-167832 | 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) | 569 nanogram.hour per milliliter (ng*h/mL) | Standard Deviation 102 |
| Stage 1: 90 mg OPC-167832 | 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) | 1290 nanogram.hour per milliliter (ng*h/mL) | Standard Deviation 532 |
| Stage 1: 3 mg OPC-167832 | 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) | 4050 nanogram.hour per milliliter (ng*h/mL) | Standard Deviation 1240 |
| Stage 1: RHEZ | 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) | 1450 nanogram.hour per milliliter (ng*h/mL) | Standard Deviation 392 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 1490 nanogram.hour per milliliter (ng*h/mL) | Standard Deviation 490 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 1420 nanogram.hour per milliliter (ng*h/mL) | Standard Deviation 378 |
Primary
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)
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 349 ng*h/mL | Standard Deviation 143 |
| Stage 1: 30 mg OPC-167832 | 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) | 874 ng*h/mL | Standard Deviation 127 |
| Stage 1: 90 mg OPC-167832 | 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) | 2490 ng*h/mL | Standard Deviation 928 |
| Stage 1: 3 mg OPC-167832 | 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) | 5690 ng*h/mL | Standard Deviation 1010 |
| Stage 1: RHEZ | 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) | 2500 ng*h/mL | Standard Deviation 709 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 2020 ng*h/mL | Standard Deviation 563 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 2000 ng*h/mL | Standard Deviation 730 |
Primary
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)
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 28.2 ng/mL | Standard Deviation 10.9 |
| Stage 1: 30 mg OPC-167832 | 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) | 67.3 ng/mL | Standard Deviation 11.9 |
| Stage 1: 90 mg OPC-167832 | 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) | 190 ng/mL | Standard Deviation 63.6 |
| Stage 1: 3 mg OPC-167832 | 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) | 492 ng/mL | Standard Deviation 99.8 |
| Stage 1: RHEZ | 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) | 208 ng/mL | Standard Deviation 60.5 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 175 ng/mL | Standard Deviation 31.3 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 183 ng/mL | Standard Deviation 51.9 |
Primary
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)
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 9.42 (ng/mL)/mg | Standard Deviation 3.63 |
| Stage 1: 30 mg OPC-167832 | 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) | 6.73 (ng/mL)/mg | Standard Deviation 1.19 |
| Stage 1: 90 mg OPC-167832 | 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) | 6.34 (ng/mL)/mg | Standard Deviation 2.12 |
| Stage 1: 3 mg OPC-167832 | 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) | 5.46 (ng/mL)/mg | Standard Deviation 1.11 |
| Stage 1: RHEZ | 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) | 6.94 (ng/mL)/mg | Standard Deviation 2.02 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 5.85 (ng/mL)/mg | Standard Deviation 1.04 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 6.10 (ng/mL)/mg | Standard Deviation 1.73 |
Primary
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)
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 20.7 nanogram per milliliter (ng/mL) | Standard Deviation 6.92 |
| Stage 1: 30 mg OPC-167832 | 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) | 53.7 nanogram per milliliter (ng/mL) | Standard Deviation 9.16 |
| Stage 1: 90 mg OPC-167832 | 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) | 128 nanogram per milliliter (ng/mL) | Standard Deviation 50.5 |
| Stage 1: 3 mg OPC-167832 | 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) | 391 nanogram per milliliter (ng/mL) | Standard Deviation 116 |
| Stage 1: RHEZ | 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) | 157 nanogram per milliliter (ng/mL) | Standard Deviation 44.1 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 154 nanogram per milliliter (ng/mL) | Standard Deviation 39.6 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 140 nanogram per milliliter (ng/mL) | Standard Deviation 41.2 |
Primary
Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters
Time frame: From first dose of study drug to end of follow up period (up to 34 days)
Population: Safety Analysis Set included participants who were randomized and received any dose of IMP. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | Rhythm: Ventricular Premature Beat | 0 Participants |
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Myocardial Ischemia | 2 Participants |
