Clinical trial NCT03678688
Conditions: Pulmonary TB
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2018-10-18; Completion date: 2022-03-11
Enrollment: 122 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

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).

Detailed description:

Arms: arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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. arm 5: 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. arm 6: 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. arm 7: 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. arm 8: 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. arm 9: 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.
Interventions: intervention 1: 10 mg OPC-167832 intervention 2: 30 mg OPC-167832 intervention 3: 90 mg OPC-167832 intervention 4: 3 mg OPC-167832 intervention 5: RHEZ intervention 6: 30 mg OPC-167832 + 300 mg delamanid intervention 7: 30 mg OPC-167832 + 400 mg BDQ intervention 8: 30 mg OPC-167832 + 300 mg delamanid + 400 mg BDQ
Intervention descriptions: intervention 1: Once daily oral dose of 10 mg OPC-167832 from Day 1 through Day 14. intervention 2: Once daily oral dose of 30 mg OPC-167832 from Day 1 through Day 14. intervention 3: Once daily oral dose of 90 mg OPC-167832 from Day 1 through Day 14. intervention 4: Once daily oral dose of 3 mg OPC-167832 from Day 1 through Day 14. intervention 5: RHEZ was used in both Stage 1 and Stage 2. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Participants received a single-dose from Day 1 through Day 20. The total number of tablets per day was based on the pretreatment body weight:

* Participants weighing 30 to 37 kg received 2 tablets per day
* Participants weighing 38 to 54 kg received 3 tablets per day
* Participants weighing 55 to 70 kg received 4 tablets per day
* Participants weighing \> 70 kg received 5 tablets per day intervention 6: Once daily oral dose of 30 mg OPC-167832 plus 300 mg delamanid from Day 1 through Day 14. intervention 7: Once daily oral dose of 30 mg OPC-167832 plus 400 mg BDQ from Day 1 through Day 14. Participants received a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. The dose of BDQ was 400 mg QD for Days 3 to 14. intervention 8: 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.

Protocol documents:
Prot_000.pdf: 
Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
OPC-167832
CLINICAL PROTOCOL
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
Protocol No. 323-201-00003
IND No. 129303
CONFIDENTIAL - PROPRIETARY INFORMATION
Drug Development Phase:
1/2
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
Rockville, Maryland 20850, United States
Immediately Reportable Event:
Clindev Pty Ltd
Fax:
E-mail: 
Issue Date:
26 Feb 2018
Amendment 1:
29 Jan 2019 
Amendment 2:
25 Oct 2019
Amendment 3:
20 Dec 2019
Amendment 4:
17 Aug 2020
Amendment 5:
10 May 2021
Protocol Version Number:
6.0
Clinical Study Report 323-201-00003
16.1.1 Protocol and Protocol Amendments
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Protocol 323-201-00003
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Protocol Version 6.0, 10 May 2021
Protocol Synopsis
Name of Sponsor: Otsuka Pharmaceutical Development & 
Commercialization, Inc.
Name of Investigational Medicinal Product: OPC-167832
Protocol No.: 
323-201-00003
IND No.: 129303
Protocol Title:
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
Clinical Phase:
Phase 1/2
Treatment Indication:
Pulmonary tuberculosis (TB)
Objectives:
Primary:
Stage 1
To evaluate the efficacy, pharmacokinetics (PK), safety, and 
tolerability of multiple ascending oral doses of OPC-167832 
compared with the administration of rifampicin, isoniazid, 
ethambutol, and pyrazinamide (RHEZ) in subjects with 
uncomplicated, smear-positive, drug-susceptible pulmonary 
TB.
Stage 2

To evaluate the safety and tolerability of multiple oral 
doses of OPC-167832 when administered with delamanid 
and/or bedaquiline (BDQ) compared with the 
administration of RHEZ alone in subjects with 
uncomplicated, smear-positive, drug-susceptible 
pulmonary TB.

To evaluate the PK of OPC-167832 and delamanid and/or 
BDQ after coadministration.
Secondary:
Stage 1

To evaluate the relationship between OPC-167832 
exposure and efficacy determined by changes of sputum 
lipoarabinomannan (LAM) and Mycobacteria Growth 
Indicator Tube® (MGIT) time to detection, after multiple 
ascending oral doses of OPC-167832.

To evaluate the relationship between QT interval and 
plasma concentrations of OPC-167832.
Clinical Study Report 323-201-00003
16.1.1 Protocol and Protocol Amendments
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Protocol Version 6.0, 10 May 2021
Stage 2

To evaluate the efficacy of OPC-167832 when 
administered with delamanid and/or BDQ compared with 
the administration of RHEZ alone in subjects with 
uncomplicated, smear-positive, drug-susceptible 
pulmonary TB.

To evaluate the relationship between OPC-167832 
exposure and efficacy determined by changes of sputum 
LAM and MGIT time to detection, after OPC-167832 
when administered with delamanid and/or BDQ.

To evaluate the relationship between QT interval and 
plasma concentrations of OPC-167832 when administered 
with delamanid and/or BDQ.

To evaluate the PK of DM-6705 after coadministration of 
OPC-167832 and delamanid and/or BDQ.
Stage 1 and Stage 2
To evaluate the efficacy, safety, and tolerability of 
OPC-167832 when administered with delamanid and/or BDQ 
(data derived from stage 2) compared with the administration 
of OPC-167832 alone (data derived from stage 1).
Trial Design:
This will be a multiple-dose trial of OPC-167832 with 
2 stages.
Stage 1
Stage 1 will be a randomized, open-label, active-controlled, 
multiple ascending dose stage in approximately 72 subjects. 
Dosing is planned to be conducted in 4 sequential cohorts of 
18 subjects each:

Cohort 1: 10 mg OPC-167832 or RHEZ (14 OPC-167832 
subjects and 4 RHEZ subjects)

Cohort 2: 30 mg OPC-167832 or RHEZ (14 OPC-167832 
subjects and 4 RHEZ subjects)

Cohort 3: 90 mg OPC-167832 or RHEZ (14 OPC-167832 
subjects and 4 RHEZ subjects)

Cohort 4: 3 mg OPC-167832 or RHEZ (14 OPC-167832 
subjects and 4 RHEZ subjects)
Subjects will provide signed informed consent and be 
admitted to the trial site at screening. Subjects will be 
screened for up to 4 days (Days −6 to −3) prior to the start of 
the Day −2 assessments; however, screening can be extended 
up to 7 days, if needed. Eligible subjects will be housed at the 
trial site until discharge or early termination.
Clinical Study Report 323-201-00003
16.1.1 Protocol and Protocol Amendments
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Protocol Version 6.0, 10 May 2021
In Cohort 1, subjects will be randomized to 10 mg 
OPC-167832 or RHEZ prior to first dosing on Day 1.
Subjects randomized to OPC-167832 will receive once daily 
(QD) oral doses of investigational medicinal product (IMP; 
OPC-167832) from Day 1 through Day 14. After Day 14, the 
subjects will receive treatment for pulmonary TB according to 
the local standard of care regimen (RHEZ). In subjects with 
no clinical indication to start RHEZ immediately, 
commencement of RHEZ can be delayed for up to 3 days 
(Days 15, 16, and 17) under close supervision in the trial site 
hospital ward.
Subjects randomized to RHEZ will receive QD oral doses of 
RHEZ from Day 1 through Day 20.
Subjects will be discharged on Day 20 once all safety 
assessments have been completed and all PK samples have 
been collected. After completion of the inpatient stay, all 
subjects will be referred to local community clinics to receive 
continued treatment for pulmonary TB per the local standard 
of care regimen.
Following review of the safety, tolerability, PK, and efficacy 
data from Cohort 1, a decision will be made to start Cohort 2. 
Cohort 2 will be completed as described above for Cohort 1 at 
the selected dose of OPC-167832. The same process will be 
followed for Cohort 3 after the completion of Cohort 2 and for 
Cohort 4 after the completion of Cohort 3.
The safety, tolerability, PK, and efficacy (results from Otsuka 
TB LAM enzyme-linked immunosorbent assay [ELISA] only) 
data from each cohort will be reviewed by the trial review 
team at the end of each cohort. Once all the data for dose 
selection for the next cohort are available, the data collected 
from each cohort will be provided to the trial review team. 
The data will be evaluated to determine if (i) the dose level 
for the next cohort will be escalated, (ii) the dose level from 
the previous cohort will be repeated, or (iii) the dose level will 
be decreased. The dose of OPC-167832 will not exceed the 
highest tolerated dose studied in the single ascending dose 
trial, ie, 480 mg.
For efficacy, the selection of the dose level for each cohort 
after Cohort 1 will be assisted by the results of the Otsuka TB 
Clinical Study Report 323-201-00003
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Protocol Version 6.0, 10 May 2021
LAM ELISA instead of solid media culture, since those 
results are available in near real time and will facilitate faster 
decisions.
Stage 2
Stage 2 will be a randomized, open-label, active-controlled, 
parallel group comparison stage comprising of 46 subjects 
(subjects who were randomized in stage 1 cannot enroll in 
stage 2).
Subjects will provide signed informed consent and be 
admitted to the trial site at screening. Subjects will be 
screened for up to 4 days (Days −6 to −3) prior to the start of 
the Day −2 assessments; however, screening can be extended 
up to 7 days, if needed. Eligible subjects will be housed at the 
trial site until discharge or early termination. All subjects 
enrolled during this stage of the trial will be randomized prior 
to first dosing on Day 1 to one of the following 4 treatments 
in a ratio of 14:14:14:4:

30 mg OPC-167832 and 300 mg delamanid QD 
(14 subjects)

30 mg OPC-167832 and 400 mg BDQ QD (14 subjects)

30 mg OPC-167832 and 300 mg delamanid and 400 mg 
BDQ QD (14 subjects)

RHEZ QD (4 subjects)

Subjects receiving BDQ will take a loading dose of 
700 mg BDQ on Day 1 and 500 mg on Day 2. The dose of 
BDQ will be 400 mg QD for Days 3 to 14
Based on the stage 1 PK/PD analysis of OPC-167832 plasma 
concentrations and reduction in log10CFU, a dose lower than 
the current 30 mg specified in the protocol may be considered, 
provided it can offer similar potential for efficacy as the 
30 mg dose.
Subjects randomized to OPC-167832 and/or delamanid and/or 
BDQ will receive QD oral doses of IMP (OPC-167832 and/or 
delamanid and/or BDQ) from Day 1 through Day 14. After 
Day 14, the subjects will receive treatment for pulmonary TB 
according to the local standard of care regimen (RHEZ). In 
subjects with no clinical indication to start RHEZ 
immediately, commencement of RHEZ can be delayed for up 
to 3 days (Days 15, 16, and 17) under close supervision in the 
trial site hospital ward.
Subjects randomized to RHEZ will receive QD oral doses of 
RHEZ from Day 1 through Day 20.
Clinical Study Report 323-201-00003
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Protocol Version 6.0, 10 May 2021
Subjects will be discharged on Day 20 once all safety 
assessments have been completed and all PK samples have 
been collected. After completion of the inpatient stay, all 
subjects will be referred to local community clinics to receive 
continued treatment for pulmonary TB per the local standard 
of care regimen.
Subject Population:
Approximately 118 male or female subjects with newly 
diagnosed, uncomplicated, smear-positive, drug-susceptible 
pulmonary TB who meet all of the inclusion criteria and none 
of the exclusion criteria will be enrolled and randomized into 
this trial. In stage 1, approximately 72 subjects will be 
enrolled and randomized to 1 of 4 cohorts (18 subjects per 
cohort). Approximately 46 subjects will be enrolled and 
randomized in stage 2. Subjects who were randomized to 
stage 1 cannot enroll in stage 2.
Inclusion/Exclusion 
Criteria:
Subjects are required to meet the following inclusion criteria 
(summary of main criteria):

Male or female subjects between 18 and 64 years of age 
(inclusive) with newly diagnosed (within the 3 months 
prior to screening), uncomplicated, drug-susceptible 
(rifampicin and isoniazid susceptible) pulmonary TB.

Microscopy performed on a sputum smear indicates 
presence of acid-fast bacilli (at least 1+).
Subjects will be excluded if they meet the following exclusion 
criteria (summary of main criteria):

Subjects are known or suspected of having resistance to 
rifampicin, isoniazid, ethambutol, or pyrazinamide using 
any combination of Xpert MTB/RIF, line probe assay, 
culture, and/or epidemiologic history at screening.

Any prior treatment for Mycobacterium tuberculosis 
within the past 3 years.

Clinical evidence of severe extrapulmonary TB 
(eg, miliary TB, abdominal TB, urogenital TB, 
osteoarthritic TB, TB meningitis).

Subjects with significant medical comorbidities that in the 
opinion of the investigator, should not participate in the 
trial.
Trial Site:
This trial will be conducted at 1 or more trial sites in South 
Africa.
Clinical Study Report 323-201-00003
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Protocol Version 6.0, 10 May 2021
Investigational 
Medicinal Product(s), 
Dose, Dosage 
Regimen, Treatment 
Duration, 
Formulation, Mode of 
Administration:
Stage 1
Subjects randomized to OPC-167832 will receive QD oral 
doses of IMP (OPC-167832) from Day 1 through Day 14. 
The planned dose escalation steps of OPC-167832 for 
Cohorts 1 to 4 are 10, 30, 90, and 3 mg, respectively. The 
doses for Cohorts 2, 3, and 4 may be adjusted based on the 
safety, PK, and efficacy data from the previous cohorts. The 
IMP will be administered with 240 mL of still 
(noncarbonated) water at room temperature, within 5 minutes 
after the completion of a meal.
Stage 2
Subjects randomized to the 30 mg OPC-167832 and 300 mg 
delamanid or 30 mg OPC-167832 and 400 mg BDQ, or 30 mg 
OPC-167832 and 300 mg delamanid and 400 mg BDQ will 
receive QD oral doses of IMP (OPC-167832 and/or 
delamanid and/or BDQ) from Day 1 through Day 14. The 
IMP will be administered with 240 mL of still 
(noncarbonated) water at room temperature.
Reference Product(s), 
Dose, Dosage 
Regimen, Treatment 
Duration, 
Formulation, Mode of 
Administration:
Stage 1 and Stage 2
Subjects randomized to RHEZ will receive QD oral doses of 
RHEZ from Day 1 through Day 20. Subjects will receive 
Rifafour® single-dose combination tablets. Each RHEZ tablet 
contains 150 mg rifampicin, 75 mg isoniazid, 400 mg 
pyrazinamide, and 275 mg ethambutol. Subjects will receive 
the following number of Rifafour tablets per day based on 
their pretreatment body weight:

Subjects weighing 30 to 37 kg will receive 2 tablets per 
day.

Subjects weighing 38 to 54 kg will receive 3 tablets per 
day.

Subjects weighing 55 to 70 kg will receive 4 tablets per 
day.

Subjects weighing > 70 kg will receive 5 tablets per day.
RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after 
a meal.
Note: Subjects randomized to IMP will receive treatment for 
pulmonary TB according to the local standard of care regimen 
(RHEZ) after Day 14. In subjects with no clinical indication 
to start RHEZ immediately, commencement of RHEZ can be 
delayed for up to 3 days (Days 15, 16, and 17) under close 
supervision in the trial site hospital ward.
Clinical Study Report 323-201-00003
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Protocol Version 6.0, 10 May 2021
Trial Assessments:
Pharmacokinetic:

Stage 1: blood sampling for OPC-167832, rifampin, and 
isoniazid plasma concentrations.

Stage 2: blood sampling for OPC-167832, delamanid, and 
its metabolite DM-6705, BDQ and its metabolite 
N-monodesmethyl metabolite (M2), rifampin, and 
isoniazid plasma concentrations.
Safety: adverse event reporting, clinical laboratory tests 
(serum chemistry, hematology, urinalysis, and coagulation), 
physical examination, vital signs, electrocardiograms (ECGs), 
and concomitant medications.
Efficacy: quantitative sputum testing (by Otsuka TB LAM 
ELISA, solid media, and MGIT) to assess the change in TB 
bacterial load in sputum as a measure of early bactericidal 
activity (EBA).
Pharmacodynamics: Holter monitoring and sputum testing.
Screening (excluding safety assessments mentioned 
above)/Other: demographics, medical history, and prior 
medications; height and weight; chest x-ray; spot sputum for 
confirmation of acid-fast bacilli (microscopy from smear 
≥ 1+) and drug-susceptible TB; serum hepatitis (hepatitis B 
surface antigen and hepatitis C antibodies) and human 
immunodeficiency virus screening; urine pregnancy testing; 
follicle-stimulating hormone testing; and urine/blood alcohol 
and urine drug screen.
Criteria for 
Evaluation:
Primary Endpoints:
Efficacy - Stage 1 
Efficacy will be assessed by the change in TB bacterial load 
in sputum as a measure of EBA. Bacterial load in sputum at 
each collection time point will be measured by 
colony-forming unit (CFU) counts on agar media culture. The 
EBA will be measured as the slope of the change in log-CFU 
on agar media from baseline (ie, the mean of the values from 
Day -2 and Day -1) to Day 14.
Pharmacokinetics - Stage 1
The following PK parameters will be determined for plasma 
OPC-167832:

Day 1: Maximum (peak) plasma concentration (Cmax), 
time to Cmax (tmax), and area under the concentration-time 
curve (AUC) from time zero to time t (the last observable 
concentration) (AUCt).
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Protocol Version 6.0, 10 May 2021

Day 14: Cmax during the dosing interval at steady-state 
(Cmax,ss), tmax, terminal-phase elimination half-life (t1/2,z), 
apparent clearance of drug from plasma at steady-state 
(CLss/F), AUCt, AUC calculated over the dosing interval 
at steady-state (AUCτ), accumulation ratio of Cmax 
(RCmax), accumulation ratio of AUC (RAUC), Cmax 
normalized to dose (Cmax/Dose), and AUCτ normalized to 
dose (AUCτ/Dose).
Pharmacokinetics - Stage 2
The following PK parameters will be determined for plasma 
OPC-167832, delamanid, and BDQ:

Day 1: Cmax, tmax, and AUCt.

Day 14: Cmax,ss, tmax, t1/2,z, CLss/F, AUCτ, RCmax, RAUC, 
and Cmax normalized to dose (Cmax/Dose), and AUCτ 
normalized to dose (AUCτ/Dose).
Pharmacokinetics/Pharmacodynamics – Stage 1
The maximum effect (Emax) and exposure producing 80% of 
Emax (EC80) for OPC-167832, regardless of dose level, will be 
determined from an exposure-response analysis of the decline 
of log-CFU counts on agar media.
Pharmacokinetics/Pharmacodynamics – Stage 2
The Emax and EC80 for OPC-167832 in combination with 
delamanid and/or BDQ will be determined from an exposure-
response analysis of the decline of log-CFU counts on agar 
media.
Safety and tolerability - Stage 1 and Stage 2
Safety and tolerability will be assessed based on the incidence 
of adverse events and the incidence of abnormal findings in 
clinical laboratory tests (serum chemistry, hematology, 
urinalysis, and coagulation), vital signs, ECGs, and physical 
examinations.
Secondary Endpoints:
Efficacy - Stage 1 
The slope of the change in log-LAM values and the change in 
time to detection in the MGIT system will be assessed from 
baseline to Day 14.
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Efficacy - Stage 2 
Efficacy will be assessed by the change in TB bacterial load 
in sputum as a measure of EBA. Bacterial load in sputum at 
each collection time point will be measured by CFU counts on 
agar media. 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.
Pharmacokinetics - Stage 1
Plasma concentrations of rifampin and isoniazid at 2 and 
6 hours postdose will be determined for compliance.
Pharmacokinetics - Stage 2
The following PK parameters will be determined for plasma 
DM-6705 (metabolite of delamanid) and M2 (metabolite of 
BDQ):

Day 1: Cmax, tmax, and AUCt.

Day 14: Cmax,ss, tmax, t1/2,z, and AUCt.
Plasma concentrations of rifampin and isoniazid at 2 and 
6 hours postdose will be determined for compliance.
Pharmacokinetics/Pharmacodynamics - Stage 1 and Stage 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 (stage 2) will be 
evaluated.
Safety and tolerability - Stage 1 and Stage 2
Safety and tolerability 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). Safety and tolerability will be 
assessed based on the incidence of adverse events and the 
incidence of abnormal findings in clinical laboratory tests 
(serum chemistry, hematology, urinalysis, and coagulation), 
vital signs, ECGs, and physical examinations.
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Statistical Methods:
The trial is not powered for formal statistical hypothesis 
testing or comparisons. The sample size is based on sample 
sizes from several similar trials in the literature.
Pharmacokinetics
Pharmacokinetic concentrations and parameters will be 
summarized by treatment using descriptive statistics (number, 
median, mean, standard deviation (SD), percent coefficient of 
variation, minimum, and maximum).
Pharmacokinetic concentrations and parameters will also be 
listed by subject.
Population PK modeling will be performed on OPC-167832 
PK data from both stages.
Pharmacokinetics/Pharmacodynamics
Exposure-response modeling will be performed in both stages 
for OPC-167832 PK measures versus bacterial load using 
LAM and CFU counts on agar media.
The relationship between QT interval (Holter data) and 
plasma concentrations of OPC-167832 (stage 1) and 
OPC-167832 when administered with delamanid and/or BDQ 
(stage 2) will be examined using an exposure-response 
analysis.
Safety
Safety data will be summarized by randomized treatment 
using descriptive statistics (number, median, mean, SD, 
minimum, and maximum) for numeric variables and 
frequency and count for discrete variables. Incidence of 
clinically notable values will be summarized where 
applicable. Safety assessments will also be listed by subject.
Efficacy
Efficacy data will be summarized by randomized treatment 
using descriptive statistics (number, median, mean, SD, 
percent coefficient of variation, minimum, and maximum) or 
presented in figures (where applicable). In addition, listings 
will be presented for efficacy assessments by subject.
Trial Duration:
In stage 1 or stage 2, the expected duration of trial 
participation for each individual subject, including screening, 
the treatment period, and follow-up is approximately 34 days.

Screening: Subjects will be admitted to the trial site at 
screening and will be screened for up to 4 days (Days −6 
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to −3); however, screening can be extended up to 7 days, 
if needed.

Treatment Period: Subjects can proceed with the Day −2 
assessments as soon as the screening assessments have 
been completed.
Subjects randomized to OPC-167832 (stage 1) or 
OPC-167832 and/or delamanid and/or BDQ (stage 2) will 
receive QD oral doses of IMP from Day 1 through Day 
14. After Day 14, the subjects will receive treatment for 
pulmonary TB according to the local standard of care 
regimen (RHEZ). In subjects with no clinical indication to 
start RHEZ immediately, commencement of RHEZ can be 
delayed for up to 3 days (Days 15, 16, and 17) under close 
supervision in the trial site hospital ward.
Subject randomized to RHEZ will receive QD doses of 
RHEZ from Day 1 through Day 20.
Subjects will be discharged on Day 20.

