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).

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

Pulmonary TB

Tuberculosis

RHEZ

quabodepistat (OPC-167832)

delamanid (OPC-67683) + quabodepistat (OPC-167832)

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

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.

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.

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.

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.

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.

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.

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.

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.

N-Desmethyl Bedaquiline is a metabolite of BDQ.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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

University of Cape Town (Pty) Ltd.

Satellite Site: Task at Brooklyn Chest Hospital

TASK Clinical Research Centre

Stage 1:
The change in TB bacterial load in sputum as a measure of early bactericidal activity (EBA) and measured by colony-forming unit (CFU) counts on solid media cultures. The EBA will be measured as the slope of the change in log-CFU from baseline (ie, the mean of the values from Day -2 and Day -1) to Day 14.

Stage 1:
PK parameters will be determined for plasma OPC-167832
Stage 2:
PK parameters will be determined for plasma OPC-167832, Delamanid, and BDQ

Stage 1 and Stage 2: The incidence of AEs and the incidence of abnormal laboratory findings in clinical laboratory tests (serum chemistry, hematology, urinalysis, and coagulation), physical examinations, vital signs, and electrocardiograms will be assessed.

Stage 1:
The slope of the change in log-LAM values of OPC-167832 and the change in TTD in the Mycobacteria Growth Indicator Tube® (MGIT) system.
Stage 2:
The change in TB bacterial load in sputum as a measure of early bactericidal activity (EBA) and measured by colony-forming unit (CFU) counts on solid media cultures. The EBA will be measured as the slope of the change in log-CFU from baseline (ie, the mean of the values from Day -2 and Day -1) to Day 14.

Stage 1 and Stage 2 Plasma concentrations of rifampin and isoniazid at 2 and 6 hours post-dose will be determined for compliance.

Stage 1 and 2
The maximum effect and EC80 for OPC-167832, regardless of dose level, will be determined from an exposure-response analysis of the results from the Otsuka TB ELISA LAM.
The relationship between QT interval and plasma concentrations of OPC-167832 (stage
1) and OPC-167832 when administered with delamanid and/or BDQ (stage 2) will be evaluated.

Stage 1 and 2:
Incidence of AEs and the incidence of abnormal laboratory findings in clinical laboratory tests (serum chemistry, hematology, urinalysis, and coagulation), physical examinations, vital signs, and electrocardiograms of OPC-167832 when administered with delamanid and/or BDQ (data derived from stage 2) will be compared with the administration of OPC-167832 alone (data derived from stage 1).

Trial at a glance

Trial results

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

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