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Symmetrical T-wave Inversion | 1 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Symmetrical T-wave Inversion | 0 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Myocardial Ischemia | 0 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | Rhythm: Ventricular Premature Beat | 1 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Symmetrical T-wave Inversion | 1 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | Rhythm: Ventricular Premature Beat | 1 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Myocardial Ischemia | 0 Participants |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Symmetrical T-wave Inversion | 0 Participants |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | Rhythm: Ventricular Premature Beat | 0 Participants |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Myocardial Ischemia | 0 Participants |
| Stage 1: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | Rhythm: Ventricular Premature Beat | 1 Participants |
| Stage 1: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Myocardial Ischemia | 0 Participants |
| Stage 1: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Symmetrical T-wave Inversion | 1 Participants |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Symmetrical T-wave Inversion | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | Rhythm: Ventricular Premature Beat | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Myocardial Ischemia | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Myocardial Ischemia | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | Rhythm: Ventricular Premature Beat | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Symmetrical T-wave Inversion | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Myocardial Ischemia | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | Rhythm: Ventricular Premature Beat | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Symmetrical T-wave Inversion | 0 Participants |
| Stage 2: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Symmetrical T-wave Inversion | 0 Participants |
| Stage 2: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | Rhythm: Ventricular Premature Beat | 0 Participants |
| Stage 2: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters | ST/T Morphology: Myocardial Ischemia | 0 Participants |
Primary
Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values
Time frame: From first dose of study drug to end of follow up period (up to 34 days)
Population: Safety Analysis Set included participants who were randomized and received any dose of IMP. Number analyzed is the number of participants with data available for analysis for each specified vital sign parameter.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Heart Rate: > 120 beats per minute (bpm) and >= 15 bpm Change from Baseline | 1 Participants |
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Diastolic Blood Pressure: < 50 mmHg and >= 15 mmHg Decrease from Baseline | 0 Participants |
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Systolic Blood Pressure: < 90 mmHg and >= 20 mmHg Decrease from Baseline | 1 Participants |
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Weight: >= 5% Increase from Baseline | 3 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Weight: >= 5% Increase from Baseline | 4 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Heart Rate: > 120 beats per minute (bpm) and >= 15 bpm Change from Baseline | 1 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Diastolic Blood Pressure: < 50 mmHg and >= 15 mmHg Decrease from Baseline | 1 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Systolic Blood Pressure: < 90 mmHg and >= 20 mmHg Decrease from Baseline | 3 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Diastolic Blood Pressure: < 50 mmHg and >= 15 mmHg Decrease from Baseline | 2 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Weight: >= 5% Increase from Baseline | 2 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Systolic Blood Pressure: < 90 mmHg and >= 20 mmHg Decrease from Baseline | 2 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Heart Rate: > 120 beats per minute (bpm) and >= 15 bpm Change from Baseline | 0 Participants |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Heart Rate: > 120 beats per minute (bpm) and >= 15 bpm Change from Baseline | 1 Participants |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Diastolic Blood Pressure: < 50 mmHg and >= 15 mmHg Decrease from Baseline | 1 Participants |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Systolic Blood Pressure: < 90 mmHg and >= 20 mmHg Decrease from Baseline | 2 Participants |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Weight: >= 5% Increase from Baseline | 1 Participants |
| Stage 1: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Systolic Blood Pressure: < 90 mmHg and >= 20 mmHg Decrease from Baseline | 0 Participants |
| Stage 1: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Diastolic Blood Pressure: < 50 mmHg and >= 15 mmHg Decrease from Baseline | 0 Participants |
| Stage 1: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Heart Rate: > 120 beats per minute (bpm) and >= 15 bpm Change from Baseline | 1 Participants |