Follow-up: 14 (± 3) days after the last dose of trial 
treatment.
Trial duration: approximately 24 months.
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Table of Contents
Protocol Synopsis...........................................................................................2
Table of Contents ........................................................................................13
List of In-text Tables...................................................................................19
List of In-text Figures .................................................................................20
List of Appendices .......................................................................................21
List of Abbreviations and Definitions of Terms .......................................22
1
Introduction........................................................................................24
1.1
Nonclinical Data................................................................................................25
1.2
Clinical Data......................................................................................................26
1.3
Pharmacokinetics ..............................................................................................27
1.3.1
OPC-167832 ...................................................................................................27
1.3.2
Delamanid.......................................................................................................27
1.3.3
Bedaquiline.....................................................................................................28
1.4
Risks and Benefits.............................................................................................28
1.4.1
OPC-167832 ...................................................................................................28
1.4.2
Delamanid.......................................................................................................29
1.4.3
Bedaquiline.....................................................................................................30
1.4.4
Rifampicin, Isoniazid, Ethambutol, and Pyrazinamide ..................................30
2
Trial Rationale and Objectives .........................................................30
2.1
Trial Rationale...................................................................................................30
2.2
Dosing Rationale...............................................................................................31
2.2.1
Stage 1 ............................................................................................................31
2.2.2
Stage 2 ............................................................................................................32
2.3
Trial Objectives.................................................................................................32
2.3.1
Primary Objective...........................................................................................32
2.3.1.1
Stage 1.........................................................................................................32
2.3.1.2
Stage 2.........................................................................................................33
2.3.2
Secondary Objectives .....................................................................................33
2.3.2.1
Stage 1.........................................................................................................33
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2.3.2.2
Stage 2.........................................................................................................33
2.3.2.3
Stage 1 and Stage 2 .....................................................................................33
3
Trial Design.........................................................................................34
3.1
Type/Design of Trial .........................................................................................34
3.1.1
Stage 1 ............................................................................................................34
3.1.2
Stage 2 ............................................................................................................38
3.2
Trial Treatments ................................................................................................42
3.2.1
Investigational Medicinal Products ................................................................42
3.2.1.1
Stage 1.........................................................................................................42
3.2.1.2
Stage 2.........................................................................................................42
3.2.2
Reference Product...........................................................................................42
3.2.2.1
Stage 1 and Stage 2 .....................................................................................42
3.3
Trial Population.................................................................................................43
3.3.1
Number of Subjects and Description of Population .......................................43
3.3.2
Subject Selection and Numbering ..................................................................43
3.4
Eligibility Criteria .............................................................................................43
3.4.1
Informed Consent ...........................................................................................44
3.4.2
Inclusion Criteria ............................................................................................44
3.4.3
Exclusion Criteria...........................................................................................45
3.5
Endpoints...........................................................................................................46
3.5.1
Primary Endpoints ..........................................................................................46
3.5.1.1
Efficacy - Stage 1........................................................................................46
3.5.1.2
Pharmacokinetics - Stage 1.........................................................................47
3.5.1.3
Pharmacokinetics - Stage 2.........................................................................47
3.5.1.4
Pharmacokinetics/Pharmacodynamics - Stage 1.........................................47
3.5.1.5
Pharmacokinetics/Pharmacodynamics - Stage 2.........................................47
3.5.1.6
Safety and Tolerability - Stage 1 and Stage 2.............................................47
3.5.2
Secondary Endpoints ......................................................................................48
3.5.2.1
Efficacy - Stage 1 and Stage 2 ....................................................................48
3.5.2.2
Pharmacokinetics - Stage 1.........................................................................48
3.5.2.3
Pharmacokinetics - Stage 2.........................................................................48
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3.5.2.4
Pharmacokinetics/Pharmacodynamics - Stage 1 and Stage 2.....................48
3.5.2.5
Safety and Tolerability - Stage 1 and Stage 2.............................................49
3.6
Measures to Minimize/Avoid Bias....................................................................49
3.7
Trial Procedures ................................................................................................49
3.7.1
General Inpatient Procedures..........................................................................55
3.7.2
Dietary Requirements.....................................................................................55
3.7.3
Schedule of Assessments................................................................................55
3.7.4
Prior and Concomitant Medications...............................................................64
3.7.5
Efficacy Assessments .....................................................................................64
3.7.5.1
Spot Sputum Samples .................................................................................64
3.7.5.2
Overnight Sputum Samples ........................................................................64
3.7.6
Safety Assessments.........................................................................................65
3.7.6.1
Adverse Events ...........................................................................................65
3.7.6.2
Clinical Laboratory Tests............................................................................65
3.7.6.3
Physical Examination and Vital Sign Assessments ....................................66
3.7.6.4
Standard 12-lead Electrocardiograms .........................................................67
3.7.7
Pharmacokinetic and Pharmacodynamic Assessments ..................................67
3.7.7.1
Pharmacokinetic Assessments ....................................................................67
3.7.7.2
Pharmacodynamic Assessments .................................................................68
3.7.8
Genetic Assessments ......................................................................................68
3.7.9
Future Biospecimen Research Samples..........................................................68
3.7.10
End of Trial.....................................................................................................68
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................68
3.8.1
Entire Trial or Treatment Arm(s) ...................................................................68
3.8.2
Individual Site.................................................................................................68
3.8.3
Individual Subject Discontinuation ................................................................69
3.8.3.1
Treatment Discontinuation..........................................................................69
3.8.3.2
Documenting Reasons for Discontinuation ................................................69
3.8.3.3
Withdrawal of Consent ...............................................................................70
3.9
Screen Failures ..................................................................................................70
3.10
Definition of Completed Subjects.....................................................................70
3.11
Definition of Subjects Lost to Follow-up..........................................................70
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3.12
Subject Compliance...........................................................................................71
3.13
Protocol Deviations...........................................................................................71
4
Restrictions .........................................................................................71
4.1
Prohibited Medications .....................................................................................71
4.2
Other Restrictions..............................................................................................73
5
Reporting of Adverse Events.............................................................73
5.1
Definitions.........................................................................................................73
5.2
Eliciting and Reporting Adverse Events ...........................................................75
5.3
Immediately Reportable Events ........................................................................75
5.4
Potential Serious Hepatotoxicity.......................................................................76
5.5
Pregnancy..........................................................................................................76
5.6
Procedure for Breaking the Blind......................................................................78
5.7
Follow-up of Adverse Events............................................................................78
5.7.1
Follow-up of Nonserious Adverse Events......................................................78
5.7.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................78
5.7.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring After Last Scheduled Contact .........................79
6
Pharmacokinetic Analysis .................................................................79
6.1
Pharmacokinetic Methods.................................................................................79
6.2
Pharmacodynamic Methods ..............................................................................79
6.3
Pharmacokinetics/Pharmacodynamics Methods...............................................80
6.4
Pharmacogenomic Methods ..............................................................................80
7
Statistical Analysis..............................................................................80
7.1
Determination of Sample Size...........................................................................80
7.2
Datasets for Analysis.........................................................................................80
7.3
Handling of Missing Data .................................................................................81
7.4
Primary and Secondary Endpoint Analyses......................................................81
7.4.1
Primary Efficacy Endpoint Analyses..............................................................81
7.4.1.1
Stage 1.........................................................................................................81
7.4.1.1.1
Two-time Point Early Bactericidal Activity Calculation ........................81
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7.4.1.1.2
Early Bactericidal Activity Estimation via Linear Mixed Effects 
Modeling..................................................................................................82
7.4.2
Secondary Efficacy Endpoint Analyses..........................................................82
7.4.3
Interim Analysis..............................................................................................83
7.5
Analysis of Demographic and Baseline Characteristics....................................83
7.6
Safety Analysis..................................................................................................83
7.6.1
Adverse Events...............................................................................................83
7.6.2
Clinical Laboratory Tests Data.......................................................................84
7.6.3
Physical Examination and Vital Signs Data...................................................84
7.6.4
Electrocardiogram Data..................................................................................84
7.7
Pharmacodynamic Analysis ..............................................................................84
7.8
Other Efficacy Analysis ....................................................................................84
7.8.1
Bacterial Load Changes as Measured by the Change of Sputum 
Lipoarabinomannan Concentration ................................................................84
7.8.2
Exploratory Analysis ......................................................................................85
8
Management of Investigational Medicinal Product........................85
8.1
Packaging and Labeling ....................................................................................85
8.2
Storage...............................................................................................................85
8.3
Accountability ...................................................................................................86
8.4
Returns and Destruction....................................................................................86
8.5
Reporting of Product Quality Complaints.........................................................86
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................87
8.5.2
Information Required for Reporting Product Quality Complaints.................87
8.5.3
Return Process for Product Quality Complaints.............................................87
8.5.4
Assessment/Evaluation...................................................................................87
9
Records Management ........................................................................88
9.1
Source Documents.............................................................................................88
9.2
Data Collection..................................................................................................88
9.3
File Management at the Trial Site.....................................................................89
9.4
Record Retention at the Trial Site.....................................................................89
10
Quality Control and Quality Assurance...........................................90
10.1
Monitoring.........................................................................................................90
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10.2
Auditing.............................................................................................................90
10.3
Protocol Deviations...........................................................................................90
11
Ethics and Responsibility...................................................................91
12
Confidentiality....................................................................................92
13
Amendment Policy .............................................................................92
14
Publication Authorship Requirements.............................................93
15
References ...........................................................................................94
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List of In-text Tables
Table 3.4.2-1
Inclusion Criteria ...........................................................................45
Table 3.4.3-1
Exclusion Criteria ..........................................................................45
Table 3.7-1
Schedule of Assessments - Stage 1 and Stage 2 ............................50
Table 3.7.3-1
Trial Days and Activities ...............................................................56
Table 3.7.6.2-1
Clinical Laboratory Tests...............................................................65
Table 4.1-1
List of Selected Cytochrome P450 3A4 Inhibitors Prohibited 
During the Trial..............................................................................72
Table 4.1-2
List of Selected Cytochrome P450 3A4 Inducers Prohibited 
During the Trial..............................................................................72
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List of In-text Figures
Figure 3.1.1-1
Trial Design Schematic - Stage 1...................................................36
Figure 3.1.2-1
Trial Design Schematic - Stage 2...................................................40
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List of Appendices
Appendix 1
Names of OPDC Personnel............................................................96
Appendix 2
Institutions Concerned with the Trial ............................................97
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
Anti-HCV
Hepatitis C antibodies
AST 
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC24h
Area under the concentration-time curve from zero to 24 hours
AUC
Area under the concentration-time curve from time zero to infinity
AUC
Area under the concentration-time curve calculated over the dosing 
interval at steady-state
AUCt
Area under the concentration-time curve from time zero to time t (the 
last observable concentration)
BDQ
Bedaquiline
BMI
Body mass index
CIOMS
Council for International Organizations of Medical Science
CFU
Colony-forming unit
CLss/F
Apparent clearance of drug from plasma at steady-state
Cmax
Maximum (peak) plasma concentration
Cmax,ss
Cmax during the dosing interval at steady-state
CYP
Cytochrome P450
DAIDS
Division of AIDS
DprE1
Decaprenylphosphoryl-β-D-ribose 2’-oxidase
EBA
Early bactericidal activity
EC80
Exposure producing 80% of maximum effect
ECG
Electrocardiogram
eCRF
Electronic case report form
ELISA
Enzyme-linked immunosorbent assay
Emax
Maximum effect
ET
Early termination
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
HBsAg
Hepatitis B surface antigen
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICF
Informed consent form
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
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Abbreviation
Definition
IEC
Independent ethics committee
IMP
Investigational medicinal product
IND
Investigational New Drug
IRE
Immediately reportable event
LAM
Lipoarabinomannan
M2
N-monodesmethyl metabolite
MAME
Maximum efficacy
MDR
Multidrug-resistant
MedDRA
Medical Dictionary for Regulatory Activities
MGIT
Mycobacteria Growth Indicator Tube®
MIC
Minimum inhibitory concentration
MITT
Modified intent to treat
NOAEL
No observed adverse effect level
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc.
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PQC
Product quality complaint
QD
Once daily
QTcF
Corrected QT interval using Fridericia’s method
QTcB
Corrected QT interval using Bazett’s method
RAUC
Accumulation ratio of AUC
RBC
Red blood cell
RCmax
Accumulation ratio of Cmax
RHEZ
Rifampicin, isoniazid, ethambutol, and pyrazinamide
SAD
Single ascending dose
SAE
Serious adverse event
SD
Standard deviation
t1/2,z
Terminal-phase elimination half-life
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
tmax
Time to maximum (peak) plasma concentration
TTD
Time to detection
UGT
Uridine diphosphate glucuronosyltransferase
ULN
Upper limit of normal
US 
United States
WBC
White blood cell
XDR
Extensively drug-resistant
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1
Introduction
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis 
(M. tuberculosis). Tuberculosis remains a major global health problem ranking alongside 
human immunodeficiency virus (HIV) infection as a leading cause of death worldwide.
Standard treatment for TB requires the combination of 3 or 4 drugs in order to cure the 
disease and prevent the emergence of drug resistance. Active, drug-susceptible TB is 
typically treated with a 6-month regimen, including a 2-month initial phase of isoniazid, 
rifampicin, pyrazinamide, and ethambutol, and followed by a 4-month continuation phase 
of isoniazid and rifampicin. Given the long period of treatment, management of the side 
effects from treatment with these drugs is necessary. For multidrug-resistant (MDR) TB, 
conventional treatment is even less satisfactory, requiring up to 20 months of 
chemotherapy with generally less effective and more toxic second-line drugs, including 
injectable drugs, with only about 54% of diagnosed MDR TB patients being successfully 
treated.1 Shortening the treatment period, reducing the side effects, and improving the 
treatment outcomes are major obstacles to be addressed in the treatment of TB.
Progress has been made in the research and development of new anti-TB drugs to help 
overcome the current TB treatment situation. In recent years, bedaquiline (Sirturo™) and 
the sponsor’s delamanid (Deltyba™) were approved for use as part of a combination 
therapy in adults with pulmonary MDR TB. However, it is difficult to construct effective 
combination regimens due to the limited availability of safe and potent oral anti-TB drugs 
that can be used in combination with BDQ and/or delamanid. Thus, there is an urgent 
need for the both development of new potent anti-TB agents effective against 
drug-susceptible and drug-resistant strains of M. tuberculosis and with low toxicity, and 
for the development of new regimens that can shorten the treatment period for both 
drug-susceptible and MDR TB. Recognizing this serious situation, Otsuka 
Pharmaceutical Co., Ltd. initiated a program to screen for new anti-TB agents that can be 
used in combination with delamanid. As a result of research efforts, Otsuka 
Pharmaceutical Co., Ltd. discovered OPC-167832. OPC-167832 in combination with 
delamanid may provide the foundation for a pan-TB regimen for the treatment of 
pulmonary TB.2 
This 2-stage trial will evaluate the safety, tolerability, pharmacokinetics (PK), and 
efficacy of multiple doses of OPC-167832 and evaluate the safety, PK, and efficacy when 
OPC-167832 is combined with delamanid or BDQ (a marketed MDR-TB drug), or 
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OPC-167832, delamanid, and BDQ administered together in subjects with 
uncomplicated, smear-positive, drug-susceptible pulmonary TB.
During stage 1, OPC-167832 in multiple ascending doses or standard treatment 
(rifampicin, isoniazid, ethambutol, and pyrazinamide [RHEZ]) will be administered to 
sequential cohorts of subjects. In stage 2, subjects will be randomized to receive multiple 
doses of a 30 mg of OPC-167832 in combination with delamanid (OPC-67683), BDQ, 
delamanid and BDQ, or RHEZ alone.
Efficacy will be determined by the decrease of sputum colony-forming units (CFUs) 
obtained on agar media and sputum lipoarabinomannan (LAM) concentrations, 
determined by the Otsuka TB LAM enzyme-linked immunosorbent assay (ELISA). 
Otsuka TB LAM ELISA is an immunoassay that quantifies the sputum LAM 
concentration in approximately 6 hours. Lipoarabinomannan 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.3,4 After reviewing a “Letter of Intent” submitted by the sponsor 
and the Critical Path to TB Drug Regimens, the United States (US) Food and Drug 
Administration (FDA) has accepted sputum LAM in to its biomarker qualification 
program. The qualification effort is ongoing to qualify sputum LAM as a 
pharmacodynamic (PD) biomarker and as a TB drug development tool. In stage 1, the 
selection of the dose level for each cohort after Cohort 1, as it relates to efficacy, will be 
based on the Otsuka TB LAM ELISA results instead of solid media culture, since LAM 
results are available in near real time and will facilitate faster decisions. The final 
assessment of the early bactericidal activity (EBA) for each treatment arm will be based 
on the CFU counts on solid media culture.
One dose of OPC-167832 will be chosen from stage 1, and evaluated in combinations 
with delamanid, or BDQ or the 3-drugs together in stage 2 to evaluate the safety and PK 
of the combinations and the efficacy when compared with OCP-167832 alone obtained in 
stage 1.
Please refer to the Investigator’s Brochure (IB)2 for more detailed information on 
nonclinical data and clinical data for OPC-167832. Brief summaries are included below.
 
 
 
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1.2
Clinical Data
The first-in-human trial of OPC-167832 was a single ascending dose (SAD) trial 
(Trial 323-201-00001) of doses ranging from 30 to 480 mg in separate cohorts of healthy 
subjects to determine the safety, tolerability, and PK of OPC-167832.5 
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1.3
Pharmacokinetics
1.3.1
OPC-167832
The results from Trial 323-201-00001 indicated that the median area under the 
concentration-time curve (AUC) from time zero to infinity (AUC∞) at 30 mg was 
 h∙ng/mL, which was greater than the maximal effective AUC in a nonclinical 
model, 
 h∙ng/mL. The maximum (peak) plasma concentration (Cmax) and AUC of 
OPC-167832 increased less than proportionately from 
 mg and then increased 
approximately proportionately. The terminal half-life ranged from about 
 hours 
and the peak (Cmax) occurred at around  hours postdose. The median Cmax at the highest 
dose (480 mg) was about 
 micromoles/L, which was well below the IC50 of inhibition 
of any of the isozymes.5 
1.3.2
Delamanid
Systemic exposure is greater when delamanid is taken with food: about 2-fold greater 
with a standard meal and 4-fold greater with a high-fat meal. Peak plasma concentrations 
are reached in approximately 4 hours postdose, regardless of food intake. The elimination 
half-life of delamanid is about 30 to 38 hours, allowing steady-state to be reached after 
10 to 14 days of dosing. The terminal-phase elimination half-life (t1/2,z) of its major 
metabolite (DM-6705) is approximately 230 hours, and steady-state is reached by 
8 weeks.
The single-dose 14C-delamanid trial indicated that delamanid and its metabolites were 
predominantly excreted in the feces, while renal excretion is a negligible pathway for 
elimination. In vitro data suggest that delamanid is essentially metabolized by albumin, 
resulting in the formation of the primary metabolite DM-6705, which in turn is 
metabolized to DM-6704 and DM-6706. In vitro metabolism studies in human liver 
microsomes suggest limited contribution of CYP isoenzymes to the metabolism of 
delamanid, although CYP isoenzymes appear to be involved in consecutive metabolism. 
Eight metabolites have been identified in human plasma following multiple oral doses, 
though present at low concentrations after 10 to 14 days of dosing, representing all 
together about 1% to 10% of parent delamanid. Delamanid does not show clinically 
meaningful induction and/or inhibitory effects on CYP isoenzyme activity. Delamanid 
binds to all plasma proteins (> 99.5%) and most extensively (> 97%) to albumin and 
lipoproteins. The primary metabolites DM-6704, DM-6705, and DM-6706 extensively 
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(> 97%) bind to human serum proteins. Delamanid does not show affinity for red blood 
cells. Delamanid and metabolite PK parameters do not notably vary with gender or race.
Administration of delamanid has been shown to result in QT interval prolongation, an 
effect associated with delamanid and its metabolites but is most closely correlated with 
DM-6705 plasma concentrations. DM-6705 accumulates slowly over time to reach 
maximal concentrations after 6 to 10 weeks of treatment. The QT interval prolongation 
increased accordingly and reversed upon discontinuation of treatment.6 
1.3.3
Bedaquiline
Bedaquiline is a diarylquinoline derivative that inhibits the proton pump of 
M.tuberculosis ATP synthase. After oral administration BDQ Cmax are typically achieved 
at approximately 5 hours post-dose. The Cmax and the AUC increased proportionally up 
to the highest doses studied in healthy volunteers (700 mg single-dose and once daily 
400 multiple doses). Administration of BDQ with a standard meal containing increased 
the relative bioavailability by about 2-fold compared to administration under fasted 
conditions.
CYP3A4 was the major CYP isoenzyme involved in vitro in the metabolism of 
bedaquiline and the formation of the N-monodesmethyl metabolite (M2), which is 4 to 
6-times less active in terms of antimycobacterial potency. Based on preclinical studies, 
bedaquiline is mainly eliminated in feces. The urinary excretion of unchanged 
bedaquiline was < 0.001% of the dose in clinical studies, indicating that renal clearance 
of unchanged drug is insignificant. After reaching Cmax, BDQ concentrations decline tri-
exponentially. The mean terminal elimination half-life of BDQ and the M2 is 
approximately 5.5 months. This long terminal elimination phase likely reflects slow 
release of bedaquiline and M2 from peripheral tissues.7 
1.4
Risks and Benefits
1.4.1
OPC-167832
The results from safety pharmacology studies 
 
 
 