| Stage 1: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Weight: >= 5% Increase from Baseline | 9 Participants |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Weight: >= 5% Increase from Baseline | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Heart Rate: > 120 beats per minute (bpm) and >= 15 bpm Change from Baseline | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Systolic Blood Pressure: < 90 mmHg and >= 20 mmHg Decrease from Baseline | 1 Participants |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Diastolic Blood Pressure: < 50 mmHg and >= 15 mmHg Decrease from Baseline | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Systolic Blood Pressure: < 90 mmHg and >= 20 mmHg Decrease from Baseline | 1 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Diastolic Blood Pressure: < 50 mmHg and >= 15 mmHg Decrease from Baseline | 2 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Weight: >= 5% Increase from Baseline | 5 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Heart Rate: > 120 beats per minute (bpm) and >= 15 bpm Change from Baseline | 1 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Diastolic Blood Pressure: < 50 mmHg and >= 15 mmHg Decrease from Baseline | 0 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Weight: >= 5% Increase from Baseline | 2 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Systolic Blood Pressure: < 90 mmHg and >= 20 mmHg Decrease from Baseline | 1 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Heart Rate: > 120 beats per minute (bpm) and >= 15 bpm Change from Baseline | 0 Participants |
| Stage 2: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Heart Rate: > 120 beats per minute (bpm) and >= 15 bpm Change from Baseline | 0 Participants |
| Stage 2: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Weight: >= 5% Increase from Baseline | 2 Participants |
| Stage 2: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Systolic Blood Pressure: < 90 mmHg and >= 20 mmHg Decrease from Baseline | 0 Participants |
| Stage 2: RHEZ | Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values | Diastolic Blood Pressure: < 50 mmHg and >= 15 mmHg Decrease from Baseline | 0 Participants |
Primary
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.
Time frame: From first dose of study drug to end of follow up period (up to 34 days)
Population: Safety Analysis Set included participants who were randomized and received any dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs) | 10 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs) | 13 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs) | 13 Participants |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs) | 11 Participants |
| Stage 1: RHEZ | Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs) | 15 Participants |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs) | 9 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs) | 11 Participants |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs) | 9 Participants |
| Stage 2: RHEZ | Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs) | 3 Participants |
Primary
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.
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 22.3 hours |
| Stage 1: 30 mg OPC-167832 | 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) | 15.3 hours |
| Stage 1: 90 mg OPC-167832 | 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) | 14.2 hours |
| Stage 1: 3 mg OPC-167832 | 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) | 14.4 hours |
| Stage 1: RHEZ | 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) | 14.4 hours |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 14.7 hours |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 11.2 hours |
Primary
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)
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 3.17 hours |
| Stage 1: 30 mg OPC-167832 | 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) | 4.15 hours |
| Stage 1: 90 mg OPC-167832 | 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) | 3.15 hours |
| Stage 1: 3 mg OPC-167832 | 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) | 3.25 hours |
| Stage 1: RHEZ | 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) | 2.83 hours |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 3.17 hours |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 3.83 hours |
Primary
Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2) | 3.17 hours |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2) | 3.15 hours |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2) | 3.13 hours |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2) | 3.17 hours |
| Stage 1: RHEZ | Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2) | 2.83 hours |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2) | 3.13 hours |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2) | 2.83 hours |
Primary
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.
Time frame: Baseline to Day 14
Population: MITT Analysis Set included randomized participants who were agar media culture positive at baseline (either at Day -2 or at Day -1, or both), received any dose of IMP, and had at least one post-baseline CFU count value. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 1: Change From Baseline in TB Bacterial Load in Sputum as a Measure of Early Bactericidal Activity (EBA) | -1.93 sputum log10CFU/mL | Standard Error 0.98 |
| Stage 1: 30 mg OPC-167832 | Stage 1: Change From Baseline in TB Bacterial Load in Sputum as a Measure of Early Bactericidal Activity (EBA) | -2.12 sputum log10CFU/mL | Standard Error 1.01 |
| Stage 1: 90 mg OPC-167832 | Stage 1: Change From Baseline in TB Bacterial Load in Sputum as a Measure of Early Bactericidal Activity (EBA) | -2.08 sputum log10CFU/mL | Standard Error 0.75 |
| Stage 1: 3 mg OPC-167832 | Stage 1: Change From Baseline in TB Bacterial Load in Sputum as a Measure of Early Bactericidal Activity (EBA) | -1.69 sputum log10CFU/mL | Standard Error 1.15 |
| Stage 1: RHEZ | Stage 1: Change From Baseline in TB Bacterial Load in Sputum as a Measure of Early Bactericidal Activity (EBA) | -2.79 sputum log10CFU/mL | Standard Error 0.96 |
95% CI: [0.485, 0.939]
95% CI: [0.467, 0.911]
95% CI: [0.517, 1.051]
95% CI: [0.497, 1.02]
95% CI: [0.567, 0.973]
95% CI: [0.547, 0.943]
95% CI: [0.353, 0.896]
95% CI: [0.338, 0.871]
Primary
Stage 2: AUC0-24 of Bedaquiline
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: AUC0-24 of Bedaquiline | 44900 ng*h/mL | Standard Deviation 12800 |
| Stage 1: 30 mg OPC-167832 | Stage 2: AUC0-24 of Bedaquiline | 47000 ng*h/mL | Standard Deviation 15600 |
Primary
Stage 2: AUC0-24 of Delamanid
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: AUC0-24 of Delamanid | 2140 ng.h/mL | Standard Deviation 613 |
| Stage 1: 30 mg OPC-167832 | Stage 2: AUC0-24 of Delamanid | 2440 ng.h/mL | Standard Deviation 957 |
Primary
Stage 2: AUCτ/Dose of Bedaquiline
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: AUCτ/Dose of Bedaquiline | 140 (ng*h/mL)/mg | Standard Deviation 40 |
| Stage 1: 30 mg OPC-167832 | Stage 2: AUCτ/Dose of Bedaquiline | 165 (ng*h/mL)/mg | Standard Deviation 48 |
Primary
Stage 2: AUCτ/Dose of Delamanid
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: AUCτ/Dose of Delamanid | 18.2 (ng*h/mL)/mg | Standard Deviation 5.4 |
| Stage 1: 30 mg OPC-167832 | Stage 2: AUCτ/Dose of Delamanid | 19.5 (ng*h/mL)/mg | Standard Deviation 7.71 |
Primary
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)
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | 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) | 116 (ng*h/mL)/mg | Standard Deviation 47.6 |
| Stage 1: 30 mg OPC-167832 | 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) | 87.4 (ng*h/mL)/mg | Standard Deviation 12.7 |
| Stage 1: 90 mg OPC-167832 | 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) | 82.8 (ng*h/mL)/mg | Standard Deviation 30.9 |
| Stage 1: 3 mg OPC-167832 | 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) | 63.3 (ng*h/mL)/mg | Standard Deviation 11.2 |
| Stage 1: RHEZ | 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) | 83.5 (ng*h/mL)/mg | Standard Deviation 23.6 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | 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) | 67.2 (ng*h/mL)/mg | Standard Deviation 18.8 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | 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) | 66.5 (ng*h/mL)/mg | Standard Deviation 24.3 |
Primary
Stage 2: AUCτ of Bedaquiline
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: AUCτ of Bedaquiline | 55900 ng*h/mL | Standard Deviation 16000 |
| Stage 1: 30 mg OPC-167832 | Stage 2: AUCτ of Bedaquiline | 66000 ng*h/mL | Standard Deviation 19200 |
Primary
Stage 2: AUCτ of Delamanid
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: AUCτ of Delamanid | 5460 ng*h/mL | Standard Deviation 1620 |
| Stage 1: 30 mg OPC-167832 | Stage 2: AUCτ of Delamanid | 5860 ng*h/mL | Standard Deviation 2310 |