 
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Single oral doses up to 480 mg OPC-167832 were well tolerated during 
Trial 323-201-00001; there were no serious or severe adverse events (AEs) and no 
subjects were discontinued from the trial due to an AE.5 
1.4.2
Delamanid
In healthy subjects, events that occurred with a frequency greater than placebo and in 
≥ 3% of subjects who received delamanid were headache, nausea, diarrhea, vomiting, 
dizziness, abdominal pain, insomnia, generalized rash, back pain, and arthralgia. 
Additional information regarding the safety and the potential risks and benefits of 
delamanid is provided in the IB.6 
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1.4.3
Bedaquiline
Both delamanid and BDQ have been studied together as part of a National Institutes of 
Health-sponsored combination drug-drug interaction/safety trial. Bedaquiline is indicated 
as part of combination therapy in adults (≥ 18 years) with pulmonary MDR-TB. For the 
known and potential risks of BDQ, please see the package insert for BDQ tablets.7 
1.4.4
Rifampicin, Isoniazid, Ethambutol, and Pyrazinamide
Rifafour® tablets are a combination of four first line agents used in the treatment of TB. 
Rifampicin is a semi-synthetic, broad-spectrum bactericidal antibiotic. Isoniazid is a 
synthetic, antitubercular agent which is bacteriostatic against semi-dormant bacilli and 
bactericidal against actively dividing mycobacteria. Pyrazinamide may be bactericidal or 
bacteriostatic, depending on its concentration and the susceptibility of the organism. 
Ethambutol is a synthetic, bacteriostatic antitubercular agent. All agents are readily 
absorbed following oral administration, with wide distribution to most tissues and fluids 
including cerebrospinal fluid. For the known and potential risks of RHEZ, please see the 
package insert for Rifafour single-dose combination tablets.8 
2
Trial Rationale and Objectives
2.1
Trial Rationale
This trial will evaluate the safety, tolerability, PK, and efficacy of multiple oral doses of 
OPC-167832 in subjects with uncomplicated, smear-positive, drug-susceptible 
pulmonary TB.
The proposed dose levels to be studied in stage 1 are 3, 10, 30, and 90 mg (see 
Section 2.2.1 for the dosing rationale). The results from stage 1 will be used to determine 
the doses of OPC-167832 to be administered in stage 2. The stage 2 doses will not exceed 
the highest dose studied in stage 1. In stage 2 of the trial, the effect of the 
co-administration of OPC-167832 and delamanid on safety, tolerability, PK, and efficacy 
will be examined. Delamanid is approved in several countries (European Union, Japan, 
South Korea, India, South Africa, Peru, Mongolia, Ukraine, Turkmenistan, Turkey, 
Philippines, China, and Hong Kong) for the treatment of pulmonary MDR TB and is 
currently being investigated by the sponsor for the same indication in the US. 
Bedaquiline is indicated as part of combination therapy in adults (≥ 18 years) with 
pulmonary MDR-TB.
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There is no need for an OPC-167832 alone treatment arm in stage 2, as the doses for 
OPC-167832 in stage 2 are defined from PK modeling of the data from all the cohorts in 
stage 1. Based on the stage 1 PK/PD analysis of OPC-167832 plasma concentrations and 
reduction in log10CFU, a dose lower than the current 30 mg specified in the protocol may 
be considered, provided it can offer similar potential for efficacy as the 30 mg dose.
The standard treatment recommended by the World Health Organization for the treatment 
of drug-susceptible TB will be used as an active-control; the recommended treatment is a 
combination of RHEZ.9 
Subjects randomized to OPC-167832 (stage 1) or OPC-167832 and/or delamanid and/or 
BDQ (stage 2) will receive once daily (QD) oral doses of investigational medicinal 
product (IMP; OPC-167832 [stage 1] or OPC-167832 and/or delamanid and/or BDQ 
[stage 2]) from Day 1 through Day 14. After Day 14, the subjects will receive treatment 
for pulmonary TB according to the local standard of care regimen (RHEZ). In subjects 
with no clinical indication to start RHEZ immediately, commencement of RHEZ can be 
delayed for up to 3 days (Days 15, 16, and 17) under close supervision in the trial site 
hospital ward. The reason for starting the local standard of care regimen on Day 18 is that 
PK samples will be drawn after the last dose on Day 14 to estimate the terminal 
elimination rate and the terminal half-life of OPC-167832 (stages 1 and 2) and delamanid 
(stage 2) following multiple dose administration. In order to obtain accurate estimates of 
these PK parameters, ideally, no additional medication should be administered for 
approximately 4 to 5 half-lives after the last dose of trial treatment (IMP or RHEZ).
Subjects with known or suspected resistance to OPC-167832, delamanid, or RHEZ will 
be excluded from this trial. After completion of the inpatient stay, all subjects will be 
referred to local community clinics to receive continued treatment for pulmonary TB with 
the local standard of care regimen.
Overall, the results of this trial will be used for further development of OPC-167832.
2.2
Dosing Rationale
2.2.1
Stage 1
The planned dose escalation steps of OPC-167832 for Cohorts 1 to 4 are 10, 30, 90, and 
3 mg, respectively.
Single doses up to and including 480 mg OPC-167832 were well tolerated in the SAD 
trial of OPC-167832 (Trial 323-201-00001). Based on modeling and simulation, 
following multiple doses of 60 mg, 95% of subjects are expected to have steady-state 
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AUC values greater than 2252 h∙ng/mL, the minimum AUC to achieve maximum 
efficacy (MAME) based on a nonclinical model of infection in mice.10 In order to 
completely characterize the entire exposure-response, doses lower than 30 mg need to be 
studied, as the median AUC∞ following a 30 mg dose exceeded the MAME 
(Section 1.3.1). Therefore, dose levels of 10, 30, 90, and 3 mg are proposed to be studied. 
The dose of OPC-167832 will not exceed the highest tolerated dose studied in the SAD 
trial, ie, 480 mg.
The RHEZ treatment group will receive Rifafour single-dose combination tablets based 
on the subject’s pretreatment body weight.
2.2.2
Stage 2
The stage 2 dose of OPC-167832 will be 30 mg, based on preliminary data. Based on the 
stage 1 PK/PD analysis of OPC-167832 plasma concentrations and reduction in 
log10CFU, a dose lower than the current 30 mg specified in the protocol may be 
considered, provided it can offer similar potential for efficacy as the 30 mg dose.
Delamanid has been studied in an EBA trial (Trial 242-06-101) in South Africa in 
drug-susceptible pulmonary TB patients with monotherapy of 100 mg QD, 200 mg QD, 
300 mg QD, or 400 mg QD doses for 14 days. In this trial, the EBA plateaued at 300 mg 
QD, hence, in order to maximize the chances of observing activity in combination with 
OPC-167832, the 300 mg dose of delamanid will be used. 
Subjects will receive a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. The 
dose of BDQ will be 400 mg QD for Days 3 to 14. The BDQ dosing regimen, including 
the loading dose paradigm, are based on those utilized in two BDQ EBA trials.11,12
The RHEZ treatment group will receive Rifafour tablets based on the subject’s 
pretreatment body weight.
2.3
Trial Objectives
2.3.1
Primary Objective
2.3.1.1
Stage 1
To evaluate the efficacy, PK, safety, and tolerability of multiple ascending oral doses of 
OPC-167832 compared with the administration of RHEZ in subjects with uncomplicated, 
smear-positive, drug-susceptible pulmonary TB.
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2.3.1.2
Stage 2

To evaluate the safety, and tolerability of OPC-167832 when administered with 
delamanid and/or BDQ compared with the administration of RHEZ alone in subjects 
with uncomplicated, smear-positive, drug-susceptible pulmonary TB.

To evaluate the PK of OPC-167832 and delamanid, and/or BDQ after 
coadministration.
2.3.2
Secondary Objectives
2.3.2.1
Stage 1

To evaluate the relationship between OPC-167832 exposure and efficacy, determined 
by changes of sputum LAM and MGIT time to detection (TTD) after multiple 
ascending oral doses of OPC-167832.

To evaluate the relationship between QT interval and plasma concentrations of 
OPC-167832.
2.3.2.2
Stage 2

To evaluate the efficacy of OPC-167832 when administered with delamanid and/or 
BDQ compared with the administration of RHEZ alone in subjects with 
uncomplicated, smear-positive, drug susceptible pulmonary TB.

To evaluate the relationship between OPC-167832 exposure and efficacy, determined 
by changes of sputum LAM and MGIT TTD after OPC-167832 when administered 
with delamanid and/or BDQ.

To evaluate the relationship between QT interval and plasma concentrations of 
OPC-167832 when administered with delamanid and/or BDQ.

To evaluate the PK of DM-6705 after coadministration of OPC-167832 and 
delamanid and/or BDQ.
2.3.2.3
Stage 1 and Stage 2
To evaluate the efficacy, safety, and tolerability of OPC-167832 when administered with 
delamanid and/or BDQ (data derived from stage 2) compared with the administration of 
OPC-167832 alone (data derived from stage 1).
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3
Trial Design
3.1
Type/Design of Trial
This will be a multiple-dose trial of OPC-167832 with 2 stages at 1 or more trial sites in 
South Africa.
3.1.1
Stage 1
Stage 1 will be a randomized, open-label, active-controlled, multiple ascending dose 
stage in approximately 72 subjects. Dosing is planned to be conducted in 4 sequential 
cohorts of 18 subjects each:

Cohort 1: 10 mg OPC-167832 or RHEZ (14 OPC-167832 subjects and 4 RHEZ 
subjects)

Cohort 2: 30 mg OPC-167832 or RHEZ (14 OPC-167832 subjects and 4 RHEZ 
subjects)

Cohort 3: 90 mg OPC-167832 or RHEZ (14 OPC-167832 subjects and 4 RHEZ 
subjects)

Cohort 4: 3 mg OPC-167832 or RHEZ (14 OPC-167832 subjects and 4 RHEZ 
subjects)
Subjects will provide signed informed consent and be admitted to the trial site at 
screening. Subjects will be screened for up to 4 days (Days −6 to −3) prior to the start of 
the Day −2 assessments; however, screening can be extended up to 7 days, if needed. 
Eligible subjects will be housed at the trial site until discharge or early termination (ET).
In Cohort 1, subjects will be randomized to 10 mg OPC-167832 or RHEZ prior to first 
dosing on Day 1. Subjects will be centrally randomized through an interactive voice 
response technology system with no stratification.
Subjects randomized to OPC-167832 will receive QD oral doses of IMP (OPC-167832) 
from Day 1 through Day 14. The IMP will be administered as described in 
Section 3.2.1.1. After Day 14, the subjects will receive treatment for pulmonary TB 
according to the local standard of care regimen (RHEZ). In subjects with no clinical 
indication to start RHEZ immediately, commencement of RHEZ can be delayed for up to 
3 days (Days 15, 16, and 17) under close supervision in the trial site hospital ward.
Subjects randomized to RHEZ will receive QD oral doses of RHEZ from Day 1 through 
Day 20. RHEZ will be administered as described in Section 3.2.2.1.
Subjects will be discharged on Day 20 once all safety assessments have been completed 
and all PK samples have been collected. After completion of the inpatient stay, all 
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subjects will be referred to local community clinics to receive continued treatment for 
pulmonary TB per the local standard of care regimen.
Following review of the safety, tolerability, PK, and efficacy data from Cohort 1, a 
decision will be made to start Cohort 2. Cohort 2 will be completed as described above 
for Cohort 1 at the selected dose of OPC-167832. The same process will be followed for 
Cohort 3 after the completion of Cohort 2 and for Cohort 4 after the completion of 
Cohort 3.
The safety, tolerability, PK, and efficacy (
) 
data from each cohort will be reviewed by the trial review team at the end of each cohort. 
Once all the data for dose selection for the next cohort are available, the data collected 
from each cohort will be provided to the trial review team. The data will be evaluated to 
determine if (i) the dose level for the next cohort will be escalated, (ii) the dose level 
from the previous cohort will be repeated, or (iii) the dose level will be decreased. The 
dose of OPC-167832 will not exceed the highest tolerated dose studied in the SAD trial, 
ie, 480 mg.
The trial review team will consist of Otsuka Pharmaceutical Development & 
Commercialization, Inc. (OPDC) staff, including the project leader, Clinical Management 
representative(s), Global Pharmacovigilance representative(s), Clinical Pharmacology 
representative(s), OPDC medical monitor; the principal investigator (or designee); 
Microbiology and Diagnostic Director; and other staff, as needed.
Decisions to proceed to the next dose level should be based on, but not limited to, the 
following safety aspects:

No death assessed as related to OPC-167832

No more than 2 subjects with Grade 4/5 AEs (“Division of AIDS [DAIDS] Table for 
Grading the Severity of Adult and Pediatric AEs” [Appendix 3]) assessed as related 
to OPC-167832  
For efficacy, the selection of the dose level for each cohort after Cohort 1 will be assisted 
by the results of the Otsuka TB LAM ELISA instead of solid media culture, since those 
results are available in near real time and will facilitate faster decisions.
The trial design schematic is presented in Figure 3.1.1-1.
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Figure 3.1.1-1
Trial Design Schematic - Stage 1
aThe safety, tolerability, PK, and efficacy data (
) from the previous cohort(s) will be evaluated to determine the dose 
for the next cohort.
SCREENING
Day −6 to −3
(screening can be extended up to 
7 days, if needed)
FOLLOW-UP
14 ± 3 days after the 
last dose of Trial 
Treatment (IMP or 
RHEZ) 
TREATMENT PERIOD
Day 1 to 14
Admission
Subjects will be admitted to the 
trial site at screening
4 sequential cohorts 
of 18 subjects each 
(approximately 
72 subjects)
Subjects with newly 
diagnosed, uncomplicated, 
smear-positive, 
drug-susceptible pulmonary 
TB
14-day 
postdose 
follow-up 
telephone 
contact
Randomization 
on Day 1
Within each 
cohort, 
14 subjects will 
receive 
OPC-167832 
and 4 subjects 
will receive 
RHEZ.
Cohort 1: 10 mg OPC-167832b or RHEZc
Cohort 2: 30 mga OPC-167832b or RHEZc
Cohort 3: 90 mga OPC-167832b or RHEZc
Efficacy, PK, and safety assessments will be performed from Day −2 through Day 20
Discharge
Subjects will be discharged 
from the trial site on Day 20d
Cohort 4: 3 mga OPC-167832 b or RHEZc
POST-TREATMENT PERIOD
Day 15 to 20
BASELINE
Day -2 to Day -1
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bSubjects randomized to OPC-167832 will receive QD oral doses of IMP from Day 1 through Day 14. After Day 14, the subjects will receive treatment for 
pulmonary TB, according to the local standard of care regimen (RHEZ). In subjects with no clinical indication to start RHEZ immediately, commencement 
of RHEZ can be delayed for up to 3 days (Days 15, 16, and 17) under close supervision in the trial site hospital ward.
cSubjects randomized to RHEZ will receive QD oral doses of RHEZ from Day 1 through Day 20.
dAfter completion of the inpatient stay, all subjects will be referred to local community clinics to receive continued treatment for pulmonary TB per the local 
standard of care regimen.
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3.1.2
Stage 2
Stage 2 will only start once stage 1 has been concluded and after data are available from 
the nonclinical toxicological study to evaluate the effect of co-administration of 
OPC-167832 and delamanid on QTc.
The dose of OPC-167832 for stage 2 has been determined based on the safety, 
tolerability, PK, and efficacy data from stage 1 of this trial. Based on the stage 1 PK/PD 
analysis of OPC-167832 plasma concentrations and reduction in log10CFU, a dose lower 
than the current 30 mg specified in the protocol may be considered, provided it can offer 
similar potential for efficacy as the 30 mg dose.
Stage 2 will be a randomized, open-label, active-controlled, parallel group comparison 
stage comprising of 46 subjects (subjects who were randomized in stage 1 cannot enroll 
in stage 2).
Subjects will provide signed informed consent and be admitted to the trial site at 
screening. Subjects will be screened for up to 4 days (Days −6 to −3) prior to the start of 
the Day −2 assessments; however, screening can be extended up to 7 days, if needed. 
Eligible subjects will be housed at the trial site until discharge or ET. All subjects 
enrolled during this stage of the trial will be randomized prior to first dosing on Day 1 to 
one of the following 4 treatments in a ratio of 14:14:14:4:

30 mg OPC-167832 and 300 mg QD delamanid (14 subjects)

30 mg OPC-167832 and 400 mg BDQ (14 subjects)

30 mg OPC-167832 and 300 mg delamanid QD and 400 mg BDQ (14 subjects)

RHEZ QD (4 subjects)

Subjects receiving BDQ will take a loading dose of 700 mg BDQ on Day 1 and 
500 mg on Day 2. The dose of BDQ will be 400 mg QD for days 3 to 14
Subjects will be centrally randomized through an interactive voice response system with 
no stratification.
Subjects randomized to OPC-167832 and/or delamanid and/or BDQ will receive QD oral 
doses of IMP (OPC-167832 and/or delamanid and/or BDQ) from Day 1 through Day 14. 
The IMP will be administered as described in Section 3.2.1.2. After Day 14, the subjects 
will receive treatment for pulmonary TB according to the local standard of care regimen 
(RHEZ). In subjects with no clinical indication to start RHEZ immediately, 
commencement of RHEZ can be delayed for up to 3 days (Days 15, 16, and 17) under 
close supervision in the trial site hospital ward.
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Subjects randomized to RHEZ will receive QD oral doses of RHEZ from Day 1 through 
Day 20. RHEZ will be administered as described in Section 3.2.2.1.
Subjects will be discharged on Day 20 once all safety assessments have been completed 
and all PK samples have been collected. After completion of the inpatient stay, all 
subjects will be referred to local community clinics to receive continued treatment for 
pulmonary TB per the local standard of care regimen.
The trial design schematic is presented in Figure 3.1.2-1.
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Figure 3.1.2-1
Trial Design Schematic - Stage 2
aSubjects randomized to OPC-167832 and/or delamanid and/or BDQ will receive QD oral doses of IMP from Day 1 through Day 14. After Day 14, the 
subjects will receive treatment for pulmonary TB, according to the local standard of care regimen (RHEZ). In subjects with no clinical indication to start 
RHEZ immediately, commencement of RHEZ can be delayed for up to 3 days (Days 15, 16, and 17) under close supervision in the trial site hospital ward. 
TREATMENT PERIOD
Day 1 to 14
A single cohort of 
46 subjects
Subjects with newly 
diagnosed, uncomplicated, 
smear-positive, 
drug-susceptible pulmonary 
TB
14-day 
postdose 
follow-up 
telephone 
contact
Randomization on Day 1
Subjects will be randomized to one of the following 4 treatments:

30 mg OPC-167832 and 300 mg delamanid QD (14 subjects)a

30 mg OPC-167832 and 400 mg BDQ QD (14 subjects)a

30 mg OPC-167832 and 300 mg delamanid and 400 mg BDQ QD (14 
subjects)a

RHEZ QD (4 subjects)b
Efficacy, PK, and safety assessments will be performed from Day −2 through 
Day 20, as applicable
SCREENING
Day −6 to −3
(screening can be extended up to 
7 days, if needed)
Admission
Subjects will be admitted to the 
trial site at screening
Discharge
Subjects will be discharged 
from the trial site on Day 20c
FOLLOW-UP
14 ± 3 days after the 
last dose of trial 
treatment (IMP or 
RHEZ)
POST-TREATMENT PERIOD
Day 15 to 20
BASELINE
Day -2 to Day -1
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Based on the stage 1 PK/PD analysis of OPC-167832 plasma concentrations and reduction in log10CFU, a dose lower than the current 30 mg specified in 
the protocol may be considered, provided it can offer similar potential for efficacy as the 30 mg dose.
bSubjects randomized to RHEZ will receive QD oral doses of RHEZ from Day 1 through Day 20.
cAfter completion of the inpatient stay, all subjects will be referred to local community clinics to receive continued treatment for pulmonary TB per the local 
standard of care regimen.
Note: Subjects receiving BDQ will take a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. The dose of BDQ will be 400 mg QD for 
days 3 to 14.
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3.2
Trial Treatments
3.2.1
Investigational Medicinal Products
3.2.1.1
Stage 1
Subjects randomized to OPC-167832 will receive QD oral doses of IMP (OPC-167832) 
from Day 1 through Day 14.
The planned dose escalation steps of OPC-167832 for Cohorts 1 to 4 are 10, 30, 90, and 
3 mg, respectively. The doses for Cohorts 2, 3, and 4 may be adjusted based on the 
safety, PK, and efficacy data from the previous cohorts as described in Section 3.1.1. The 
IMP will be administered with 240 mL of still (noncarbonated) water at room 
temperature, within 5 minutes after the completion of a meal.
3.2.1.2
Stage 2
Subjects randomized to 30 mg OPC-167832 and 300 mg delamanid or 30 mg 
OPC-167832 and 400 mg BDQ, or 30 mg OPC-167832 and 300 mg delamanid and 
400 mg BDQ will receive QD oral doses of IMP (OPC-167832 and/or delamanid and/or 
BDQ) from Day 1 through Day 14. Subjects receiving BDQ will take a loading dose of 
700 mg BDQ on Day 1 and 500 mg on Day 2. The dose of BDQ will be 400 mg QD for 
days 3 to 14.
Delamanid (300 mg) should be administered orally once daily (QD), within 5 to 
10 minutes after the completion of a meal. 
OPC-167832 (30 mg QD) and BDQ should be administered orally, approximately 
30 minutes after administration of delamanid.
The dose of OPC-167832 for stage 2 was determined from stage 1 of this trial. The IMP 
will be administered with 240 mL of still (noncarbonated) water at room temperature.
3.2.2
Reference Product
3.2.2.1
Stage 1 and Stage 2
Subjects randomized to RHEZ will receive QD oral doses of RHEZ from Day 1 through 
Day 20.
Subjects will receive Rifafour single-dose combination tablets. Each RHEZ tablet 
contains 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg 
ethambutol.8 Subjects will receive the following number of Rifafour tablets per day based 
on their pretreatment body weight:

Subjects weighing 30 to 37 kg will receive 2 tablets per day.
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
Subjects weighing 38 to 54 kg will receive 3 tablets per day.

Subjects weighing 55 to 70 kg will receive 4 tablets per day.

Subjects weighing > 70 kg will receive 5 tablets per day.
RHEZ will be administered with 240 mL of still (noncarbonated) water 1 hour prior to a 
meal or 2 hours after a meal.
Note: Subjects randomized to IMP will receive treatment for pulmonary TB according to 
the local standard of care regimen (RHEZ) after Day 14. In subjects with no clinical 
indication to start RHEZ immediately, commencement of RHEZ can be delayed for up to 
3 days (Days 15, 16, and 17) under close supervision in the trial site hospital ward.
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
Approximately 118 male or female subjects with newly diagnosed, uncomplicated, 
smear-positive, drug-susceptible pulmonary TB who meet all of the inclusion criteria 
(Section 3.4.2) and none of the exclusion criteria (Section 3.4.3) will be enrolled and 
randomized into this trial.
In stage 1, approximately 72 subjects will be enrolled and randomized to 1 of 4 cohorts 
(18 subjects per cohort). Approximately 46 subjects will be enrolled and randomized in 
stage 2. Subjects who were randomized in stage 1 cannot enroll in stage 2.
3.3.2
Subject Selection and Numbering
At screening, subjects will be assigned a unique identification number (subject identifier) 
upon signing the informed consent form (ICF). Subjects who meet the inclusion criteria 
and do not fulfill any of the exclusion criteria will be eligible for the trial and will be 
enrolled as needed. Eligible subjects who are enrolled in the trial will be assigned a 
unique subject randomization number for treatment assignment. The trial site will 
maintain a list identifying all subjects by their identification numbers and initials.
Subjects may be replaced at the discretion of the sponsor if discontinuations or 
withdrawals occur, so that at least 18 subjects complete each cohort of stage 1 and 
approximately 46 subjects’ complete stage 2.
3.4
Eligibility Criteria
Exceptions for eligibility criteria will not be permitted during the trial, either by the 
investigator or by the medical monitor.
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3.4.1
Informed Consent
Written informed consent will be freely obtained from all subjects (or their guardian or 
legally acceptable representative, as applicable for local laws) in their native or preferred 
language (English/Afrikaans/Xhosa) before any trial-related procedures (including any 
screening procedures) are performed. Consent will be documented on a written ICF. The 
ICF will be approved by the same independent ethics committee (IEC) that approves this 
protocol. Each ICF will comply with the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline13 and local regulatory requirements. The 
investigator agrees to obtain the ICF to be provided by the sponsor in English and, if 
applicable, the primary language(s) of the patient, as applicable, prior to submission to 
the IEC.
The investigator will ensure that the sponsor reviews and authorizes any site-specific ICF 
used in the trial before submission to the IEC.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented prior to initiation of any procedures that are performed solely for the purpose 
of determining eligibility for research, including withdrawal from current medication(s).
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator (or a qualified designee), and it has 
been documented that the subject has had the opportunity to ask questions, the 
IEC-approved written ICF will be signed and dated by both the subject and the person 
obtaining consent (investigator or designee), as well as by any other parties required by 
the IEC. The subject will receive a copy of the signed ICF; the original shall be kept on 
file by the investigator. Additional copies will be filed according to local requirements.
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol results in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on trial participation.
3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria in Table 3.4.2-1.
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Table 3.4.2-1
Inclusion Criteria
1.
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.
2.
Male or female subjects between 18 and 64 years of age (inclusive) at the screening visit.
3.
Body mass index ≥ 16.0 and ≤ 32.0 kg/m2 (inclusive) at the screening visit.
4.
Newly diagnosed,a uncomplicated, drug-susceptibleb pulmonary TB. 
5.
Microscopy performed on a sputum smear at screening indicates presence of acid-fast bacilli (at 
least 1+). 
6.
Able to produce an adequate volume of sputum (approximately 10 mL or more estimated overnight 
production).
7.
Female subjects 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 (IMP or RHEZ).
8.
Male subjects 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).
aWithin the 3 months prior to screening.
bRifampicin and isoniazid susceptible.
3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1
Exclusion Criteria
1.
Subjects are known or suspected of having resistance to rifampicin, isoniazid, ethambutol, or 
pyrazinamide using any combination of Xpert MTB/RIF, line probe assay, culture, and/or 
epidemiologic history at screening.
2.
Poor general condition where no delay in treatment can be tolerated or where immediate hospital 
admission is warranted.
3.
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).
4.
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.
5.
Known bleeding disorders or family history of bleeding disorders.
6.
Any diseases or conditions in which the use of delamanid, rifampicin, isoniazid, pyrazinamide, 
ethambutol, or BDQ is contraindicated.
7.
Any prior treatment for M. tuberculosis within the past 3 years.
8.
Any treatment with a drug active against M. tuberculosis (eg, quinolones) within the 3 months 
prior to screening.
9.
Clinical evidence of severe extrapulmonary TB (eg, miliary TB, abdominal TB, urogenital TB, 
osteoarthritic TB, TB meningitis).
10.
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.
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Table 3.4.3-1
Exclusion Criteria
11.
Any renal impairment characterized by serum creatinine clearance of < 60 mL/min, or hepatic 
impairment characterized by alanine transaminase, aspartate transaminase, or total bilirubin 
> 1.5 × upper limit of normal of the clinical laboratory reference range at screening.
12.
Stage 1: Subjects who are HIV positive are excluded from the trial.
Stage 2: Subjects with HIV co-infection who are on antiretroviral drugs during screening or with 
CD4 cell count < 500/mm3 are excluded from the trial.
13.
Changes in the ECG such as QTcF > 450 msec, atrioventricular block II or III, bi-fasicular block, 
at screening or current or history of clinically significant ventricular arrhythmias. Other ECG 
changes if considered clinically significant by the investigator.
14.
Subjects receiving any of the prohibited medications within the specified periods or who would be 
likely to require prohibited concomitant therapy during the trial.
15.
Female subjects 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.
16.
History of significant drug and/or alcohol abuse within 2 years prior to screening.
17.
History of or current hepatitis or carriers of HBsAg and/or anti-HCV.
18.
Positive urine or blood alcohol test and/or urine drug screen for substance abuse at screening (not 
including cannabinoids).
19.
History of having taken an investigational drug within 30 days preceding trial entry (ie, prior to 
screening).
20.
A history of difficulty in donating blood.
21.
Donation of blood or plasma within 30 days prior to dosing.
22.
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.
23.
History of serious mental disorders that, in the opinion of the investigator, would exclude the 
subject from participating in this trial.
24.
Any known prior exposure to OPC-167832, delamanid, or BDQ.
25.
Subjects with significant medical comorbidities that in the opinion of the investigator, should not 
participate in the trial.
Anti-HCV = hepatitis C antibodies; HBsAg = hepatitis B surface antigen.
Subjects excluded for positive drug/alcohol screen are not eligible to be rescreened for 
participation in the trial. However, subjects excluded for other reasons may be rescreened 
at any time if the exclusion characteristic has changed. In the event that the subject is 
rescreened a new ICF must be signed, a new screening number assigned, and all 
screening procedures repeated.
3.5
Endpoints
3.5.1
Primary Endpoints
3.5.1.1
Efficacy - Stage 1 
Efficacy will be assessed by the change in TB bacterial load in sputum as a measure of 
EBA. Bacterial load in sputum at each collection time point will be measured by CFU 
counts on agar media culture. 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.
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3.5.1.2
Pharmacokinetics - Stage 1
The following PK parameters will be determined for plasma OPC-167832:

Day 1: Cmax, time to Cmax (tmax), and AUC from time zero to time t (the last 
observable concentration) (AUCt).