Primary
Stage 2: CLss/F of BDQ From Plasma
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: CLss/F of BDQ From Plasma | 140 mL/min | Standard Deviation 85.9 |
| Stage 1: 30 mg OPC-167832 | Stage 2: CLss/F of BDQ From Plasma | 109 mL/min | Standard Deviation 31.4 |
Primary
Stage 2: CLss/F of Delamanid From Plasma
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: CLss/F of Delamanid From Plasma | 983 mL/min | Standard Deviation 264 |
| Stage 1: 30 mg OPC-167832 | Stage 2: CLss/F of Delamanid From Plasma | 966 mL/min | Standard Deviation 330 |
Primary
Stage 2: Cmax/Dose of Bedaquiline
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Cmax/Dose of Bedaquiline | 12.6 (ng/mL)/mg | Standard Deviation 4.62 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Cmax/Dose of Bedaquiline | 15.2 (ng/mL)/mg | Standard Deviation 4.14 |
Primary
Stage 2: Cmax/Dose of Delamanid
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Cmax/Dose of Delamanid | 1.34 (ng/mL)/mg | Standard Deviation 0.339 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Cmax/Dose of Delamanid | 1.47 (ng/mL)/mg | Standard Deviation 0.625 |
Primary
Stage 2: Cmax of Bedaquiline
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Cmax of Bedaquiline | 5150 ng/mL | Standard Deviation 1860 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Cmax of Bedaquiline | 5750 ng/mL | Standard Deviation 2320 |
Primary
Stage 2: Cmax of Delamanid
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Cmax of Delamanid | 181 ng/mL | Standard Deviation 41.8 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Cmax of Delamanid | 198 ng/mL | Standard Deviation 57.5 |
Primary
Stage 2: Cmax,ss of Bedaquiline
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Cmax,ss of Bedaquiline | 5030 ng/mL | Standard Deviation 1850 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Cmax,ss of Bedaquiline | 6080 ng/mL | Standard Deviation 1660 |
Primary
Stage 2: Cmax,ss of Delamanid
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Cmax,ss of Delamanid | 401 ng/mL | Standard Deviation 102 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Cmax,ss of Delamanid | 442 ng/mL | Standard Deviation 188 |
Primary
Stage 2: RAUC of Delamanid
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: RAUC of Delamanid | 2.69 ratio | Standard Deviation 0.683 |
| Stage 1: 30 mg OPC-167832 | Stage 2: RAUC of Delamanid | 2.49 ratio | Standard Deviation 0.897 |
Primary
Stage 2: RCmax of Delamanid
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: RCmax of Delamanid | 2.26 ratio | Standard Deviation 0.647 |
| Stage 1: 30 mg OPC-167832 | Stage 2: RCmax of Delamanid | 2.19 ratio | Standard Deviation 0.601 |
Primary
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.
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: T1/2,z of Bedaquiline | NA hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: T1/2,z of Bedaquiline | 81.1 hours |
Primary
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.
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: T1/2,z of Delamanid | 25.4 hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: T1/2,z of Delamanid | 25.1 hours |
Primary
Stage 2: Tmax of Bedaquiline
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Tmax of Bedaquiline | 5.17 hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: Tmax of Bedaquiline | 4.85 hours |
Primary
Stage 2: Tmax of Bedaquiline
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Tmax of Bedaquiline | 5.17 hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: Tmax of Bedaquiline | 4.83 hours |
Primary
Stage 2: Tmax of Delamanid
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Tmax of Delamanid | 3.83 hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: Tmax of Delamanid | 3.83 hours |
Primary
Stage 2: Tmax of Delamanid
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Tmax of Delamanid | 3.82 hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: Tmax of Delamanid | 4.82 hours |
Secondary
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.
Time frame: Baseline to Day 14
Population: MITT Analysis Set included randomized participants who were agar media culture positive at baseline (either at Day -2 or at Day -1, or both), received any dose of IMP, and had at least one post-baseline CFU count value. Overall number of participants analyzed is the number of participants with data available for analysis. As pre-specified in the protocol and SAP, for Stage 2 data for participants in RHEZ arm was not included in this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Raw | -1.52 log10 LAM picograms (pg)/ml | Standard Deviation 0.79 |
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Processed | -1.43 log10 LAM picograms (pg)/ml | Standard Deviation 1.07 |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Raw | -1.41 log10 LAM picograms (pg)/ml | Standard Deviation 0.75 |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Processed | -1.55 log10 LAM picograms (pg)/ml | Standard Deviation 0.9 |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Raw | -1.44 log10 LAM picograms (pg)/ml | Standard Deviation 0.67 |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Processed | -1.40 log10 LAM picograms (pg)/ml | Standard Deviation 0.77 |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Raw | -1.35 log10 LAM picograms (pg)/ml | Standard Deviation 0.76 |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Processed | -1.42 log10 LAM picograms (pg)/ml | Standard Deviation 0.74 |
| Stage 1: RHEZ | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Raw | -1.19 log10 LAM picograms (pg)/ml | Standard Deviation 0.75 |
| Stage 1: RHEZ | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Processed | -1.05 log10 LAM picograms (pg)/ml | Standard Deviation 0.61 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Raw | -1.93 log10 LAM picograms (pg)/ml | Standard Deviation 1.22 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Processed | -2.05 log10 LAM picograms (pg)/ml | Standard Deviation 1.26 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Processed | -0.87 log10 LAM picograms (pg)/ml | Standard Deviation 0.66 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Raw | -0.97 log10 LAM picograms (pg)/ml | Standard Deviation 0.62 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Raw | -2.06 log10 LAM picograms (pg)/ml | Standard Deviation 1.03 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System | Processed | -1.84 log10 LAM picograms (pg)/ml | Standard Deviation 1.39 |
Secondary
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.
Time frame: Day 1 to Day 14 of treatment period + 42 days of inoculation period (up to 56 days)
Population: MITT Analysis Set included randomized participants who were agar media culture positive at baseline (either at Day -2 or at Day -1, or both), received any dose of IMP, and had at least one post-baseline CFU count value. Overall number of participants analyzed is the number of participants with data available for analysis. As pre-specified in the protocol and SAP, for Stage 2 data for participants in RHEZ arm was not included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System | 4.28 days | Standard Deviation 2.88 |
| Stage 1: 30 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System | 9.54 days | Standard Deviation 13.63 |
| Stage 1: 90 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System | 18.15 days | Standard Deviation 15.06 |
| Stage 1: 3 mg OPC-167832 | Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System | 3.33 days | Standard Deviation 2.74 |
| Stage 1: RHEZ | Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System | 7.44 days | Standard Deviation 1.65 |
| Stage 2: 30 mg OPC-167832 + 400 mg BDQ | Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System | 8.93 days | Standard Deviation 10.31 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System | 5.33 days | Standard Deviation 2.54 |
| Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ | Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System | 14.26 days | Standard Deviation 13.57 |
Secondary
Stage 1: Plasma Concentration of Isoniazid
Time frame: 2 hours and 6 hours post-dose on Day 14
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 1: Plasma Concentration of Isoniazid | 2 hours Post-dose | 4.16 microgram per millilitre (ug/mL) | Standard Deviation 1.45 |
| Stage 1: 10 mg OPC-167832 | Stage 1: Plasma Concentration of Isoniazid | 6 hours Post-dose | 1.58 microgram per millilitre (ug/mL) | Standard Deviation 0.837 |
Secondary
Stage 2: AUC0-24 for DM-6705
DM-6705 is a metabolite of delamanid.
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: AUC0-24 for DM-6705 | Day 1 | 103 ng*h/mL | Standard Deviation 54.2 |
| Stage 1: 10 mg OPC-167832 | Stage 2: AUC0-24 for DM-6705 | Day 14 | 1620 ng*h/mL | Standard Deviation 458 |
| Stage 1: 30 mg OPC-167832 | Stage 2: AUC0-24 for DM-6705 | Day 1 | 166 ng*h/mL | Standard Deviation 124 |
| Stage 1: 30 mg OPC-167832 | Stage 2: AUC0-24 for DM-6705 | Day 14 | 1980 ng*h/mL | Standard Deviation 850 |
Secondary
Stage 2: AUC0-24 for N-Desmethyl Bedaquiline
N-Desmethyl Bedaquiline is a metabolite of BDQ.