Day 14: Cmax during the dosing interval at steady-state (Cmax,ss), tmax, t1/2,z, apparent 
clearance of drug from plasma at steady-state (CLss/F), AUCt, AUC calculated over 
the dosing interval at steady-state (AUCτ), accumulation ratio of Cmax (RCmax), and 
accumulation ratio of AUC (RAUC), Cmax normalized to dose (Cmax/Dose), and AUCτ 
normalized to dose (AUCτ/Dose).
3.5.1.3
Pharmacokinetics - Stage 2
The following PK parameters will be determined for plasma OPC-167832, delamanid, 
and BDQ:

Day 1: Cmax, tmax, and AUCt.

Day 14: Cmax,ss, tmax, t1/2,z, CLss/F, AUCτ, RCmax, RAUC, and Cmax normalized to dose 
(Cmax/Dose), and AUCτ normalized to dose (AUCτ/Dose).
3.5.1.4
Pharmacokinetics/Pharmacodynamics - Stage 1
The maximum effect (Emax) and exposure producing 80% of Emax (EC80) for 
OPC-167832, regardless of dose level, will be determined from an exposure-response 
analysis of the decline of log-CFU count on agar media.
3.5.1.5
Pharmacokinetics/Pharmacodynamics - Stage 2
The Emax and EC80 for OPC-167832 in combination with delamanid and/or BDQ will be 
determined from an exposure-response analysis of the decline of log-CFU counts on agar 
media.
3.5.1.6
Safety and Tolerability - Stage 1 and Stage 2
Safety and tolerability will be assessed based on the incidence of AEs and the incidence 
of abnormal findings in clinical laboratory tests (serum chemistry, hematology, 
urinalysis, and coagulation), physical examinations, vital signs, and electrocardiograms 
(ECGs).
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3.5.2
Secondary Endpoints
3.5.2.1
Efficacy - Stage 1 and Stage 2
The slope of the change in log-LAM values and the change in TTD in the Mycobacteria 
Growth Indicator Tube® (MGIT) system will be assessed from baseline to Day 14.
Stage 2
Efficacy will be assessed by the change in TB bacterial load in sputum as a measure of 
EBA. Bacterial load in sputum at each collection time point will be measured by CFU 
counts on agar media culture. 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 
and compared with the administration of 30 mg OPC-167832 alone (data derived from 
Stage 1).
3.5.2.2
Pharmacokinetics - Stage 1
Plasma concentrations of rifampin and isoniazid at 2 and 6 hours postdose will be 
determined for compliance.
3.5.2.3
Pharmacokinetics - Stage 2
The following PK parameters will be determined for plasma DM-6705 (metabolite of 
delamanid) and M2 (metabolite of BDQ):

Day 1: Cmax, tmax, and AUCt.

Day 14: Cmax,ss, tmax, t1/2,z, and AUCt.
Plasma concentrations of rifampin and isoniazid at 2 and 6 hours postdose will be 
determined for compliance.
3.5.2.4
Pharmacokinetics/Pharmacodynamics - Stage 1 and Stage 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.
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3.5.2.5
Safety and Tolerability - Stage 1 and Stage 2
Safety and tolerability 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). Safety and tolerability will be assessed based on the 
incidence of AEs and the incidence of abnormal findings in clinical laboratory tests 
(serum chemistry, hematology, urinalysis, and coagulation), physical examinations, vital 
signs, and ECGs.
3.6
Measures to Minimize/Avoid Bias
This trial is open-label due to the impracticality of blinding all dose levels of IMP and 
due to a weight-based standard of care of RHEZ. However, the microbiology laboratory 
will be blinded to the treatment assignment of each patient, in an effort to minimize bias.
3.7
Trial Procedures
The trial duration is expected to be approximately 24 months. In stage 1 or stage 2, the 
expected duration of trial participation for each individual subject, including screening, 
the treatment period, and follow-up is approximately 34 days.
Trial assessment time points are summarized in Table 3.7-1.
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Table 3.7-1
Schedule of Assessments - Stage 1 and Stage 2
In-clinic
Screening
Baseline
Treatment Period
Post-treatment Period
Follow-
up
Day −6 to 
Day −3a
Day
−2b
Day
−1
Day
1
Day
2
Day
3
Day
4
Days 
5 and 
6
Day
7
Days 8 
through 
13
Day
14
Day
15
Days 16 
through 
19
Day 
20/ET
14 ( 3) 
Days
c
Informed consent
X
Review 
inclusion/exclusion 
criteria
X
X
Demographic 
information
X
Medical history
X
Height and weightd
X
X
X
X
X
BMI
X
Complete physical 
examinatione
X
X
Targeted physical 
examinatione
X
X
X
X
X
X
X
X
X
X
X
Chest x-rayf
X
Spot sputum for 
confirmation of 
drug-susceptible 
TBg
X
Serum hepatitis 
(HBsAg and 
anti-HCV) and 
HIVh screen
X
Admission to trial 
site
X
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Table 3.7-1
Schedule of Assessments - Stage 1 and Stage 2
In-clinic
Screening
Baseline
Treatment Period
Post-treatment Period
Follow-
up
Day −6 to 
Day −3a
Day
−2b
Day
−1
Day
1
Day
2
Day
3
Day
4
Days 
5 and 
6
Day
7
Days 8 
through 
13
Day
14
Day
15
Days 16 
through 
19
Day 
20/ET
14 ( 3) 
Days
c
Urine pregnancy 
testi
X
FSHj
X
Urine/blood alcohol 
and urine drug 
screen
X
Serum chemistry, 
hematology, 
coagulation, and 
urinalysisk
X
X
X
X
X
X
Vital signsl
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGm
X
X
X
X
Holtern
X
X
X
Randomizationo
X
Administration of 
IMPp
X
X
X
X
X
X
X
X
Administration of 
RHEZq
X
X
X
X
X
X
X
X
X
X
Xr
Treatment for 
pulmonary TB 
according to the 
local standard of 
care regimen
Xs
Xs
Xr
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Table 3.7-1
Schedule of Assessments - Stage 1 and Stage 2
In-clinic
Screening
Baseline
Treatment Period
Post-treatment Period
Follow-
up
Day −6 to 
Day −3a
Day
−2b
Day
−1
Day
1
Day
2
Day
3
Day
4
Days 
5 and 
6
Day
7
Days 8 
through 
13
Day
14
Day
15
Days 16 
through 
19
Day 
20/ET
14 ( 3) 
Days
c
PK blood samples 
for OPC-167832 
only (stage 1) or 
OPC-167832, 
delamanid, 
DM-6705, and 
BDQ (stage 2)t
X
X
X
(Days 
12 and 
13 only)
X
X
X
X
PK blood samples 
rifampicin, and 
isoniazid (stages 1 
and 2)u
X
(X)
Overnight sputum 
collectionv
X
X
X
X
X
(Day 6 
only)
X
(Days 8, 
10, and 
12 only)
X
Mealsw
X
X
X
X
X
X
X
X
X
X
X
X
X
Discharge from trial 
site
X
Assess AEsx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record 
prior/concomitant 
medicationsy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone contact
X
Note: This table presents the trial assessment time points and should be used in conjunction with the Trial Days and Activities table (Table 3.7.3-1), which 
summarizes the timing of assessments and activities by trial period/trial day.
BMI = body mass index; FSH = follicle-stimulating hormone.
aScreening can be extended up to 7 days (Day −9 to Day −3), if needed.
bSubjects can begin with the Day −2 assessments as soon as all their screening assessments have been completed.
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cFollow-up: 14 (± 3) days after the last dose of trial treatment. Trial treatment is defined as IMP or RHEZ, received on Days 1 to 14.
dHeight will only be measured at screening.
eComplete physical examinations will be performed at screening and on Day −1. Targeted physical examinations will be performed on Days 1 through 14 
(predose and 4 hours postdose) and Days 15 through 20 or at ET. A targeted physical examination should include at a minimum a general assessment and 
examination of the cardiac and respiratory systems (additional systems may be assessed as clinically indicated). The 4-hour post-dose targeted physical 
examination could be performed ± 30 minutes after the expected post-dose timepoint.
fIf a chest x-ray is available that has been taken within 2 weeks prior to screening, which in the opinion of the investigator is a reflection of the subject’s TB 
status, is of adequate quality, and which can be kept with the trial documentation for the required duration, this x-ray can be used as the screening x-ray.
gConfirmation of acid-fast bacilli (microscopy from smear ≥ 1+) and drug-susceptible TB using any combination of Xpert MTB/RIF, line probe assay, 
culture, and/or epidemiologic history.
hFor HIV positive subjects who are included in stage 2, HIV testing does not need to be repeated at screening if the HIV positive status has been documented 
prior to screening (within the last month) and the documentation can be kept with the trial documentation for the required duration. For subjects who are 
HIV positive, blood samples are to be drawn for CD4 assessment at the local laboratory.
iFemale subjects only.
jPostmenopausal female subjects only.
kSerum chemistry, hematology, urinalysis, and coagulation testing will be performed at screening, Day −1, Day 4 (predose), Day 7 (predose), Day 14 
(predose), and Day 20 or at ET.
lVital signs (blood pressure, heart rate, temperature, and respiratory rate) will be assessed at screening and on Day −1, Day 1 (predose and at 1, 2, 4, 8, and 
12 hours postdose), Days 2 through 6 (predose and 2 and 4 hours postdose), Day 7 (predose and 1, 2, 4, 8, and 12 hours postdose), Days 8 through 13 
(predose and 2 and 4 hours postdose), Day 14 (predose and 1, 2, 4, 8, and 12 hours postdose), and Days 15 through 20 or at ET. At screening, blood 
pressure and heart rate will be taken with the subject in the supine (performed first) and sitting position after remaining for  3 minutes in each position 
and temperature and respiratory rate will be taken with the subject in the supine position. At all other time points, vital signs will be obtained after the 
subject has been at rest in the supine position for at least 1 minute. Vital signs will be obtained prior to the ECG and PK blood draw at the nominal time 
points, where applicable. The post-dose vital signs could be performed within 15 minutes earlier than the expected post-dose timepoints.
mStandard 12-lead ECGs will be collected in triplicate (5 minutes apart) at screening and on Day −1, Day 7 (predose), and Day 14 (predose). The ECGs will 
be recorded after the subject has been supine and at rest for ≥ 10 minutes prior to the first ECG and subjects will remain supine through the final ECG. 
Electrocardiograms will be obtained prior to the PK blood draw and after vital signs at the nominal time points, where applicable.
nHolter monitoring will be performed on Days −1, 1, and 14.
oSubjects will be randomized prior to first dosing on Day −1 or Day 1.
pSubjects randomized to IMP (OPC-16782 [stage 1] or OPC-167832 and/or delamanid and/or BDQ [stage 2]) will receive QD oral doses of IMP on Days 1 
through 14. The IMP will be administered with 240 mL of still (noncarbonated) water at room temperature. 
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Protocol Version 6.0, 10 May 2021
qSubjects randomized to RHEZ will receive QD oral doses of RHEZ on Days 1 through 20. RHEZ will be administered with 240 mL of still (noncarbonated) 
water 1 hour prior to a meal or 2 hours after a meal.
rAfter completion of Day 20 or at ET, all subjects will be referred to local community clinics to receive continued treatment for pulmonary TB per the local 
standard of care regimen.
sSubjects randomized to IMP (OPC-16782 [stage 1] or OPC-167832 and/or delamanid and/or BDQ [stage 2]) will receive treatment for pulmonary TB 
according to the local standard of care regimen (RHEZ) after Day 14. In subjects with no clinical indication to start RHEZ immediately, commencement of 
RHEZ can be delayed for up to 3 days (Days 15, 16, and 17) under close supervision in the trial site hospital ward.
tFor subjects randomized to OPC-167832 (stage 1); OPC-167832 and/or delamanid and/or BDQ (stage 2), PK blood samples for OPC-167832 only (stage 1) 
or OPC-167832, delamanid, its metabolite DM-6705, or BDQ (stage 2) will be collected on Day 1 (predose [within 2 hours prior to dosing] and 0.5, 1, 2, 3, 
4, 5, 6, 8, and 12 hours postdose), Day 2 (24 hours after the Day 1 dose), Day 12 (predose [within 2 hours prior to dosing]  ), Day 13 (predose [within 2 
hours prior to dosing]), Day 14 (predose [within 2 hours prior to dosing] and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose), Day 15 (24 and 36 hours after 
the Day 14 dose), Day 16 (48 hours after the Day 14 dose), Day 17 (72 hours after the Day 14 dose), Day 18 (96 hours after the Day 14 dose), Day 19 
(120 hours after the Day 14 dose), and Day 20 (144 hours after the Day 14 dose). For the delamanid / OPC-167832 / BDQ arms, the PK samples will be 
drawn based on the delamanid dosing. If a PK blood sample cannot be drawn at the designated time, a window of  15 minutes for each blood draw is 
acceptable, with the exception of the 0.5 hour draw. The acceptable window for the 0.5 hour draw is + 5 minutes. For all blood draws, the exact time should 
be recorded. A PK sample should be collected for the ET visit, if applicable.
uFor subjects randomized to RHEZ, PK blood samples for rifampicin, and isoniazid (stages 1 and 2) will be collected on Day 14 (2 and 6 hours postdose). If a 
PK blood sample cannot be drawn at the designated time, a window of  15 minutes for each blood draw is acceptable, with the exact time recorded. A PK 
sample should be collected for the ET visit, if applicable.
vSputum samples (approximately 10 mL or more) will be collected from between approximately 3:00 PM (first day of collection) and 7:00 AM (second day of 
collection) for 16 hours overnight. The overnight sputum specimen collection will begin on Days −2, −1, 2, 4, 6, 8, 10, 12, and 14. The 16-hour sputum 
sampling must be finished prior to the administration of the next day’s IMP or RHEZ, if applicable. Sputum will be cultured on solid media for 
quantification of bacterial load and in the MGIT system for TTD determination and assessed in the LAM assay. In addition, MIC testing for OPC-167832 
will be performed on Day -2 and Day 14 specimens in stages 1 and 2. MIC testing for delamanid and BDQ will be performed on Day -2 and Day 14 
specimens in stage 2 only.
wMeals are breakfast, lunch, dinner, and an evening snack. On days when subjects are admitted and discharged, not all meals may be provided depending on 
the time of admission or discharge.
xAdverse events will be assessed and recorded starting at the time the ICF is signed.
yRecording of prior/concomitant medication taken within 30 days prior to signing of the ICF through completion of trial.
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Protocol Version 6.0, 10 May 2021
3.7.1
General Inpatient Procedures
Subjects will remain either in a seated or semi-recumbent position for the first 4 hours 
following dosing except during brief periods where protocol-related procedures will be 
performed. During the 4 hours postdose, restroom visits should be brief (< 10 minutes). 
Following the 4-hour postdose period, the subjects will be allowed to ambulate, but 
should not exercise strenuously.
3.7.2
Dietary Requirements
During the in-clinic period, meals will include breakfast, lunch, dinner, and an evening 
snack. On days when subjects are admitted and discharged, not all meals may be 
provided depending on the time of admission or discharge.
RHEZ will be administered with 240 mL of still (noncarbonated) water 1 hour prior to a 
meal or 2 hours after a meal. OPC-167832, delamanid, and BDQ (stage 2 only) will be 
administered with 240 mL of still (noncarbonated) water at room temperature. 
3.7.3
Schedule of Assessments
Vital signs will be obtained prior to the ECG and PK blood draw at the nominal time 
points, where applicable. The post-dose vital signs could be performed within 15 minutes 
earlier than the expected post-dose timepoints. Electrocardiograms will be obtained prior 
to the PK blood draw and after vital signs at the nominal time points, where applicable.
If a PK blood sample cannot be drawn at the designated time, a window of ± 15 minutes 
for each blood draw is acceptable, with the exception of the 0.5 hour draw. The 
acceptable window for the 0.5 hour draw is + 5 minutes. For all blood draws, the exact 
time should be recorded. For the delamanid / OPC-167832 and the delamanid / 
OPC-167832 / BDQ arms, the PK sample will be drawn based on the delamanid dosing.
The 16-hour sputum sampling must be finished prior to the administration of the next 
day’s IMP or RHEZ, if applicable.
Trial days and activities are summarized in Table 3.7.3-1 (Note: activities to be 
performed throughout the trial are provided in the last row of the table).
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Protocol Version 6.0, 10 May 2021
Table 3.7.3-1
Trial Days and Activities
Screening (Days −6 to −3)
(Screening can be extended up to 7 days [Day −9 to Day −3], if needed)
Subjects will be screened for up to 4 days prior to the Day −2 assessments. At the screening, the 
following will be performed:

Review trial procedures and information regarding the nature of the trial and obtain informed 
consent prior to any trial-related procedures.

Admission of subjects to trial site.

Review inclusion and exclusion criteria.

Collect demographic information.

Document medical history.

Measure height and weight and calculate BMI.

Perform a complete physical examination.

Perform a chest x-ray (if a chest x-ray is available that has been taken within 2 weeks prior to 
screening, which in the opinion of the investigator is a reflection of the subject’s TB status, is of 
adequate quality, and which can be kept with the trial documentation for the required duration, this 
x-ray can be used as the screening x-ray).

Perform spot sputum for confirmation of acid-fast bacilli (microscopy from smear ≥ 1+) and drug-
susceptible TB using any combination of Xpert MTB/RIF, line probe assay, culture, and/or 
epidemiologic history.

Perform serum hepatitis (HBsAg and anti-HCV) and HIV screen. For HIV positive subjects who are 
included in stage 2, HIV testing does not need to be repeated at screening for HIV positive subjects 
if the HIV positive status has been documented within a month prior to screening and the 
documentation can be kept with the trial documentation for the required duration. For subjects who 
are HIV positive, blood samples are to be drawn for CD4 assessment at the local laboratory.

Perform urine pregnancy test (female subjects only).

Perform FSH testing (postmenopausal female subjects only).

Perform urine/blood alcohol and urine drug screen.

Collect serum chemistry, hematology, urinalysis, and coagulation clinical laboratory samples.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate). Blood pressure and 
heart rate will be taken with the subject in the supine (performed first) and sitting position after 
remaining for  3 minutes in each position and temperature and respiratory rate will be taken with 
the subject in the supine position.

Collect a standard 12-lead ECG in triplicate (5 minutes apart). The ECGs will be recorded after the 
subject has been supine and at rest for ≥ 10 minutes prior to the first ECG and subjects will remain 
supine through the final ECG.
Day −2
Subjects can proceed with the Day −2 assessments as soon as the screening assessments have been 
completed. On Day −2, the following will be performed:

Start overnight sputum collection for Day −2 sample (approximately 10 mL or more) at 
approximately 3:00 PM.

Provide meals as necessary.
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Protocol Version 6.0, 10 May 2021
Table 3.7.3-1
Trial Days and Activities
Day −1
On Day −1, the following will be performed:

End overnight sputum collection (for Day −2 sample) at approximately 7:00 AM. Sputum will be 
cultured on solid media for quantification of bacterial load and in the MGIT system for TTD 
determination, and assessed in the LAM assay. Positive MTB isolates will be tested for MIC to 
OPC-167832 in stages 1 and 2, and for MIC to delamanid in stage 2 only.

Review inclusion and exclusion criteria.

Measure weight.

Perform a complete physical examination.

Collect serum chemistry, hematology, urinalysis, and coagulation clinical laboratory samples.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate). Vital signs will be 
obtained after the subject has been at rest in the supine position for at least 1 minute.

Collect a standard 12-lead ECG in triplicate (5 minutes apart). The ECGs will be recorded after the 
subject has been supine and at rest for ≥ 10 minutes prior to the first ECG and subjects will remain 
supine through the final ECG.

Perform Holter monitoring.

Start overnight sputum collection for Day −1 sample (approximately 10 mL or more) at 
approximately 3:00 PM.

Provide breakfast, lunch, dinner, and an evening snack.
Day 1
On Day 1, the following will be performed:

End overnight sputum collection (for Day −1 sample) at approximately 7:00 AM. Sputum will be 
cultured on solid media for quantification of bacterial load and in the MGIT system for TTD 
determination, and assessed in the LAM assay.