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: AUC0-24 for N-Desmethyl Bedaquiline | Day 1 | 1380 ng*h/mL | Standard Deviation 731 |
| Stage 1: 10 mg OPC-167832 | Stage 2: AUC0-24 for N-Desmethyl Bedaquiline | Day 14 | 10100 ng*h/mL | Standard Deviation 3080 |
| Stage 1: 30 mg OPC-167832 | Stage 2: AUC0-24 for N-Desmethyl Bedaquiline | Day 1 | 1410 ng*h/mL | Standard Deviation 326 |
| Stage 1: 30 mg OPC-167832 | Stage 2: AUC0-24 for N-Desmethyl Bedaquiline | Day 14 | 11800 ng*h/mL | Standard Deviation 1920 |
Secondary
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.
Time frame: Baseline to Day 14
Population: MITT Analysis Set included randomized participants who were agar media culture positive at baseline (either at Day -2 or at Day -1, or both), received any dose of IMP, and had at least one post-baseline CFU count value. Overall number analyzed is the number of participants with data available for analysis. As pre-specified in the protocol and SAP, for Stage 2 data for participants in RHEZ arm was not included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Change From Baseline in TB Bacterial Load in Sputum as a Measure of EBA | -2.17 Sputum log10 CFU/mL | Standard Error 1.83 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Change From Baseline in TB Bacterial Load in Sputum as a Measure of EBA | -1.97 Sputum log10 CFU/mL | Standard Error 1.29 |
| Stage 1: 90 mg OPC-167832 | Stage 2: Change From Baseline in TB Bacterial Load in Sputum as a Measure of EBA | -2.73 Sputum log10 CFU/mL | Standard Error 1.51 |
95% CI: [0.626, 3.175]
95% CI: [0.362, 2.151]
95% CI: [0.736, 2.656]
95% CI: [0.564, 2.206]
Secondary
Stage 2: Cmax of DM-6705
DM-6705 is a metabolite of delamanid.
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Cmax of DM-6705 | 10.3 ng/mL | Standard Deviation 10.5 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Cmax of DM-6705 | 14.6 ng/mL | Standard Deviation 11.6 |
Secondary
Stage 2: Cmax of N-Desmethyl Bedaquiline
N-Desmethyl Bedaquiline is a metabolite of BDQ.
Time frame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Cmax of N-Desmethyl Bedaquiline | 95.4 ng/mL | Standard Deviation 44.7 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Cmax of N-Desmethyl Bedaquiline | 88.2 ng/mL | Standard Deviation 17.5 |
Secondary
Stage 2: Cmax,ss of DM-6705
DM-6705 is a metabolite of delamanid.
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Cmax,ss of DM-6705 | 84.0 ng/mL | Standard Deviation 27.5 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Cmax,ss of DM-6705 | 112 ng/mL | Standard Deviation 51.9 |
Secondary
Stage 2: Cmax,ss of N-Desmethyl Bedaquiline
N-Desmethyl Bedaquiline is a metabolite of BDQ.