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and at 1, 
2, 4, 8, and 12 hours postdose. Vital signs will be obtained after the subject has been at rest in the 
supine position for at least 1 minute. The post-dose vital signs could be performed within 15 
minutes earlier than the expected post-dose timepoints.

Perform Holter monitoring.

Randomize subjects to a treatment prior to first dosing.

For subjects randomized to OPC-167832 (stage 1) and/or delamanid and/or BDQ (stage 2), collect 
PK blood samples for OPC-167832 only (stage 1) or OPC-167832, delamanid and its metabolite 
DM-6705 or BDQ and its metabolite M2 (stage 2) at predose (within 2 hours prior to dosing) and 
0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature.

Provide breakfast, lunch, dinner, and an evening snack.
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Protocol Version 6.0, 10 May 2021
Table 3.7.3-1
Trial Days and Activities
Day 2
On Day 2, the following will be performed:

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 2 and 
4 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine position 
for at least 1 minute. The post-dose vital signs could be performed within 15 minutes earlier than 
the expected post-dose timepoints.

For subjects randomized to OPC-167832 (stage 1) and/or delamanid and/or BDQ (stage 2), collect 
PK blood sample for OPC-167832 only (stage 1) or OPC-167832, delamanid, and its metabolite 
DM-6705, or BDQ and its metabolite M2 (stage 2) at 24 hours after the Day 1 dose.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature.

Start overnight sputum collection for Day 2 sample (approximately 10 mL or more) at 
approximately 3:00 PM.

Provide breakfast, lunch, dinner, and an evening snack.
Day 3
On Day 3, the following will be performed:

End overnight sputum collection (for Day 2 sample) at approximately 7:00 AM. Sputum will be 
cultured on solid media for quantification of bacterial load and in the MGIT system for TTD 
determination, and assessed in the LAM assay.

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 2 and 
4 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine position 
for at least 1 minute. The post-dose vital signs could be performed within 15 minutes earlier than 
the expected post-dose timepoints.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature.

Provide breakfast, lunch, dinner, and an evening snack.
Day 4
On Day 4, the following will be performed:

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Collect serum chemistry, hematology, urinalysis, and coagulation clinical laboratory samples at 
predose.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 2 and 
4 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine position 
for at least 1 minute. The post-dose vital signs could be performed within 15 minutes earlier than 
the expected post-dose timepoints.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature.

Start overnight sputum collection for Day 4 sample (approximately 10 mL or more) at 
approximately 3:00 PM.

Provide breakfast, lunch, dinner, and an evening snack.
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Protocol Version 6.0, 10 May 2021
Table 3.7.3-1
Trial Days and Activities
Days 5 and 6
On Days 5 and 6, the following will be performed:

End overnight sputum collection (for Day 4 sample) at approximately 7:00 AM (Day 5 only). 
Sputum will be cultured on solid media for quantification of bacterial load and in the MGIT system 
for TTD determination, and assessed in the LAM assay.

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 2 and 
4 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine position 
for at least 1 minute. The post-dose vital signs could be performed within 15 minutes earlier than 
the expected post-dose timepoints.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature.

Start overnight sputum collection for Day 6 sample (approximately 10 mL or more) at 
approximately 3:00 PM (Day 6 only).

Provide breakfast, lunch, dinner, and an evening snack.
Day 7
On Day 7, the following will be performed:

End overnight sputum collection (for Day 6 sample) at approximately 7:00 AM. Sputum will be 
cultured on solid media for quantification of bacterial load and in the MGIT system for TTD 
determination, and assessed in the LAM assay.

Measure weight.

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Collect serum chemistry, hematology, urinalysis, and coagulation clinical laboratory samples at 
predose.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 1, 2, 
4, 8, and 12 hours postdose. Vital signs will be obtained after the subject has been at rest in the 
supine position for at least 1 minute. The post-dose vital signs could be performed within 15 
minutes earlier than the expected post-dose timepoints.

Collect a standard 12-lead ECG in triplicate (5 minutes apart) at predose. The ECGs will be 
recorded after the subject has been supine and at rest for ≥ 10 minutes prior to the first ECG and 
subjects will remain supine through the final ECG.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature.

Provide breakfast, lunch, dinner, and an evening snack.
Day 8
On Day 8, the following will be performed:

Start overnight sputum collection for Day 8 sample (approximately 10 mL or more) at 
approximately 3:00 PM.

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 2 and 
4 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine position 
for at least 1 minute. The post-dose vital signs could be performed within 15 minutes earlier than 
the expected post-dose timepoints.
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Protocol Version 6.0, 10 May 2021
Table 3.7.3-1
Trial Days and Activities

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. IMP will be administered with 
240 mL of still (noncarbonated) water at room temperature. 

Provide breakfast, lunch, dinner, and an evening snack.
Day 9
On Day 9, the following will be performed:

End overnight sputum collection (for Day 8 sample) at approximately 7:00 AM. Sputum will be 
cultured on solid media for quantification of bacterial load and in the MGIT system for TTD 
determination, and assessed in the LAM assay.

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 2 and 
4 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine position 
for at least 1 minute. The post-dose vital signs could be performed within 15 minutes earlier than 
the expected post-dose timepoints.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature. 

Provide breakfast, lunch, dinner, and an evening snack.
Day 10
On Day 10, the following will be performed:

Start overnight sputum collection for Day 10 sample (approximately 10 mL or more) at 
approximately 3:00 PM.

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 2 and 
4 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine position 
for at least 1 minute. The post-dose vital signs could be performed within 15 minutes earlier than 
the expected post-dose timepoints.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature. 

Provide breakfast, lunch, dinner, and an evening snack.
Day 11
On Day 11, the following will be performed:

End overnight sputum collection (for Day 10 sample) at approximately 7:00 AM. Sputum will be 
cultured on solid media for quantification of bacterial load and in the MGIT system for TTD 
determination, and assessed in the LAM assay.

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 2 and 
4 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine position 
for at least 1 minute. The post-dose vital signs could be performed within 15 minutes earlier than 
the expected post-dose timepoints.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature. 

Provide breakfast, lunch, dinner, and an evening snack.
Clinical Study Report 323-201-00003
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Protocol Version 6.0, 10 May 2021
Table 3.7.3-1
Trial Days and Activities
Day 12
On Day 12, the following will be performed:

Start overnight sputum collection for Day 12 sample (approximately 10 mL or more) at 
approximately 3:00 PM.

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 2 and 
4 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine position 
for at least 1 minute. The post-dose vital signs could be performed within 15 minutes earlier than 
the expected post-dose timepoints.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature. 

For subjects randomized to OPC-167832 (stage 1) and /or delamanid and/or BDQ (stage 2), collect 
a PK blood sample for OPC-167832 only (stage 1) or OPC-167832, delamanid and its metabolite 
DM-6705, or BDQ (stage 2) at predose.

Provide breakfast, lunch, dinner, and an evening snack.
Day 13
On Day 13, the following will be performed:

End overnight sputum collection (for Day 12 sample) at approximately 7:00 AM. Sputum will be 
cultured on solid media for quantification of bacterial load and in the MGIT system for TTD 
determination, and assessed in the LAM assay.

Perform a targeted physical examination at predose and 4 hours postdose. The 4-hour post-dose 
targeted physical examination could be performed ± 30 minutes after the expected post-dose 
timepoint.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) at predose and 2 and 
4 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine position 
for at least 1 minute. The post-dose vital signs could be performed within 15 minutes earlier than 
the expected post-dose timepoints.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature. 

For subjects randomized to OPC-167832 (stage 1) and/or delamanid and/or BDQ(stage 2), collect a 
PK blood sample for OPC-167832 only (stage 1) or OPC-167832, delamanid and its metabolite 
DM-6705, or BDQ and its metabolite M2 (stage 2) at predose.

Provide breakfast, lunch, dinner, and an evening snack.
Day 14
On Day 14, the following will be performed:

Measure weight. Perform a targeted physical examination at predose and 4 hours postdose. The 4-
hour post-dose targeted physical examination could be performed ± 30 minutes after the expected 
post-dose timepoint.

Collect serum chemistry, hematology, urinalysis, and coagulation clinical laboratory samples at 
predose.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate) predose and 1, 2, 4, 
8, and 12 hours postdose. Vital signs will be obtained after the subject has been at rest in the supine 
position for at least 1 minute. The post-dose vital signs could be performed within 15 minutes 
earlier than the expected post-dose timepoints.

Collect a standard 12-lead ECG in triplicate (5 minutes apart) at predose. The ECGs will be 
recorded after the subject has been supine and at rest for ≥ 10 minutes prior to the first ECG and 
subjects will remain supine through the final ECG.
Clinical Study Report 323-201-00003
16.1.1 Protocol and Protocol Amendments
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Protocol Version 6.0, 10 May 2021
Table 3.7.3-1
Trial Days and Activities

Perform Holter monitoring.

For subjects randomized to OPC-167832 (stage 1) and/or delamanid and/or BDQ (stage 2), collect 
PK blood samples for OPC-167832 only (stage 1) or OPC-167832, delamanid and its metabolite 
DM-6705 or BDQ and its metabolite M2 (stage 2) at predose (within 2 hours prior to dosing) and 
0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose.

For subjects randomized to RHEZ only, collect PK blood samples for rifampin and isoniazid at 2 
and 6 hours postdose.

Administer oral dose of RHEZ or IMP. RHEZ will be administered with 240 mL of still 
(noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. The IMP will be administered 
with 240 mL of still (noncarbonated) water at room temperature.

Start overnight sputum collection for Day 14 sample (approximately 10 mL or more) at 
approximately 3:00 PM.

Provide breakfast, lunch, dinner, and an evening snack.
Day 15
On Day 15, the following will be performed:

End overnight sputum collection (for Day 14 sample) at approximately 7:00 AM. Sputum will be 
cultured on solid media for quantification of bacterial load and in the MGIT system for TTD 
determination, and assessed in the LAM assay. Positive MTB isolates will be tested for MIC to 
OPC-167832 in stages 1 and 2, and for MIC to delamanid in stage 2 only.

Perform a targeted physical examination.

Assess vital signs.

For subjects randomized to OPC-167832 (stage 1) and/or delamanid and/or BDQ (stage 2), collect 
PK blood samples for OPC-167832 only (stage 1) or OPC-167832, delamanid and its metabolite 
DM-6705, or BDQ and its metabolite M2 (stage 2) at 24 and 36 hours after the Day 14 dose.

Administer RHEZ to subjects randomized to RHEZ. RHEZ will be administered with 240 mL of 
still (noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. Administer treatment for 
pulmonary TB to subjects randomized to IMP according to the local standard of care regimen 
(RHEZ) if clinically necessary.a

Provide breakfast, lunch, dinner, and an evening snack.
Day 16
On Day 16, the following will be performed:

Perform a targeted physical examination.

Assess vital signs.

For subjects randomized to OPC-167832 (stage 1) and/or delamanid and/or BDQ (stage 2), collect 
PK blood samples for OPC-167832 only (stage 1) or OPC-167832, delamanid and its metabolite 
DM-6705, or BDQ and its metabolite M2 (stage 2) at 48 hours postdose.

Administer RHEZ to subjects randomized to RHEZ. RHEZ will be administered with 240 mL of 
still (noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. Administer treatment for 
pulmonary TB to subjects randomized to IMP according to the local standard of care regimen 
(RHEZ) if clinically necessary.a

Provide breakfast, lunch, dinner, and an evening snack.
Day 17
On Day 17, the following will be performed:

Perform a targeted physical examination.

Assess vital signs.

For subjects randomized to OPC-167832 (stage 1) and/or delamanid and/or BDQ (stage 2), collect 
PK blood samples for OPC-167832 only (stage 1) or OPC-167832, delamanid and its metabolite 
DM-6705 or BDQ and its metabolite M2 (stage 2) at 72 hours postdose.

Administer RHEZ to subjects randomized to RHEZ. RHEZ will be administered with 240 mL of 
still (noncarbonated) water 1 hour prior to a meal or 2 hours after a meal. Administer treatment for 
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Table 3.7.3-1
Trial Days and Activities
pulmonary TB to subjects randomized to IMP according to the local standard of care regimen 
(RHEZ) if clinically necessary.a

Provide breakfast, lunch, dinner, and an evening snack.
Day 18
On Day 18, the following will be performed:

Perform a targeted physical examination.

Assess vital signs.

Provide treatment for pulmonary TB according to the local standard of care regimen.

For subjects randomized to OPC-167832 (stage 1) and/or delamanid and/or BDQ (stage 2), collect 
PK blood samples for OPC-167832 only (stage 1) or OPC-167832, delamanid and its metabolite 
DM-6705, or BDQ and its metabolite M2 (stage 2) at 96 hours postdose.

Administer RHEZ (treatment for pulmonary TB to all subjects according to the local standard of 
care regimen) to all subjects.

Provide breakfast, lunch, dinner, and an evening snack.
Day 19
On Day 19, the following will be performed:

Perform a targeted physical examination.

Assess vital signs.

Provide treatment for pulmonary TB according to the local standard of care regimen.

For subjects randomized to OPC-167832 (stage 1) and/or delamanid and/or BDQ (stage 2), collect 
PK blood samples for OPC-167832 only (stage 1) or OPC-167832, delamanid and its metabolite 
DM-6705, or BDQ and its metabolite M2 (stage 2) at 120 hours postdose.

Administer treatment for pulmonary TB to all subjects according to the local standard of care 
regimen (RHEZ).

Provide breakfast, lunch, dinner, and an evening snack.
Day 20/ET
On Day 20 (or at ET), the following will be performed:

Perform a targeted physical examination.

Measure weight.

Assess vital signs (blood pressure, heart rate, temperature, and respiratory rate). Vital signs will be 
obtained after the subject has been at rest in the supine position for at least 1 minute.

Collect serum chemistry, hematology, urinalysis, and coagulation clinical laboratory samples.

For subjects randomized to OPC-167832 (stage 1) and/or delamanid and/or BDQ (stage 2), collect a 
PK blood sample for OPC-167832 only (stage 1) or OPC-167832, delamanid and its metabolite 
DM-6705, or BDQ and its metabolite M2 (stage 2) at 144 hours after the Day 14 dose.b

Administer treatment for pulmonary TB to all subjects according to the local standard of care 
regimen (RHEZ).

After completion of the inpatient stay, all subjects must be referred to local community clinics to 
receive continued treatment for pulmonary TB per the local standard of care regimen.

Provide meals as needed.

Discharge subjects from the trial site.
Follow-up (14  3 Days After the Last Dose of Trial Treatment [IMP or RHEZ])
Contact the subjects via telephone for follow-up of AEs and concomitant medication.
Throughout the Trial
The following will be performed from the screening visit through and during the follow-up telephone 
call:

Assess and record AEs

Record prior/concomitant medications (including current oral antipsychotic medication), as 
applicable.
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aIn subjects with no clinical indication to start RHEZ immediately, commencement of RHEZ can be 
delayed for up to 3 days (Days 15, 16, or 17) under close supervision in the trial site hospital ward
bThe Day 20 PK sample will be collected during the ET visit.
3.7.4
Prior and Concomitant Medications
The investigator will record all medications and therapies taken by the subject from 
30 days prior to signing of informed consent through the end of the evaluation period 
(defined as the time period during which subjects are evaluated for primary and/or 
secondary objectives) on the case report form. The investigator will record all 
medications and therapies taken by the subject for treatment of an AE or which caused an 
AE until the end of the trial (defined as the last date of contact or date of final contact 
attempt) on the case report form.
3.7.5
Efficacy Assessments
3.7.5.1
Spot Sputum Samples
Spot sputum samples will be collected at the time point presented in the Schedule of 
Assessments, Table 3.7-1. Microscopy results from a smear will be used to confirm the 
presence of acid-fast bacilli (≥ 1+). Confirmation of drug-susceptible TB will be 
performed using any combination of Xpert MTB/RIF, line probe assay, culture, and/or 
epidemiologic history.
3.7.5.2
Overnight Sputum Samples
Sputum samples (approximately 10 mL or more) will be collected from between 
approximately 3:00 PM (first day of collection) and 7:00 AM (second day of collection) 
for 16 hours overnight at the time points presented in the Schedule of Assessments, Table 
3.7-1. The 16-hour sputum sampling must be finished prior to the administration of each 
day’s IMP or RHEZ. The appropriately labeled sputum container must be placed in a 
biohazard bag, in the fridge until collection by the courier. The fridge temperature should 
be between 2 and 8°C.
Sputum will be cultured on solid media for quantification of bacterial load and in the 
MGIT system for TTD determination, and assessed in the LAM assay.
Minimum inhibitory concentration testing for delamanid, BDQ (stage 2 only), and 
OPC-167832 (stage 1 and stage 2) will be batch tested at the end of each stage of the trial 
on baseline (Day −2) and Day 14 positive isolates.
M. tuberculosis isolates will be retained at the local laboratory for potential additional 
analysis of the TB bacilli.
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3.7.6
Safety Assessments
3.7.6.1
Adverse Events
Refer to Section 5 for the methods and timing for assessing, recording, and analyzing 
AEs.
3.7.6.2
Clinical Laboratory Tests
The clinical laboratory tests listed in Table 3.7.6.2-1 will be collected at the times 
presented in the Schedule of Assessments, Table 3.7-1, and processed in accordance with 
directions from the clinical laboratory.
Table 3.7.6.2-1
Clinical Laboratory Tests
Hematology:
Hematocrit
Hemoglobin
Platelet count
Mean corpuscular hemoglobin concentration
Mean corpuscular volume
RBC count
WBC count with differential
Urinalysis:
Appearance
Bilirubin
Color
Glucose
Ketones
Leukocytes
Microscopic analysis of RBC/WBC (per high 
powered field)
Nitrites
Occult blood
Protein
Urobilinogen
Coagulation:
International normalized ratio
Partial thromboplastin time
Prothrombin time
Additional Tests:
anti-HCV
CD4 count 
HBsAg
HIV
Urine pregnancy test (female subjects)
FSH (postmenopausal female subjects)
Serum Chemistry:
Albumin
ALP
ALT
AST
Bilirubin, total
Blood urea nitrogen
Calcium
Carbon dioxide
Creatinine
Creatine kinase
GGT
Glucose
Lactic dehydrogenase
Magnesium
Potassium
Protein, total
Sodium
Uric acid
Triglycerides
Drug Screen (all items in urine except where noted)
Alcohol (urine or blood test)
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Methadone
Opiates
Phencyclidine
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
GGT = gamma glutamyl transferase; RBC = red blood cell; WBC = white blood cell.
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A urine pregnancy test will be conducted prior to trial intervention (at screening) in 
female subjects; results will be available prior to the first administration of IMP or RHEZ 
on Day 1.
3.7.6.3
Physical Examination and Vital Sign Assessments
Complete and targeted physical examinations will be performed at the time points 
presented in the Schedule of Assessments, Table 3.7-1.
The physical examination will include an evaluation of the following: head, ears, eyes, 
nose, and throat; neck and chest; abdomen; extremities; nervous system; and skin and 
mucosae. A targeted physical examination is a review that focuses on subject driven 
issues eg, the investigator enquires if the subject has any complaints, pains or 
disturbances and this would lead to further evaluation of the problematic area. At a 
minimum, there should be an assessment of general appearance and a chest examination 
should be performed. The 4-hour post-dose targeted physical examination could be 
performed ± 30 minutes after the expected post-dose timepoint. The principal investigator 
or appointed medical doctor is primarily responsible for performing the physical 
examination. Whenever possible, the same individual should perform all physical 
examinations for each subject. If the appointed designee is to perform the physical 
examination, he/she must be permitted by local regulations and his/her name must be 
included on the FDA Form 1572. Any clinically significant condition present at physical 
examinations performed after the first dose of IMP or RHEZ on Day 1 that was not 
present at the baseline examination should be documented as an AE and followed to a 
satisfactory conclusion.
Body height and weight will also be measured at the time points presented in the 
Schedule of Assessments, Table 3.7-1. For the measurement of height, the measurement 
will be made without shoes. For the measurement of weight, all efforts will be made to 
use the same scale for all measurements throughout the trial.
Vital signs (blood pressure, heart rate, temperature, and respiratory rate) will be assessed 
at the time points presented in the Schedule of Assessments, Table 3.7-1. Vital signs will 
be obtained prior to PK blood draws and ECGs at the nominal time points, where 
applicable. At screening, blood pressure and heart rate will be taken with the subject in 
the supine (performed first) and sitting position after remaining for  3 minutes in each 
position and temperature and respiratory rate will be taken with the subject in the supine 
position. At all other time points, vital signs will be obtained after the subject has been at 
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rest in the supine position for at least 1 minute. The post-dose vital signs could be 
performed within 15 minutes earlier than the expected post-dose timepoints.
3.7.6.4
Standard 12-lead Electrocardiograms
Standard 12-lead ECGs will be collected in triplicate (5 minutes apart) at the time points 
presented in the Schedule of Assessments, Table 3.7-1. The mean ECGs of the 3 time 
points will be utilized to determine subject's eligibility during screening. The ECGs will 
be collected prior to PK blood draws and after vital signs at the nominal time points, 
where applicable.
Standard 12-lead ECGs will be recorded after the subject has been supine and at rest 
for ≥ 10 minutes prior to the first ECG and subjects will remain supine through the final 
ECG. Heart rate, ventricular rate, RR interval, PR interval, QRS duration, and QT 
intervals will be recorded. The QTcF and corrected QT interval using Bazett’s method 
(QTcB) will be calculated. The 12-lead ECGs will be evaluated at the trial sites to 
determine the subject’s eligibility and to monitor safety during the trial. The principal 
investigators or designees (licensed physician) will review, sign, and date each ECG 
reading, noting whether or not any abnormal results are of clinical significance. The ECG 
will be repeated if any results are considered to be clinically significant. The reviewers 
must be listed on FDA Form 1572 and the trial site delegation of responsibility form. 
Electrocardiogram data will be recorded electronically by the central ECG laboratory(ies) 
and by the trial site(s). Eligibility for the trial will be based on the central ECG report at 
the screening visit.
3.7.7
Pharmacokinetic and Pharmacodynamic Assessments
3.7.7.1
Pharmacokinetic Assessments
Blood samples for PK analysis will be collected at the time points presented in the 
Schedule of Assessments, Table 3.7-1. If a sample cannot be drawn at the designated 
time, a window of  15 minutes for each blood draw is acceptable; the exact time of the 
draw must be recorded in the electronic case report form (eCRF).
Stage 1: Concentrations of OPC-167832, rifampicin, and isoniazid will be analyzed. 
Stage 2: Concentrations of OPC-167832, delamanid, and its metabolite DM-6705, BDQ, 
rifampicin, and isoniazid will be analyzed.
Additional metabolites that are not identified in the protocol may also be analyzed if new 
information becomes available.
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Plasma samples will be shipped to the bioanalytical laboratory identified in Appendix 2 
and stored in a freezer at the trial site(s). Detailed handling and shipping instructions are 
provided in the Operations Manual.
3.7.7.2
Pharmacodynamic Assessments
Holter monitoring will be performed on Days −1, 1, and 14 as per the Schedule of 
Assessments, Table 3.7-1.
Overnight sputum specimens will be provided to the microbiological laboratory for 
sputum culture and Otsuka TB LAM ELISA measurements.
3.7.8
Genetic Assessments
No assessments of human genetic material are planned for this protocol.
3.7.9
Future Biospecimen Research Samples
No future biospecimen research assessments are planned for this protocol.
3.7.10
End of Trial
The end of trial date is defined as the last date of contact or the date of the final contact 
attempt from the post-treatment follow-up eCRF page for the last subject completing or 
withdrawing from the trial.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial or Treatment Arm(s)
In the event of sponsor termination or suspension of the trial for any reason, prompt 
notification will be given to investigators, IEC, and regulatory authorities in accordance 
with regulatory requirements.
3.8.2
Individual Site
The sponsor, investigator, or the IEC has the right to terminate the participation of a 
particular trial site, if necessary, due to lack of subject enrollment, noncompliance with 
the protocol, or if judged to be necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP. The sponsor is to be 
notified promptly if the trial was terminated by the investigator or the IEC at the trial site.
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3.8.3
Individual Subject Discontinuation
3.8.3.1
Treatment Discontinuation
After the first dose of IMP or RHEZ on Day 1, a subject may stop treatment permanently 
for a variety of reasons. Treatment discontinuations may be initiated by a subject or may 
become medically necessary due to AEs, required treatment with a disallowed medication 
or therapy, or other reasons, as determined by the investigator. If a subject discontinues 
treatment, their participation in the trial will be discontinued. Discontinued subjects 
should be encouraged to complete all ET and follow-up assessments with ET assessments 
conducted as soon as possible after the subject is withdrawn. 
3.8.3.2
Documenting Reasons for Discontinuation
All subjects have the right to withdraw and the investigator can discontinue a subject’s 
participation in the trial at any time if medically necessary.
In addition, subjects meeting the following criteria must be withdrawn from the trial 
(only one reason for discontinuation [the main reason] can be recorded in the eCRF):

Death

TB disease relapse or TB disease progression

Failure to meet inclusion and exclusion criteria

Lost to follow-up

Occurrence of QTcF > 500 msec

Noncompliance with IMP or RHEZ (if confirmed not related to an AE)

Physician decision (other than AE)

Pregnancy (see Section 5.5)

Major protocol deviation (other than noncompliance with IMP or RHEZ)

Site terminated by sponsor

Trial terminated by sponsor

Withdrawal of consent by parent/guardian (if confirmed not related to an AE)

Withdrawal of consent by subject (if confirmed not related to an AE)
If the subject discontinues IMP or RHEZ due to an AE, the investigator, or other trial 
personnel, will make every effort to follow the event until it has resolved or stabilized. 
Follow-up procedures in Section 3.8.3.1 must be followed. Subjects may be replaced, if 
discontinuations/withdrawals occur, as described in Section 3.3.
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3.8.3.3
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation.
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be understood, documented, and 
managed to protect the rights of the subject and the integrity of the trial.
Subjects who withdraw, should be encouraged to complete all ET and follow-up 
assessments with ET assessments conducted as soon as possible after the subject is 
withdrawn.
3.9
Screen Failures
Subjects who sign an ICF but who do not receive IMP or RHEZ are permitted to be 
rescreened. In the event that the subject is rescreened for trial participation, a new ICF 
must be signed, a new screening number assigned, and all screening procedures repeated.
A screen failure subject is one from whom informed consent is obtained and is 
documented (ie, subject signs an ICF), but who is not randomized or assigned trial 
treatment.
3.10
Definition of Completed Subjects
The evaluation period is defined as the time period during which subjects are evaluated 
for primary and/or secondary objectives of the trial irrespective of whether the subject 
actually consumes all doses of IMP or RHEZ. Subjects who are evaluated at the last 
scheduled visit during the evaluation period will be defined as trial completers. For 
purposes of this trial, subjects who complete Day 20 will be defined as trial completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before 14 (± 3) days after the last dose of trial 
treatment (IMP or RHEZ) and who do not have a known reason for discontinuation (eg, 
withdrew consent or AE, etc.), except those who have completed the trial as defined in 
Section 3.10, will be classified as “lost to follow-up” as the reason for discontinuation.
The trial site will make 3 documented attempts to contact the subject by telephone and in 
the event the site is unable to reach the subject by telephone, the site will attempt to 
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contact the subject via certified mail or an alternative similar method where appropriate, 
before assigning a “lost to follow-up” status.
3.12
Subject Compliance
The time and dose of IMP and RHEZ administration during the trial will be recorded on 
the eCRF. Information regarding any inappropriately administered doses will also be 
documented on the eCRF.
All doses of IMP and RHEZ will be administered at the trial site while subjects are 
inpatient. Compliance will be ensured by a hand and mouth check during the oral dosing 
administration.
3.13
Protocol Deviations
In the event of a major deviation from the protocol due to an emergency, accident, or 
mistake (eg, IMP or RHEZ dispensing or subject dosing error or concomitant 
medication), the investigator or designee will contact the sponsor at the earliest possible 
time by telephone. The investigator, medical monitor, and sponsor will come to a joint 
decision as quickly as possible regarding the subject’s continuation in the trial. If the 
decision reached is to allow the subject to continue in the trial, this must be documented 
by the investigator and the sponsor, and approved or disapproved by the medical monitor.
4
Restrictions
4.1
Prohibited Medications
Quinolones and prednisolone should not be used within 3 months prior to the screening 
visit and during the screening period until Day 20. Subjects should not be taking or start 
antiretroviral therapy within 2 weeks of the completion of the trial.
The selected CYP3A4 inhibitors and inducers presented in Table 4.1-1 and Table 4.1-2, 
respectively should be not used from Day −2 until Day 20.14 
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Table 4.1-1
List of Selected Cytochrome P450 3A4 Inhibitors Prohibited 
During the Trial
Potent CYP3A4 Inhibitors:
Viekira PAK2
Danoprevir 
Indinavir 
Elvitegravir
Tipranavir
Saquinavir 
Ritonavir
Lopinavir
Cobicistat 
Itraconazole
Ketoconazole
Voriconazole
Troleandomycin
Mibefradil
Telaprevir
Clarithromycin
Posaconazole
Nelfinavir
Telithromycin
Nefazodone
Grapefruit juice
Idelalisib
Conivaptan
Boceprevir
Moderate CYP3A Inhibitors:
Erythromycin
Faldaprevir
Fluconazole
Imatinib
Atazanavir
Verapamil
Diltiazem
Netupitant
Darunavir
Nilotinib
Dronedarone
Tofisopam
Crizotinib
Cyclosporine
Atazanavir
Ciprofloxacin
Aprepitant
Isavuconazole
Casopitant
Cimetidine
Amprenavir
Note: Please communicate with the sponsor’s medical monitor if the subject needs to receive any 
medication (other than IMP or RHEZ) that is not on this list.
Table 4.1-2
List of Selected Cytochrome P450 3A4 Inducers Prohibited 
During the Trial
Potent CYP3A4 Inducers:
Carbamazepine
Enzalutamide 
Mitotane
Phenytoin
Rifampin
St. John’s wort
Moderate CYP3A Inducers:
Bosentan
Efavirenz
Etravirine
Modafinil
Note: Please communicate with the sponsor’s medical monitor if the subject needs to receive any 
medication (other than IMP or RHEZ) that is not on this list.
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4.2
Other Restrictions
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 until Day 20 is prohibited. Restrictions on activity following dosing are 
described in Section 3.7.1.
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. Adverse events would not include information recorded 
as medical history at screening for preplanned procedures for which the underlying 
condition was known and no worsening occurred.
An adverse reaction is any untoward and unintended response to an IMP related to any 
dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. For the purpose of Investigational New Drug (IND) safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between 
the IMP and the AE. “Suspected adverse reaction” implies a lesser degree of certainty 
about causality than “adverse reaction”.
A serious AE (SAE) includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred. It does not include an event that, had it 
occurred in a more severe form, might have caused death.

Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions.

Requires inpatient hospitalization or prolongs hospitalization

Hospitalization itself should not be reported as a serious treatment-emergent AE 
(TEAE); whenever possible the reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not considered 
serious TEAEs.

Congenital anomaly/birth defect.
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
Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above, eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse.
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE.
Immediately Reportable Event:

Any SAE

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 5.4).

Pregnancies are also defined as immediately reportable events (IREs). Although 
normal pregnancy is not an AE, it will mandate IMP discontinuation and must be 
reported on an IRE form to the sponsor. Pregnancy will only be documented on the 
AE eCRF if there is a complication or abnormality in the newborn.
Clinical Laboratory Assessment Value Changes: It is the investigator’s responsibility to 
review the results of all laboratory tests as they become available. This review will be 
documented by the investigator’s dated signature on the laboratory report. For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically relevant) change from baseline for that individual subject. This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed. The investigator may repeat the laboratory test or request additional 
tests to verify the results of the original laboratory tests. If this laboratory value is 
considered clinically relevant by the investigator (eg, subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, treatment interruption, or fulfills a seriousness criterion, this is 
considered an AE.
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the eCRF. The intensity of an AE is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
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In addition, all AEs will be graded on a 5-point scale according to the “DAIDS Table for 
Grading the Severity of Adult and Pediatric AEs” (Appendix 3).
Causality: Assessment of causal relationship of an AE to the use of trial treatment (IMP 
or RHEZ):
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the trial treatment (IMP or RHEZ) and the 
AE.
Not Related: 
There is no temporal or reasonable relationship between the trial 
treatment (IMP or RHEZ) and the AE.
5.2
Eliciting and Reporting Adverse Events
The investigator will assess subjects for the occurrence of AEs from the time the ICF is 
signed until the end of the trial. For this trial, information on AEs will be followed for up 
to 14 (± 3) days after the last dose of trial treatment (IMP or RHEZ) has been 
administered. To avoid bias in eliciting AEs, subjects should be asked the following 
nonleading question: “How are you feeling?” All AEs (serious and nonserious) reported 
by the subject must be recorded on the source documents and eCRFs provided by the 
sponsor. Serious AE collection is to begin after a subject has signed the ICF.
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
AEs only if there are unusual or severe clinical features that were not present, not 
experienced earlier, or not expected based on the course of the condition.
In addition, the sponsor and Clindev Pty Ltd must be notified immediately by fax or 
e-mail of any IREs according to the procedure outlined below in Section 5.3. Special 
attention should be paid to recording hospitalization and concomitant medications.
5.3
Immediately Reportable Events
The investigator must report any SAE, potential serious hepatotoxicity, or confirmed 
pregnancy, immediately after either the investigator or trial site personnel become aware 
of the event. An IRE form should be completed and sent by fax or e-mail using the 
contact information on the title page of this protocol, and as follows:
Fax:
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E-mail: 
(Please note that the IRE form is a specific form provided by the sponsor and is NOT the 
AE eCRF.)
Subjects experiencing SAEs should be followed clinically as described in Section 5.7.2. 
It is expected that the investigator will provide or arrange appropriate supportive care for 
the subject and will provide prompt updates on the subject’s status to the sponsor.
5.4
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is  3 times the upper limit of normal (ULN), a total 
bilirubin level should also be evaluated. If the total bilirubin is ≥ 2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on the eCRF.
5.5
Pregnancy
Women of childbearing potential are women whose menstruation has started and who are 
not documented as sterile (eg, have had a bilateral oophorectomy, or hysterectomy, or 
who have been postmenopausal for at least 12 months).
For men and women of childbearing potential, who are sexually active, there must be a 
documented agreement that the subject and their partner will take effective measures 
(ie, 2 different approved methods of birth control or remains abstinent) to prevent 
pregnancy during the course of the trial and for 12 weeks after the last dose of trial 
treatment (IMP or RHEZ). Unless the subject is sterile (ie, women who have had a 
bilateral oophorectomy, have had a hysterectomy, or have been postmenopausal for at 
least 12 consecutive months; or men who have had a bilateral orchidectomy) or remains 
abstinent during the trial and for 12 weeks after the last dose of trial treatment (IMP or 
RHEZ), 2 of the following approved methods of birth control must be used: vasectomy, 
tubal ligation, intrauterine device, birth control pills, birth control implant, birth control 
depot injection, condom, sponge, or occlusive cap (vaginal diaphragm or cervical/vault 
cap). Due to safety considerations, spermicides are no longer recommended to be used by 
subjects who will be participating in this trial. Any single method of birth control, 
including vasectomy and tubal ligation, may fail, leading to pregnancy. The contraceptive 
method will be documented in the eCRF. Male subjects must also agree not to donate 
sperm from trial screening through 12 weeks after the last dose of trial treatment (IMP or 
RHEZ).
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Before enrolling men and women in this clinical trial, investigators must review the 
below information about trial participation as part of the ICF process. The topics should 
generally include:

General information

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Follow-up of a reported pregnancy
Before trial enrollment, men and women of childbearing potential must be advised of the 
importance of avoiding pregnancy during trial participation and the potential risk factors 
for an unintentional pregnancy. Subjects must sign the ICF confirming that the 
above-mentioned risk factors and the consequences were discussed.
A urine pregnancy test for human chorionic gonadotropin will be performed at screening 
on all female subjects. If a urine test is performed and is positive, the investigator will 
follow-up with a confirmatory serum test.
During the trial, all women of childbearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (eg, missed or late 
menstrual cycle). Male subjects should also be instructed to contact the investigator 
immediately, during the trial, if their partners suspect that they might be pregnant (eg, 
missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. Exceptions to trial 
discontinuation may be considered for life-threatening conditions only after consultations 
with the sponsor or medical monitor.
The investigator(s) must immediately notify the sponsor of any pregnancy associated 
with IMP exposure during the trial and for at least 12 weeks after the last dose of trial 
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treatment (IMP or RHEZ), and record the event on the IRE form and forward it to the 
sponsor. The sponsor will forward the Pregnancy Surveillance Form(s) to the investigator 
for monitoring the outcome of the pregnancy. 
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to the sponsor, on the Pregnancy Surveillance Form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants will be followed for a minimum of 6 months from the date of 
birth. Local regulatory requirements must be followed for follow-up and reporting on 
pregnancy cases or infants.
5.6
Procedure for Breaking the Blind
Not applicable, this is an open-label trial.
5.7
Follow-up of Adverse Events
5.7.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing on the eCRF. For any AE having been identified throughout the trial, during 
data analysis, additional relevant medical history information may be requested by the 
sponsor to further ascertain causality (including, but not limited to, information such as 
risk-related behavior, family history and occupation).
5.7.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
This trial requires that subjects be actively monitored for ongoing SAEs and IREs up to 
14 (± 3) days after the last dose of IMP is administered.
Serious AEs and nonserious IREs that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eCRF page. If updated information 
(eg, resolved status) on SAE or IRE status becomes available after a subject’s last 
scheduled contact (up to last in-clinic visit for the entire trial), this must be reported to the 
sponsor and recorded on the AE eCRF page or the safety database if the eCRF data is 
locked, according to the appropriate reporting procedures. The investigator(s) will follow 
SAEs until the events are resolved or stabilized, or the subject is lost to follow-up or has 
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died. Resolution means the subject has returned to the baseline state of health and 
stabilized means that the investigator does not expect any further improvement or 
worsening of the subject’s condition. The investigator(s) will continue to report any 
significant follow-up information to the sponsor up to the point the event has resolved or 
stabilized, or the subject is lost to follow-up or has died.
5.7.3
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring After Last Scheduled 
Contact
Any new SAEs or IREs reported to the investigator which occur after the last scheduled 
contact and are determined by the investigator(s) to be reasonably associated with the use 
of the IMP, should be reported to the sponsor. This may include SAEs or IREs that are 
captured on follow-up telephone contact or at any other time point after the defined trial 
period. The investigator(s) should follow SAEs or IREs identified after the defined trial 
period and continue to report any significant follow-up information to the sponsor until 
the events are resolved or stabilized, or the subject is lost to follow-up or has died.
6
Pharmacokinetic Analysis
6.1
Pharmacokinetic Methods
Pharmacokinetic parameters will be determined using noncompartmental analysis 
methods. If data are not adequate, certain parameters may not be calculated. 
Pharmacokinetic concentrations and parameters will be summarized by treatment using 
descriptive statistics (number, median, mean, standard deviation [SD], percent coefficient 
of variation, minimum, and maximum). Pharmacokinetic concentrations and parameters 
will also be listed by subject.
In addition to the noncompartmental analysis, population PK modeling will be performed 
on OPC-167832 PK data from both stages.
No PK analysis will be performed on rifampin and isoniazid concentrations.
6.2
Pharmacodynamic Methods
Holter monitoring will be summarized descriptively by treatment. Data will also be 
presented in listings.
Colony-forming units from solid culture, LAM concentrations from the Otsuka TB LAM 
ELISA, and MGIT TTD will be utilized for PK/PD correlations.
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6.3
Pharmacokinetics/Pharmacodynamics Methods
Exposure-response modeling will be performed in both stages for OPC-167832 PK 
measures versus bacterial load using LAM and CFU counts on agar media, with the 
intent of identifying Emax, the maximum estimated decline in LAM and CFU counts and 
EC80, the exposure that corresponds to 80% of the Emax.
For stage 2, the Emax and EC80 for subjects receiving OPC-167832 and 300 mg 
delamanid will be compared with the Emax and EC80 of OPC-167832 given alone in 
stage 1.
Published studies have established that EC80 can be used for strong bactericidal drugs as 
the “optimal” target from the PK/PD analysis.15,16,17,18,19 In the data submitted to the 
European Medicines Agency to qualify the hollow-fiber system as a drug development 
tool for TB20 EC80 was used as the optimal target for bactericidal drugs (personal 
communication: T. Gumbo, University of Baylor, Dallas, Texas, US, and D. Hanna, 
Critical Path to TB Drug Regimens, Tempe, Arizona, US).
The relationship between QT interval (Holter data) and plasma concentrations of 
OPC-167832 (stage 1) and OPC-167832 when administered with delamanid and/or BDQ 
(stage 2) will be examined using an exposure-response analysis.
6.4
Pharmacogenomic Methods
No pharmacogenomics analysis is planned.
7
Statistical Analysis
7.1
Determination of Sample Size
The trial is not powered for formal statistical hypothesis testing or comparisons. The 
sample size is based on sample sizes from several similar trials in the literature.21 
7.2
Datasets for Analysis
The PK population will include all subjects with adequate data for deriving the PK 
parameters.
Safety analysis will be conducted based upon the safety population. All subjects who 
received any dose of IMP or RHEZ will be included in the safety population.
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Efficacy analyses will be conducted based upon the modified intent-to-treat (MITT) 
population. The MITT population will include all subjects who were quantitative 
culture-positive at baseline and met all of the inclusion criteria.
7.3
Handling of Missing Data
No data imputation will be performed for missing plasma or sputum concentrations in 
this trial.
7.4
Primary and Secondary Endpoint Analyses
Pharmacokinetic methods are described in Section 6.1 and safety analysis is described in 
Section 7.6.
Primary and secondary efficacy endpoint analyses are described in Section 7.4.1 and 
Section 7.4.2, respectively. Other efficacy analyses are described in Section 7.8. Efficacy 
data will be summarized by randomized treatment using descriptive statistics (number, 
median, mean, SD, percent coefficient of variation, minimum, and maximum) or 
presented in figures (where applicable). Change from baseline in log-CFU, log-LAM, and 
MGIT TTD will be presented by randomized treatment group in each stage. In addition, 
listings will be presented for efficacy assessments by subject.
7.4.1
Primary Efficacy Endpoint Analyses
7.4.1.1
Stage 1
The EBA of OPC-167832 will be determined by the decline in bacterial load.
Individual subject EBA estimates will be obtained using both a two-point EBA 
calculation as well as a linear-regression based approach. Early bactericidal activity 
estimates will be derived over the first 14 days (see equation 1 in Section 7.4.1.1.1).
The EBA for the RHEZ comparator arm will be based on the results for all of the subjects 
receiving RHEZ treatment in each of the treatment cohorts in stage 1. After the 
completion of stage 2, the EBA for the RHEZ comparator arm will be recalculated 
including subjects assigned to the RHEZ regimen in both stage 1 and stage 2.
7.4.1.1.1
Two-time Point Early Bactericidal Activity Calculation
Early bactericidal activity (EBA) between day x and day y will be defined by the following 
equation: 
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𝐸𝐵𝐴𝑥―𝑦,𝑖=
𝐿𝑜𝑔10 𝑣𝑎𝑙𝑢𝑒𝑥,𝑖― 𝐿𝑜𝑔10 𝑣𝑎𝑙𝑢𝑒𝑦,𝑖
𝑦― 𝑥
(1)
where y and x are trial days in integer values (with baseline defined as the average of 
measurements at Day-2 and Day -1), EBAx-y,i is the EBA estimate for the ith subject 
across days x to y, and Log10 valuex,i and Log10 valuey,i are the log10-transformed assay 
values on days x and y, respectively, for the specified assay on samples from the ith 
subject.
The EBA effect size will be expressed as a ratio of the estimated EBA for OPC-167832 
and the estimated EBA for RHEZ. For example, the 14-day EBA for delamanid 200 mg 
QD was 0.84 log-CFU and the 14-day EBA for RHEZ was 1.44 log-CFU; the 14-day 
EBA of delamanid was estimated to be 58% of the EBA of the 4-drug RHEZ regimen.22 
7.4.1.1.2
Early Bactericidal Activity Estimation via Linear Mixed Effects 
Modeling
When each stage assay data are available, linear mixed effects modeling will also be used 
to determine the EBA estimates across all available time points from baseline through 
Day 14 of treatment. Details will be documented in the statistical analysis plan prior to 
database lock.
7.4.2
Secondary Efficacy Endpoint Analyses
The secondary analyses of EBA will estimate the slope of the change in log-LAM values 
and the change in TTD in the automated MGIT system.
The analyses of the secondary endpoints of change in log-LAM values and change in 
TTD in stage 2 will be conducted in a way similar to comparisons of change in log-CFU 
specified above for stage 2. The endpoint is change in EBA from baseline to Day 14. 
Treatment group comparisons in stage 2 are:
1) OPC-167832 30 mg + delamanid 300 mg + BDQ 400 mg vs OPC-167832 30 mg 
+ delamanid 300 mg;
2) OPC-167832 30 mg + delamanid 300 mg + BDQ 400 mg vs OPC-167832 30 mg 
+ BDQ 400 mg;
3) OPC-167832 30 mg + delamanid 300 mg vs OPC-167832 30 mg in Stage 1 using 
connectivity of RHEZ in Stages 1 and 2;
4) OPC-167832 30 mg + BDQ 400 mg vs OPC-167832 30 mg in Stage 1 using 
connectivity of RHEZ in Stages 1 and 2.
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7.4.3
Interim Analysis
An interim analysis of safety, tolerability, PK, and efficacy of OPC-167832 is planned 
after the end of stage 1.
7.5
Analysis of Demographic and Baseline Characteristics
Subject demographic and baseline characteristics will be summarized by treatment using 
descriptive statistics (number, median, mean, SD, minimum, and maximum for 
continuous variables and number and percentage of subjects for discrete variables, 
eg, race and gender).
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 20.0 (or a later version if updated during the trial). All medical 
history will be listed, and the number and percentage of subjects will be summarized by 
treatment.
7.6
Safety Analysis
Safety data will be summarized by randomized treatment using descriptive statistics 
(number, median, mean, SD, minimum, and maximum) for numeric variables and 
frequency and count for discrete variables. Incidence of clinically notable values will be 
summarized where applicable. Safety assessments will also be listed by subject.
7.6.1
Adverse Events
All AEs will be coded by MedDRA system organ class and preferred term. The incidence 
of the following events will be summarized by treatment:

TEAEs

TEAEs by severity

TEAEs potentially causally related to the IMP or RHEZ

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP or RHEZ

TEAEs by DAIDS grading
Treatment-emergent AEs are defined as AEs that occur after the initiation of trial 
treatment; or an event or pre-existing medical problem that has changed adversely in 
nature or severity from baseline in a subject while receiving trial treatment.
Adverse event data will be presented in listings.
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7.6.2
Clinical Laboratory Tests Data
For clinical laboratory tests data, baseline is defined as the last nonmissing value obtained 
at a scheduled visit on or before Day −1. If the Day −1 measurement is missing, the 
baseline value will be the last nonmissing measurement from the screening visit (the 
previous scheduled visit). Clinical laboratory test parameters and mean changes from 
baseline will be summarized by treatment. The incidence of clinical laboratory test 
abnormalities, as defined in the “DAIDS Table for Grading the Severity of Adult and 
Pediatric AEs” (Appendix 3) will be summarized by treatment. Clinical laboratory test 
data will be presented in listings.
7.6.3
Physical Examination and Vital Signs Data
Physical examination data will be presented in listings.
Vital sign parameters and mean changes from baseline will be summarized by treatment. 
The incidence of vital signs abnormalities, as defined in the “DAIDS Table for Grading 
the Severity of Adult and Pediatric AEs” (Appendix 3) will be summarized by treatment. 
Vital sign data will be presented in listings.
7.6.4
Electrocardiogram Data
Electrocardiogram measurements and mean changes from baseline will be summarized 
by treatment. Baseline of ECG is defined as Day -1. If the measurement from Day -1 is 
missing, the screening ECG is taken as baseline. The incidence of potentially clinically 
significant changes and abnormalities in ECG evaluations will be summarized. 
Electrocardiogram data will be presented in listings. 
7.7
Pharmacodynamic Analysis
Pharmacodynamic methods and PK/PD methods are described in Section 6.2 and 
Section 6.3, respectively.
7.8
Other Efficacy Analysis
7.8.1
Bacterial Load Changes as Measured by the Change of Sputum 
Lipoarabinomannan Concentration
The decline in log-CFU on agar media at the end of 14 days as measured by the Otsuka 
TB LAM ELISA will be utilized with a two-time point EBA estimates (see equation 1 in 
Section 7.4.1.1.1) for the selection of the dose level for each cohort after Cohort 1, since 
those results are available in near real time and will facilitate faster decisions.
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8
Management of Investigational Medicinal Product
The IMPs to be administered during this trial include OPC-167832 (stage 1 and stage 2) 
and delamanid and/or BDQ (stage 2 only). The reference product to be administered 
includes RHEZ (stage 1 and stage 2).
Note: Subjects randomized to IMP will receive treatment for pulmonary TB according to 
the local standard of care regimen (RHEZ) after Day 14. In subjects with no clinical 
indication to start RHEZ immediately, commencement of RHEZ can be delayed for up to 
3 days (Days 15, 16, and 17) under close supervision in the trial site hospital ward.
8.1
Packaging and Labeling
OPC-167832 and delamanid will be provided to the investigator(s) and the persons 
designated by the investigator(s) or institutions by the sponsor or designated agent.
OPC-167832 and delamanid will be supplied as follows:

OPC-167832 will be supplied as 3-, 10-, and 30-mg immediate-release tablets

Delamanid will be supplied as 50-mg tablets
Each bottle of IMP provided by the sponsor will be labeled to clearly disclose the 
compound identity, protocol number, the sponsor’s name and address, instructions for 
use, route of administration, and appropriate precautionary statements.
The RHEZ will be sourced and supplied as Rifafour single-dose combination tablets by 
the trial site(s). The BDQ will be sourced in country. 
8.2
Storage
The IMP and RHEZ will be stored in a securely locked cabinet or enclosure. Access will 
be limited to the investigator(s) and designees. Neither the investigator(s) nor any 
designees may provide IMP or RHEZ to any subject not participating in this protocol.
The IMP and RHEZ will be stored according to the storage conditions indicated on the 
clinical labels.
The clinical trial site staff will maintain a temperature log in the drug storage area 
recording the temperature at least once each working day.
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8.3
Accountability
The investigator(s), or designee(s), must maintain an inventory record of IMP (including 
OPC-167832, delamanid, and BDQ) and RHEZ received, dispensed, administered, 
destroyed, or returned (as applicable).
8.4
Returns and Destruction
Upon completion or termination of the trial, all used IMP containers, unused IMPs, and 
partially-used IMPs must be returned to the sponsor or a designated agent, or destroyed at 
the trial site(s). The IMPs may be destroyed by the trial site(s), only if approved by the 
sponsor and if the IMP destruction meets all local regulations.
All IMPs returned to the sponsor must be accompanied by appropriate documentation and 
be clearly identified by the protocol number and trial site number on the outermost 
shipping container. Returned supplies should be in the original containers. The assigned 
trial monitor will facilitate the return or destruction of used IMP containers, unused 
IMPs, and partially-used IMPs.
8.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate, or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness, or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
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8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator(s) or designees must record all PQCs identified through any means from 
the receipt of the IMP (OPC-167832 and delamanid) from the sponsor, or sponsor’s 
designee, through and including reconciliation and up to destruction, including subject 
dosing. The investigator(s) or designees must notify the sponsor (or sponsor’s designee) 
by e-mail or telephone immediately after of becoming aware of the PQC according to the 
procedure outlined below.
Identification of a PQC by the subject should be reported to the trial site investigator, 
who should then follow one of the reporting mechanisms below.

E-mail - Send information required for reporting purposes (listed in Section 8.5.2) to 

Phone - 
8.5.2
Information Required for Reporting Product Quality Complaints
The following information is required for reporting purposes:

Description of complaint

Reporter identification (eg, subject, investigator, site information, etc)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, kit number, or bottle number)

Clinical protocol reference (number and trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
8.5.3
Return Process for Product Quality Complaints
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, the sponsor will provide instructions for 
complaint sample return, when applicable.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
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9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include, but are not limited to, progress 
notes, electronic data, screening logs, and recorded data from automated instruments. All 
source documents pertaining to this trial will be maintained by the investigator(s) and 
made available for direct inspection by authorized persons.
The investigator(s)/institution(s) will permit trial-related monitoring, audits, IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
9.2
Data Collection
During each subject’s visit to the trial site, a clinician participating in the trial will record 
progress notes to document all significant observations. At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject in the trial, the 
review of all inclusion/exclusion criteria prior to IMP or RHEZ administration on 
Day 1, and confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding visit or day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP or RHEZ must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of all clinicians (or designees) who made an entry 
in the progress notes.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.
Information from the trial progress notes and other source documents will be entered by 
trial site personnel directly onto eCRFs in the sponsor’s electronic data capture system.
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Any changes to information in paper source documents will be initialed and dated on the 
day the change is made by a trial site staff member authorized to make the change. 
Changes will be made by striking a single line through erroneous data (so as not to 
obliterate the original data), and clearly entering the correct data (eg, wrong data right 
data). If the reason for the change is not apparent, a brief explanation for the change will 
be written in the source documentation by the clinician.
Electronic data not entered on the eCRFs, such as data received from central laboratories 
and central ECG readers, will be reconciled by the sponsor or the contract research 
organization with the eCRF data to ensure consistency.
9.3
File Management at the Trial Site
The investigator(s) will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline E6 and as required by applicable local regulations. 
The trial site file will include all source documentation for all subjects screened or 
enrolled at the trial site. The investigator(s)/institution(s) will take measures to ensure 
confidentiality and prevent accidental or premature destruction of these documents.
9.4
Record Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that the 
participating investigator(s) maintains detailed clinical data for the longest of the 
following 3 periods:

A period of at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region (or at least 2 years after the formal discontinuation of clinical 
development of the investigational product); OR

A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.

Longer, region-specific storage requirements, if applicable. If regional requirements 
are longer, the specific information for the region should be stated in the 
investigator’s contract.
The investigator(s) must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) providing an opportunity for the sponsor to 
collect such records. The investigator(s) will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
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during this trial, including the eCRF data on the CD-ROM and any data clarification 
forms received from the sponsor (or sponsor’s designee). Such documentation is subject 
to inspection by the sponsor and relevant regulatory authorities. If the investigator 
withdraws from the trial or withdraws during the record retention period (eg, due to 
relocation or retirement or trial site closure), all trial-related records should be transferred 
to a mutually agreed-upon designee within a sponsor-specified timeframe. Notice of such 
transfer will be given to the sponsor in writing.
10
Quality Control and Quality Assurance
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s (or sponsor designee’s) monitors will visit the trial site(s) during the trial, as 
well as communicate frequently via telephone, e-mail, and written communications. In 
addition, all investigators and trial site clinical personnel will undergo initial and ongoing 
training for this particular trial, and this training will be clearly documented.
10.2
Auditing
The sponsor’s (or designee’s) Quality Assurance Unit (or representative) may conduct 
trial site audits. Audits will include, but are not limited to, IMP supply, presence of 
required documents, the informed consent process, and comparison of eCRFs with source 
documents. The investigator(s) agrees to participate with audits.
Regulatory authorities may inspect the trial site(s) during or after the trial. The 
investigator(s) will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
10.3
Protocol Deviations
Due to the complexity of clinical trial protocols and despite training and preventive 
efforts, deviations from the written protocol may occur and potentially result in harm to 
subjects, biased or inaccurate results, and possible rejection of all or part of the trial data. 
Per the ICH E3 guidance on the structure and content of clinical study reports, 
Section 10.2, protocol deviations should be summarized by site and grouped into 
different categories such as:
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
Major IMP or RHEZ dosing errors that may compromise subject safety or efficacy 
assessments.

Administration of an excluded concomitant medication during the course of the trial.
The FDA defines a protocol deviation/violation as an unplanned excursion from the 
protocol that is not implemented or intended as a systematic change.
Otsuka categorizes clinical protocol deviations as major versus minor. A major deviation 
is an intentional or accidental action or omission in a trial conduct that could potentially 
have a negative impact on the integrity of the trial’s primary scientific objectives or has a 
significant potential to have a negative impact on the safety or efficacy assessments of 
any trial subject. Major deviations are those that might significantly affect the 
completeness, accuracy, or reliability of the trial data or that might significantly affect a 
subject’s rights, safety, or well-being.
A minor deviation is an intentional or accidental action or omission during trial conduct 
in which the protocol is not strictly followed, but which has inconsequential impact on 
the integrity of the trial as a whole or the safety or efficacy analyses of an individual 
subject.
All protocol deviations will be categorized as major or minor according to the above 
definitions and only major deviations will be summarized in the clinical study report.
If the same protocol deviation occurs for multiple subjects, it must be recorded separately 
for each subject.
Investigators are expected to document potential protocol deviations as well as their 
medical assessment regarding continuation of the subject(s) due to the protocol deviation.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, FDA regulations, ICH GCP 
Guideline (E6), international ethical principles derived from the Declaration of Helsinki 
and Council for International Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations. The trial site(s) will seek approval/favorable 
opinion by an IEC according to regional requirements, and the investigator(s) will 
provide that documentation to the sponsor. The IEC will evaluate the ethical, scientific, 
and medical appropriateness of the trial. Further, in preparing and handling eCRFs, the 
investigator(s), sub-investigator(s), and their staff will take measures to ensure adequate 
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care in protecting subject privacy. To this end, a subject number or subject identifier will 
be used to identify each subject.
Financial aspects, subject insurance, and publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator(s).
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. Subjects will be identified only by unique subject identifiers in 
eCRFs. If further subject identification is required, subjects’ full names may be made 
known to a regulatory agency or other authorized officials if necessary, subject to local 
regulations.
13
Amendment Policy
The investigator(s) will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IEC. Any permanent 
change to the protocol, whether an overall change or a change for a specific trial site, 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IEC, as required by local regulations. 
Except for “administrative” or “nonsubstantial” amendments, investigators will wait for 
IEC approval/favorable opinion of the amended protocol before implementing the 
change(s). Administrative amendments are defined as having no effect on the safety of 
subjects, conduct or management of the trial, trial design, or the quality or safety of IMPs 
used in the trial. A protocol change intended to eliminate an apparent immediate hazard 
to subjects should be implemented immediately after agreement by the sponsor and 
investigator, followed by IEC notification within local applicable timelines. The sponsor 
will submit protocol amendments to the applicable regulatory agency within local 
applicable timelines.
When the IEC, investigators, or the sponsor conclude that the protocol amendment 
substantially alters the trial design or increases the potential risk to the subject, the 
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currently approved written ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IEC, repeat written informed consent 
will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).
According to ICMJE guidelines, one may be considered an author only if the following 
criteria are met:
1. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 
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15
References
1
World Health Organization. Global tuberculosis report 2017. Geneva: World Health 
Organization; 2017.
2
Otsuka Pharmaceutical Development and Commercialization, Inc. OPC-167832 
Investigator’s Brochure, Edition 4. Otsuka report, issued 04 Mar 2019.
3
Kawasaki M, Echiverri C, Gler MT, Baay MC, Oda T, Higashiyama R, et al. 
Lipoarabinomannan in sputum as a potential biomarker for bacterial load and 
treatment response in adult pulmonary TB patients. Colorado Mycobacteria 
Conference, Fort Collins, Colorado, US; 2016.
4
Liu, Y. Lipoarabinomannan as a pharmacodynamic biomarker and drug development 
tool for TB. Resist-TB webinar series. http://www.resisttb.org/?page_id=2458 
Updated Jun 2017. Accessed 29 Nov 2017.
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Otsuka Pharmaceutical Development & Commercialization, Inc. A phase 1, 
randomized, double-blind, placebo-controlled trial to assess the safety, tolerability, 
and pharmacokinetics of single ascending oral tablet doses of OPC-167832 and the 
effect of food in healthy subjects. Otsuka Protocol (Amendment 4) 323-201-00001, 
issued 26 May 2017.
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Otsuka Pharmaceutical Co., Ltd. OPC-67683 Investigator’s Brochure, Edition 15. 
Otsuka Report, issued 11 Apr 2019.
7
SIRTURO (bedaquiline) Tables Prescribing Information. Reference ID: 3237647. 
Revised Dec 2012.
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Aventis Pharma (Pty) Ltd. Rifafour e-275 tablets Package Insert. South African 
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Published 11 Feb 2002. Accessed 14 Sep 2017.
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World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis 
and patient care, 2017 update. Geneva: World Health Organization; 2017.
10 Hariguchi N. Pharmacokinetic and pharmacodynamic study of OPC-167832 in an 
experimental mouse model of chronic tuberculosis. Otsuka Study No. 037927, Otsuka 
Report No. 031553, 2015.
11 Diacon AH, Dawson R, Von Groote-Bidlingmaier F, Symons G, Venter A, Donald 
PR et al. Randomized dose-ranging study of the 14-day early bactericidal activity of 
bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary 
tuberculosis. Antomicrob Agents Chemother. 2013;57(5):2199-2203.
12 Diacon AH, Dawson R, Von Groote-Bidlingmaier F, Symons G, Venter A, Donald 
PR et al. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and 
moxifl oxacin combinations: a randomised trial. Lancet. 2012;380:986-993.
13 International Conference on Harmonisation. Guideline For Good Clinical Practice: 
E6(R1). Geneva, Switzerland: International Conference on Harmonisation; 1996.
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14 Drug development and drug interactions: table of substrates, inhibitors and inducers. 
United States Food and Drug Administration. 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/D
rugInteractionsLabeling/ucm093664.htm#table3-3 Updated 14 Nov 2017. Accessed 
23 Feb 2018.
15 Gumbo T, Angulo-Barturen I, Ferrer-Bazaga S. Pharmacokinetic-pharmacodynamic 
and dose-response relationships of antituberculosis drugs: recommendations and 
standards for industry and academia. J Infect Dis. 2015;211 Suppl 3:S96–106.
16 Tuntland T, Ethell B, Kosaka T, Blasco F, Zang R, Jain M, et al. Implementation of 
pharmacokinetic and pharmacodynamic strategies in early research phases of drug 
discovery and development at Novartis Institute of Biomedical Research. Front 
Pharmacol. 2014;5:174.
17 Srivastava S, Magombedze G, Koeuth T, Sherman C, Pasipanodya JG, Raj P, et al. 
Linezolid dose that maximizes sterilizing effect while minimizing toxicity and 
resistance emergence for tuberculosis. Antimicrob Agents Chemother 2017;61(8):1-
17.
18 Deshpande D, Srivastava S, Pasipanodya JG, Bush SJ, Nuermberger E, Swaminathan 
S, et al. Linezolid for infants and toddlers with disseminated Tuberculosis: first steps. 
Clin Infect Dis. 2016;63(Suppl 3):S80–87.
19 Modongo C, Pasipanodya JG, Magazi BT, Srivastava S, Zetola NM, Williams SM, et 
al. Artificial intelligence and amikacin exposures predictive of outcome in 
multidrugresistant tuberculosis patients. Antimicrob Agents Chemother. 
2016;60(10):5928-5931.
20 Gumbo T, Pasipanodya JG, Romero K, Hanna D, Nuermberger E. Forecasting 
accuracy of the hollow fiber model of tuberculosis for clinical therapeutic outcomes. 
Clin Infect Dis. 015;61 Suppl 1:S25–31.
21 Diacon AH, Donald PR. The early bactericidal activity of antituberculosis drugs. 
Expert Rev Anti Infect Ther. 2014;12(2):223-237.
22 Hittel N, Hackstein J. A Phase II trial to evaluate the safety, efficacy and 
pharmacokinetics of four oral doses of OPC-67683 in patients with uncomplicated, 
smear-positive, pulmonary tuberculosis. Otsuka Clinical Trial Report, Protocol 242-
06-101, issued 16 January 2008.
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Appendix 1
Names of OPDC Personnel
Report IREs (SAEs, potential serious hepatotoxicity, pregnancies, and AEs requiring 
discontinuation of IMP) to:
Fax:
E-mail: 
For Medical Emergencies (use only if OPDC personnel listed below are unavailable): 
Medical Monitor and Director, Clinical Development
 Otsuka Novel Products TB, Global Clinical Development, TB
Phone:
Fax:
Head, Clinical Pharmacology
 Clinical Pharmacology
Phone:
Fax:
Manager, Clinical Development
 Clinical Management, Global Clinical Development, TB
Phone:
Fax:
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Appendix 2
Institutions Concerned with the Trial
Independent Ethics Committee
Pharma-Ethics Independent Research Ethics Committee
123 Amcor Road
Lyttelton Manor
Centurion 0157, South Africa
Phone: +27 (0) 12 664-8690/0219
Fax:
+ 27 (0) 12 664-7860
University of Cape Town Faculty of Health Sciences Human Research Ethics Committee 
E 53 Room 46
Old Main Building
Groote Schuur Hospital
Observatory 7925, Cape Town, South Africa
Phone: +27 (0) 21 406-6626
Contract Research Organizations
PRA Health Sciences
Clindev Pty Ltd, A Micron Group Company
Trial Sites
TASK Clinical Research Centre
1 Smal Street
Bellville 7530, Cape Town, South Africa
Phone: +27 (0) 21 917-1044
Fax:
+27 (0) 21 918-1378
E-mail: tcrc@task.org.za
University of Cape Town Lung Institute (Pty) Ltd. 
George Street
Mowbray 7700, Cape Town, South Africa
Phone: +27 (0) 21 406-6850
Fax:
+27 (0) 917-1046
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Protocol Version 6.0, 10 May 2021
Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator’s Brochure) and agree that it contains all the ethical, legal, and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor’s (or designee’s) Clinical Research Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the Investigational New Drug, OPC-167832, the concurrent 
medications, the efficacy and safety parameters, and the conduct of the trial in general. I am 
aware that this protocol must receive a favorable opinion by the independent ethics committee 
(IEC) responsible for such matters in the clinical trial facility where OPC-167832 will be tested 
prior to commencement of this trial. I agree to adhere strictly to the attached protocol (unless 
amended in the manner set forth in the sponsor’s Clinical Trial Agreement, at which time I agree 
to adhere strictly to the protocol as amended).
I understand that this IEC-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered on case report forms by me and my 
staff will be utilized by the sponsor in various ways such as for submission to governmental 
regulatory authorities or in combination with clinical data gathered from other research sites, 
whenever applicable. I agree to allow sponsor and designee monitors and auditors full access to 
all medical records at the research facility for subjects screened or enrolled in the trial.
I agree to await for IEC approval before implementation of any protocol amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IEC within the required local applicable timelines. 
Administrative changes to the protocol will be transmitted to the IEC for informational purposes 
only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor’s Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol may involve a commitment to publish the data from this trial in a cooperative 
publication before publication of efficacy and safety results on an individual basis may occur, and 
I consent to be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
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This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: Protocol 323-201-00003 Amendment 5
Document Number: 
Document Version: 8.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
12-May-2021
19:31:32
Clinical Pharmacology
Approval
12-May-2021
19:33:12
Biostatistics Approval
12-May-2021
18:16:27
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SAP_001.pdf: 
 
  
Otsuka Pharmaceutical 
Development & Commercialization, Inc. 
 