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Cmax,ss of N-Desmethyl Bedaquiline | 489 ng/mL | Standard Deviation 154 |
| Stage 1: 30 mg OPC-167832 | Stage 2: Cmax,ss of N-Desmethyl Bedaquiline | 575 ng/mL | Standard Deviation 112 |
Secondary
Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline
Time frame: From first dose of study drug to end of follow up period (up to 34 days)
Population: Safety Analysis Set included participants who were randomized and received any dose of IMP. Overall number of participants analyzed is the number of participants available for analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | ST/T Morphology: Myocardial Ischemia | 0 Participants |
| Stage 1: 10 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Rhythm: Ventricular Premature Beat | 0 Participants |
| Stage 1: 10 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | ST/T Morphology: Symmetrical T-wave Inversion | 0 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | ST/T Morphology: Myocardial Ischemia | 0 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Rhythm: Ventricular Premature Beat | 0 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | ST/T Morphology: Symmetrical T-wave Inversion | 0 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Rhythm: Ventricular Premature Beat | 0 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | ST/T Morphology: Symmetrical T-wave Inversion | 0 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | ST/T Morphology: Myocardial Ischemia | 0 Participants |
Secondary
Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline
Time frame: From first dose of study drug to end of follow up period (up to 34 days)
Population: Safety Analysis Set included participants who were randomized and received any dose of IMP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Heart Rate: > 120 bpm and >= 15 bpm change from baseline | 0 Participants |
| Stage 1: 10 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Diastolic blood pressure: < 50 mmHg and >= 15 mmHg decrease from baseline | 0 Participants |
| Stage 1: 10 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Systolic blood pressure: < 90 mmHg and >= 20 mmHg decrease from baseline | 1 Participants |
| Stage 1: 10 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Weight: >= 5% increase from baseline | 0 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Weight: >= 5% increase from baseline | 5 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Heart Rate: > 120 bpm and >= 15 bpm change from baseline | 1 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Systolic blood pressure: < 90 mmHg and >= 20 mmHg decrease from baseline | 1 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Diastolic blood pressure: < 50 mmHg and >= 15 mmHg decrease from baseline | 2 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Weight: >= 5% increase from baseline | 2 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Diastolic blood pressure: < 50 mmHg and >= 15 mmHg decrease from baseline | 0 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Systolic blood pressure: < 90 mmHg and >= 20 mmHg decrease from baseline | 1 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | Heart Rate: > 120 bpm and >= 15 bpm change from baseline | 0 Participants |
Secondary
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.
Time frame: From first dose of study drug to end of follow up period (up to 34 days)
Population: Safety Analysis Set included participants who were randomized and received any dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Number of Participants With TEAEs on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | 9 Participants |
| Stage 1: 30 mg OPC-167832 | Stage 2: Number of Participants With TEAEs on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | 11 Participants |
| Stage 1: 90 mg OPC-167832 | Stage 2: Number of Participants With TEAEs on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline | 9 Participants |
Secondary
Stage 2: Plasma Concentration of Rifampin
Time frame: 2 hours and 6 hours post-dose on Day 14
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Plasma Concentration of Rifampin | 2 hours Post-dose | 4020 ng/mL | Standard Deviation 2450 |
| Stage 1: 10 mg OPC-167832 | Stage 2: Plasma Concentration of Rifampin | 6 hours Post-dose | 1880 ng/mL | Standard Deviation 811 |
Secondary
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.
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: T1/2,z of DM-6705 | NA hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: T1/2,z of DM-6705 | NA hours |
Secondary
Stage 2: Tmax of DM-6705
DM-6705 is a metabolite of delamanid.
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Tmax of DM-6705 | Day 1 | 4.82 hours |
| Stage 1: 10 mg OPC-167832 | Stage 2: Tmax of DM-6705 | Day 14 | 4.83 hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: Tmax of DM-6705 | Day 1 | 4.83 hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: Tmax of DM-6705 | Day 14 | 4.85 hours |
Secondary
Stage 2: Tmax of N-Desmethyl Bedaquiline
N-Desmethyl Bedaquiline is a metabolite of BDQ.
Time frame: 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
Population: PK Analysis Set included all participants who received at least one dose of IMP and had 1 quantifiable drug concentration. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Stage 1: 10 mg OPC-167832 | Stage 2: Tmax of N-Desmethyl Bedaquiline | Day 1 | 23.93 hours |
| Stage 1: 10 mg OPC-167832 | Stage 2: Tmax of N-Desmethyl Bedaquiline | Day 14 | 15.08 hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: Tmax of N-Desmethyl Bedaquiline | Day 1 | 11.86 hours |
| Stage 1: 30 mg OPC-167832 | Stage 2: Tmax of N-Desmethyl Bedaquiline | Day 14 | 7.83 hours |
Other Pre-specified
Correlation of QT Interval and Plasma Concentrations of OPC-167832 and/or Delamanid and/or Bedaquiline
Time frame: Day 1 and Day 14