 
Investigational Medicinal Product OPC-167832 
 
 
Protocol No. 323-201-00003 
IND No. 129303 
 
 
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 
 
Statistical Analysis Plan 
  
Version: Final 3.0 
Date:  16 May 2022  
Protocol Issue Date:  26 Feb 2018 
Protocol Amendment 1 Date: 29 Jan 2019 
Protocol Amendment 2 Date: 25 Oct 2019 
Protocol Amendment 3 Date: 20 Dec 2019 
Protocol Amendment 4 Date: 17 Aug 2020 
Protocol Amendment 5 Date: 21 May 2021 
 
 
 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
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Protocol 323-201-00003 
Statistical Analysis Plan                                        2 of 58 
Version Date: 16 May 2022 
 
Table of Contents 
Table of Contents ........................................................................................ 2 
List of Appendices ....................................................................................... 5 
List of Abbreviations and Definition of Terms ......................................... 6 
1 
Introduction........................................................................................ 7 
2 
Trial Objectives .................................................................................. 8 
2.1 
Primary Objective ............................................................................................ 8 
2.1.1 
Stage 1 .......................................................................................................... 8 
2.1.2 
Stage 2 .......................................................................................................... 8 
2.2 
Secondary Objectives ...................................................................................... 8 
2.2.1 
Stage 1 .......................................................................................................... 8 
2.2.2 
Stage 2 .......................................................................................................... 8 
2.2.3 
Stage 1 and Stage 2 ....................................................................................... 9 
3 
Trial Design ........................................................................................ 9 
3.1 
Type/Design of Trial........................................................................................ 9 
3.2 
Trial Treatments ............................................................................................ 11 
3.2.1 
Investigational Medicinal Products .............................................................. 11 
3.2.1.1 
Stage 1..................................................................................................... 11 
3.2.1.2 
Stage 2..................................................................................................... 11 
3.2.2 
Reference Product ....................................................................................... 12 
3.2.2.1 
Stage 1 and Stage 2 .................................................................................. 12 
3.3 
Trial Population ............................................................................................. 12 
3.4 
Trial Visit Window ........................................................................................ 12 
4 
Sample Size ....................................................................................... 13 
5 
Statistical Analysis Sets .................................................................... 13 
5.1 
Efficacy Analysis Set ..................................................................................... 13 
5.2 
Safety Analysis Set ........................................................................................ 13 
5.3 
Pharmacokinetic Analysis Set ........................................................................ 13 
5.4 
Handling of Missing Data .............................................................................. 13 
6 
Primary and Secondary Outcome Variables .................................. 13 
6.1 
Primary Outcome Variables ........................................................................... 13 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
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Protocol 323-201-00003 
Statistical Analysis Plan                                        3 of 58 
Version Date: 16 May 2022 
 
6.1.1 
Efficacy - Stage 1 ........................................................................................ 13 
6.1.2 
Pharmacokinetics - Stage 1 ......................................................................... 14 
6.1.3 
Pharmacokinetics - Stage 2 ......................................................................... 14 
6.1.4 
Pharmacokinetics/Pharmacodynamics - Stage 1 .......................................... 14 
6.1.5 
Pharmacokinetics/Pharmacodynamics - Stage 2 .......................................... 14 
6.1.6 
Safety and Tolerability - Stage 1 and Stage 2 .............................................. 15 
6.2 
Secondary Outcome Variables ....................................................................... 15 
6.2.1 
Efficacy ...................................................................................................... 15 
6.2.2 
Pharmacokinetics ........................................................................................ 15 
6.2.3 
Pharmacokinetics/Pharmacodynamics - Stage 1 and Stage 2 ....................... 15 
6.2.4 
Safety and Tolerability - Stage 1 and Stage 2 .............................................. 16 
7 
Disposition and Demographic Analysis .......................................... 16 
7.1 
Subject Disposition ........................................................................................ 16 
7.2 
Demographic and Baseline Characteristics..................................................... 16 
7.3 
Medical History ............................................................................................. 17 
7.4 
Treatment Compliance ................................................................................... 17 
7.5 
Prior and Concomitant Medication ................................................................ 17 
7.6 
Protocol Deviations ....................................................................................... 18 
8 
Efficacy Analyses ............................................................................. 18 
8.1 
Primary Efficacy Endpoint Analyses.............................................................. 18 
8.1.1 
Stage 1 ........................................................................................................ 18 
8.1.1.1 
Estimation of Day 14 Early Bactericidal Activity (EBA) ......................... 20 
8.1.1.1.1 
Two-time Point Early Bactericidal Activity Calculation ....................... 20 
8.1.1.1.2 
14-Day EBA Estimate Through Linear Mixed Effects Modeling .......... 20 
8.1.1.2 
Confidence Interval Estimation for EBA Ratio Between OPC and 
RHEZ ...................................................................................................... 21 
8.1.1.2.1 
Estimate EBA Ratio with Fieller’s method ........................................... 21 
8.1.1.2.2 
Estimate EBA Ratio with Taylor’s (Delta) method ............................... 22 
8.2 
Secondary Efficacy Endpoint Analyses .......................................................... 22 
8.3 
Exploratory Analyses..................................................................................... 24 
9 
Safety Analyses ................................................................................. 25 
9.1 
Extent of Exposure ........................................................................................ 25 
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16.1.9 Documentation of Statistical Methods
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Protocol 323-201-00003 
Statistical Analysis Plan                                        4 of 58 
Version Date: 16 May 2022 
 
9.2 
Adverse Events .............................................................................................. 26 
9.3 
Clinical Laboratory Data................................................................................ 26 
9.4 
Vital Sign Data .............................................................................................. 27 
9.5 
Physical Examination Data ............................................................................ 28 
9.6 
Electrocardiogram Data ................................................................................. 28 
9.7 
Other Safety Data .......................................................................................... 29 
10 
Pharmacokinetic Analyses ............................................................... 29 
11 
Pharmacokinetic/Pharmacodynamic Analyses .............................. 30 
12 
Pharmacogenomic Analyses ............................................................ 30 
13 
Interim Analysis ............................................................................... 30 
14 
Changes in Planned Analysis ........................................................... 30 
15 
Document History ............................................................................ 31 
16 
References ......................................................................................... 32 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
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Protocol 323-201-00003 
Statistical Analysis Plan                                        5 of 58 
Version Date: 16 May 2022 
 
List of Appendices 
Appendix 1 
Definition of Grades in Serum Chemistry, Hematology and 
Urinalysis Lab Test Results in the Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events ............................................................ 33 
Appendix 2 
Criteria for Potentially Clinical Significant Vital Sign 
Abnormalities  ............................................................................ 36 
Appendix 3 
Definition of Grades for Vital Sign in the Division of AIDS 
Table for Grading the Severity of Adult and Pediatric 
Adeverse Events ......................................................................... 37 
Appendix 4 
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance ...................................................................... 38 
Appendix 5 
Grading Scale for reporting Sputum Smears ................................ 39 
Appendix 6 
Technical Details ........................................................................ 40 
Appendix 7 
List of Proposed Summary Tables ............................................... 44 
Appendix 8 
List of Proposed Subject Data Listings .................................... 56 
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16.1.9 Documentation of Statistical Methods
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Protocol 323-201-00003 
Statistical Analysis Plan                                        6 of 58 
Version Date: 16 May 2022 
 
List of Abbreviations and Definition of Terms 
Abbreviation Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC24h 
Area under the concentration-time curve from zero to 24 hours 
AUC 
Area under the concentration-time curve from time zero to infinity 
AUC 
Area under the concentration-time curve calculated over the dosing 
interval at steady-state 
AUCt 
Area under the concentration-time curve from time zero to time t (the 
last observable concentration) 
BDQ 
Bedaquiline 
CRF 
Case report form 
CFU 
Colony-forming unit 
CRO 
Clinical Research Organization 
CLss/F 
Apparent clearance of drug from plasma at steady-s 
Cmax 
Maximum (peak) plasma concenration 
Cmax,ss 
Cmax during the dosing interval at steady-state 
CYP 
Cytochrome P450 
DAIDS 
Division of AIDS 
DNA 
Deoxyribonucleic acid 
EBA 
Early bactericidal activity 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
Emax 
Maximum effect 
ET 
Early Termination 
EU 
European Union 
EudraCT 
European Clinical Trial Data Base 
FDA 
(United States) Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
hCG 
Human chorionic gonadotropin 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IND 
Investigative new drug 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
LAM 
Lipoarabinomannan 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Protocol 323-201-00003 
Statistical Analysis Plan                                        7 of 58 
Version Date: 16 May 2022 
 
M2 
N-monodesmethyl metabolite 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGIT 
Mycobacteria Growth Indicator Tube® 
MIC 
Minimum inhibitory concentration 
MITT 
Modified Intent to Treat 
OPDC 
Otsuka Pharmaceutical Development & Commercialization, Inc. 
PD 
Pharmacodynamic 
PE 
Physical examination 
PK 
Pharmacokinetic(s) 
PQC 
Product quality complaint 
QD 
Once daily 
QTcB 
Corrected QT interval using Bazett’s method 
QTcF 
Corrected QT interval using Fridericia’s method 
RBC 
Red blood cell 
RHEZ 
Rifampicin, isoniazid, ethambutol, and pyrazinamide 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SD 
Standard Deviation 
t1/2,z 
Terminal-phase elimination half-life 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TTD 
Time to detection 
US or USA 
United States or United States of America 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
XDR 
Extensively drug-resistant 
1 
Introduction 
This statistical analysis plan (SAP) documents the statistical methodology and data 
analysis algorithms and conventions to be applied for the analysis of clinical trial data of 
trial 323-201-00003 for compound OPC-167832. The original protocol was dated 26 Feb 
2018. Amendment 1, 2, 3, 4 and 5 of the protocol occurred on 29 Jan 2019, 25 Oct 2019, 
20 Dec 2019, 17 August 2020, and 21 May 2021. All amendments to the protocol are 
taken into consideration in the  SAP.  
There is a separate PK plan with details on the analyses of the PK endpoints.  
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
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Version Date: 16 May 2022 
 
2 
Trial Objectives 
2.1 
Primary Objective 
2.1.1 
Stage 1 
To evaluate the efficacy, pharmacokinetics (PK), safety, and tolerability of multiple 
ascending oral doses of OPC-167832 compared with the administration of RHEZ in 
subjects with uncomplicated, smear-positive, drug-susceptible pulmonary TB. 
2.1.2 
Stage 2 
• To evaluate the safety and tolerability of multiple oral doses of OPC-167832 when 
administered with delamanid and/or bedaquiline (BDQ) compared with the 
administration of RHEZ alone in subjects with uncomplicated, smear-positive, 
drug-susceptible pulmonary TB. 
• To evaluate the PK of OPC-167832 and delamanid, and/or BDQ after 
coadministration. 
2.2 
Secondary Objectives 
2.2.1 
Stage 1 
• To evaluate the relationship between OPC-167832 exposure and efficacy determined 
by changes of sputum lipoarabinomannan (LAM) and Mycobacteria Growth Indicator 
Tube® (MGIT) time to detection (TTD), after multiple ascending oral doses of OPC-
167832. 
• To evaluate the relationship between QT interval and plasma concentrations of OPC-
167832. 
2.2.2 
Stage 2 
• To evaluate the efficacy of OPC-167832 when administered with delamanid and/or 
BDQ compared with the administration of RHEZ alone in subjects with 
uncomplicated, smear-positive, drug susceptible pulmonary TB.  
• To evaluate the relationship between OPC-167832 exposure and efficacy determined 
by changes of sputum LAM and MGIT time to detection after OPC-167832 when 
administered with delamanid and/or BDQ. 
• To evaluate the relationship between QT interval and plasma concentrations of 
OPC-167832 when administered with delamanid and/or BDQ. 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
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• To evaluate the PK of DM-6705 after coadministration of OPC-167832 and 
delamanid and/or BDQ. 
2.2.3 
Stage 1 and Stage 2 
To evaluate the efficacy, safety, and tolerability of OPC-167832 when administered with 
delamanid and/or BDQ (data derived from stage 2) compared with the administration of 
OPC-167832 alone (data derived from stage 1). 
3 
Trial Design 
3.1 
Type/Design of Trial 
3.1.1 Stage 1 
Stage 1 will be a randomized, open-label, active controlled, multiple ascending dose 
stage in approximately 72 subjects. Dosing is planned to be conducted in 4 sequential 
cohorts of 18 subjects each: 
• Cohort 1: 10 mg OPC-167832 or RHEZ (14 OPC-167832 subjects and 4 RHEZ 
subjects) 
• Cohort 2: 30 mg OPC-167832 or RHEZ (14 OPC-167832 subjects and 4 RHEZ 
subjects) 
• Cohort 3: 90 mg OPC-167832 or RHEZ (14 OPC-167832 subjects and 4 RHEZ 
subjects) 
• Cohort 4: 3 mg OPC-167832 or RHEZ (14 OPC-167832 subjects and 4 RHEZ 
subjects) 
Subjects who signed the informed consent form (ICF) will be admitted to the trial site at 
screening. Subjects will be screened for up to 4 days (Days -6 to -3) prior to the start of 
the Day -2 assessments. Screening can be extended up to 7 days. Subjects randomized to 
OPC-167832 will receive once daily (QD) oral doses of investigational medicinal product 
(IMP; OPC 167832) from Day 1 through Day 14. After Day 14, the subjects will receive 
treatment for pulmonary TB according to the local standard of care regimen (RHEZ). In 
subjects with no clinical indication to start RHEZ immediately, commencement of RHEZ 
can be delayed for up to 3 days (Days 15, 16, and 17) under close supervision in the trial 
site hospital ward.  
Subjects randomized to RHEZ will receive QD oral doses of RHEZ from Day 1 through 
Day 20.  
Subjects will be discharged on Day 20 once all safety assessments have been completed 
and all PK samples have been collected. 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
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The safety, tolerability, PK, and efficacy (results from Otsuka TB LAM enzyme-linked 
immunosorbent assay [ELISA] only) data from each cohort will be reviewed by the trial 
review team at the end of each cohort. Once all the data for dose selection for the next 
cohort is available, the data collected from each cohort will be provided to the trial 
review team. The data will be evaluated to determine if (i) the dose level for the next 
cohort will be escalated, (ii) the dose level from the previous cohort will be repeated, or 
(iii) the dose level will be decreased. The dose of OPC-167832 will not exceed the 
highest tolerated dose studied in the single ascending dose trial, i.e., 480 mg. 
Decisions to proceed to the next dose level should be based on, but not limited to, the 
following safety aspects: 
• 
No death assessed as related to OPC 167832 
• 
No more than 2 subjects with Grade 4/5 AEs (“Division of AIDS 
[DAIDS] Table for Grading the Severity of Adult and Pediatric AEs1”) 
assessed as related to OPC 167832. 
3.1.2 
Stage 2 
The dose of OPC-167832 for Stage 2 has been determined based on the safety, 
tolerability, PK and efficacy data from Stage 1 of this trial. Based on the Stage 1 PK/PD 
analysis of OPC-167832 plasma concentrations and reduction in log10CFU/mL, a dose 
lower than the current 30 mg specified in the protocol may be considered, provided it can 
offer similar potential for efficacy as the 30 mg dose.  
Stage 2 will be a randomized, open-label, active-controlled, parallel group comparison 
stage comprising of 46 subjects (subjects who were randomized in stage 1 cannot enroll 
in stage 2). 
Subjects who signed ICF will be admitted to the trial site at screening. Subjects will be 
screened for 4-7 days prior to the start of Day -2 assessments. Eligible subjects will be 
housed at the trial site until discharge or early termination. All subjects enrolled during 
this stage of the trial will be randomized prior to first dosing on Day 1 to one of the 
following 4 treatments in a ratio of 14:14:14:4: 
• 
30 mg OPC-167832 and 300 mg delamanid QD (14 subjects) 
• 
30 mg OPC-167832 and 400 mg BDQ QD (14 subjects) 
• 
30 mg OPC-167832 and 300 mg delamanid and 400 mg BDQ QD (14 
subjects) 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
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• 
RHEZ QD (4 subjects) 
Subjects receiving BDQ will take a loading dose of 700 mg BDQ on Day 1 and 500 mg 
on Day 2. The dose of BDQ will be 400 mg QD for days 3 to 14.  
Subjects will be centrally randomized through an interactive voice response system with 
no stratification.  
Subjects randomized to OPC-167832 and/or delamanid and/or BDQ will receive QD oral 
doses of IMP (OPC-167832 and/or delamanid and/or BDQ) from Day 1 through Day 14. 
After Day 14, the subjects will receive treatment for pulmonary TB according to the local 
standard of care regimen (RHEZ). In subjects with no clinical indication to start RHEZ 
immediately, commencement of RHEZ can be delayed for up to 3 days (Days 15, 16, and 
17) under close supervision in the trial site hospital ward. 
Subjects randomized to RHEZ will receive QD oral doses of RHEZ from Day 1 through 
Day 20.  
Subjects will be discharged on Day 20 once all safety assessments have been completed 
and all PK samples have been collected. 
3.2 
Trial Treatments 
3.2.1 
Investigational Medicinal Products 
3.2.1.1 
Stage 1 
Subjects randomized to OPC-167832 will receive QD oral doses of IMP (OPC-167832) 
from Day 1 through Day 14. 
The planned dose escalation steps of OPC-167832 for Cohorts 1 to 4 are 10, 30, 90, and 
3 mg, respectively. The IMP will be administered with 240 mL of still (noncarbonated) 
water at room temperature, within 5 minutes after the completion of a meal. 
3.2.1.2 
Stage 2 
Subjects randomized to 30 mg OPC-167832 and 300 mg delamanid or 30 mg OPC-
167832 and 400 mg BDQ, or 30 mg OPC-167832 and 300 mg delamanid and 400 mg 
BDQ will receive QD oral doses of IMP (OPC-167832 and/or delamanid and/or BDQ) 
from Day 1 through Day 14. Subjects receiving BDQ will take a loading dose of 700 mg 
BDQ on Day 1 and 500 mg on Day 2. The dose of BDQ will be 400 mg QD for days 3 to 
14. 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
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Delamanid (300 mg) should be administered orally once daily (QD), within 5 to 10 
minutes after the completion of a meal.  
OPC-167832 (30 mg QD) and BDQ should be administered orally, approximately 30 
minutes after administration of delamanid.  
The IMP will be administered with 240 mL of still (noncarbonated) water at room 
temperature. 
Based on the Stage 1 PK/PD analysis of OPC-167832 plasma concentrations and 
reduction in log10CFU/mL, a dose lower than the current 30 mg specified in the protocol 
maybe considered, provided it can offer similar potential for efficacy as the 30 mg dose.  
3.2.2 
Reference Product 
3.2.2.1 
Stage 1 and Stage 2 
Subjects randomized to RHEZ will receive QD oral doses of RHEZ from Day 1 through 
Day 20. 
Subjects will receive Rifafour® single-dose combination tablets. Each RHEZ tablet 
contains 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg 
ethambutol. Subjects will receive the following number of Rifafour tablets per day based 
on their pretreatment body weight: 
• Subjects weighing 30 to 37 kg will receive 2 tablets per day. 
• Subjects weighing 38 to 54 kg will receive 3 tablets per day. 
• Subjects weighing 55 to 70 kg will receive 4 tablets per day. 
• Subjects weighing > 70 kg will receive 5 tablets per day. 
RHEZ will be administered with 240 mL of still (noncarbonated) water 1 hour prior to a 
meal or 2 hours after a meal. 
3.3 
Trial Population 
Approximately 118 male or female subjects with newly diagnosed, uncomplicated, 
smear-positive, drug susceptible pulmonary TB who meet all the inclusion criteria and 
none of the exclusion criteria will be enrolled and randomized into this trial. In Stage 1, 
approximately 72 subjects will be enrolled and randomized to 1 of 4 cohorts (18 subjects 
per cohort). Approximately 46 subjects will be enrolled and randomized in Stage 2. 
Subjects who randomized to Stage 1 cannot enroll in Stage 2.  
3.4 
Trial Visit Window 
There is no visit window for trial visits on/before Day 20. The follow up visit can be 
target day plus or minus 3 days.  
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16.1.9 Documentation of Statistical Methods
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4 
Sample Size 
The trial is not powered for formal statistical hypothesis testing or comparisons. The 
sample size is based on sample sizes from several similar trials in the literature. It is 
planned to enroll 72 (18 in each cohort) subjects in stage 1 in 14:4 ratio. Stage 2 will 
enroll 46 patients in 14:14:14:4 ratio.  
5 
Statistical Analysis Sets 
5.1 
Efficacy Analysis Set 
Efficacy analyses will be conducted based upon the Modified Intent-to-Treat (mITT) 
Analysis Set. The mITT Set will include randomized subjects who are agar media culture 
positive at baseline (either at day -2 or at day -1, or both), have taken any dose of IMP, 
and have available at least one post-baseline CFU count value. 
Randomized Analysis Set includes subjects who are randomized into the study.  
5.2 
Safety Analysis Set 
Safety Analysis Set includes subjects who are randomized and take any dose of IMP 
(OPC-167832 or Delamanid or Bedaquiline or RHEZ). 
5.3 
Pharmacokinetic Analysis Set 
The PK Analysis Set will include all subjects who took at least one dose of IMP with 
adequate data for deriving the PK parameters accordingly to clinical pharmacology 
requirement. 
5.4 
Handling of Missing Data 
Missing data in PK blood sample result and efficacy data will not be imputed for this 
study unless specified in individual sections. The imputation of missing colony forming 
units or LAM results will be discussed in corresponding sections. 
6 
Primary and Secondary Outcome Variables 
6.1 
Primary Outcome Variables 
6.1.1 
Efficacy - Stage 1  
Efficacy will be assessed by the change in Mycobacterium tuberculosis bacterial (MTB) 
load in sputum as a measure of EBA. Bacterial load in sputum at each collection time 
point will be measured by colony-forming unit (CFU) counts on agar media culture. The 
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EBA will be measured as the slope of the change in log10CFU/mL on agar media from 
baseline (baseline is defined as the log10 of the mean of Day -2 and Day -1) to Day 14. 
6.1.2 
Pharmacokinetics - Stage 1 
The following PK parameters will be determined for plasma OPC-167832: 
• Day 1: Maximum (peak) plasma concentration (Cmax), time to Cmax (tmax), and area 
under the concentration-time curve (AUC) from time zero to time t (the last 
observable concentration) (AUCt). 
• Day 14: Cmax during the dosing interval at steady-state (Cmax,ss), tmax, terminal-phase 
elimination half-life (t1/2,z), apparent clearance of drug from plasma at steady-state 
(CLss/F), AUCt, AUC calculated over the dosing interval at steady-state (AUCτ), 
accumulation ratio of Cmax (RCmax), and accumulation ratio of AUC (RAUC), Cmax 
normalized to dose (Cmax/Dose), and AUCτ normalized to dose (AUCτ/Dose). 
6.1.3 
Pharmacokinetics - Stage 2 
The following PK parameters will be determined for plasma OPC-167832, delamanid and 
BDQ: 
• Day 1: Cmax, tmax, and AUCt. 
• Day 14: Cmax,ss, tmax, t1/2,z, CLss/F, AUCτ, RCmax, RAUC, and Cmax normalized to dose 
(Cmax/Dose), and AUCτ normalized to dose (AUCτ/Dose). 
6.1.4 
Pharmacokinetics/Pharmacodynamics - Stage 1 
The maximum effect (Emax) and exposure producing 80% of Emax (EC80) for 
OPC-167832, regardless of dose level, will be determined from an exposure-response 
analysis of the decline of log10CFU/mL counts on agar media. The results can be found in 
a separate population PK/PD analysis report.  
6.1.5 
Pharmacokinetics/Pharmacodynamics - Stage 2 
The Emax and EC80 for OPC-167832 in combination with delamanid and/or BDQ will be 
determined from an exposure-response analysis of the decline of log10CFU/mL counts on 
agar media. The results can be found in a separate population PK/PD analysis report.  
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6.1.6 
Safety and Tolerability - Stage 1 and Stage 2 
6.2 
Secondary Outcome Variables 
6.2.1 
Efficacy  
Stage 1 and Stage 2 
The slope of the change in log10LAM pg/mL values and the change in time to detection 
(TTD) in the Mycobacteria Growth Indicator Tube® (MGIT) system will be assessed 
from baseline to Day 14. 
Stage 2 
Efficacy will be assessed by the change in bacterial load in sputum as a measure of EBA. 
Bacterial load in sputum at each collection time point will be measured by CFU counts 
on agar media. The EBA will be measured as the slope of the change in log10CFU/mL 
from baseline (baseline is the log10 of the mean of the values from Day -2 and Day -1 
with more details in Section 8.1) to Day 14 and compared with the administration of 30 
mg OPC-167832 alone (data derived from Stage 1). Similar analyses are performed for 
log10LAM pg/mL and MGIT TTD endpoints. 
6.2.2 
Pharmacokinetics  
Stage 1 
Plasma concentrations of rifampin and isoniazid at 2 and 6 hours postdose will be 
determined for compliance. 
Stage 2 
The following PK parameters will be determined for plasma DM-6705 (metabolite of 
delamanid) and M2 (metabolite of BDQ): 
• Day 1: Cmax, tmax, and AUCt. 
• Day 14: Cmax,ss, tmax, t1/2,z, and AUCt. 
Plasma concentrations of rifampin and isoniazid at 2 and 6 hours postdose will be 
determined for compliance. 
6.2.3 
Pharmacokinetics/Pharmacodynamics - Stage 1 and Stage 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 results can be found in a separate population PK/PD analysis report.  
Clinical Study Report 323-201-00003
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Statistical Analysis Plan                                        16 of 58 
Version Date: 16 May 2022 
 
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. The results can be found in a separate population PK/PD analysis report. 
6.2.4 
Safety and Tolerability - Stage 1 and Stage 2 
Safety and tolerability 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). Safety and tolerability will be assessed based on the 
incidence of AEs and the incidence of abnormal findings in clinical laboratory tests 
(serum chemistry, hematology, urinalysis, and coagulation), vital signs, ECGs and 
physical examinations. 
7 
Disposition and Demographic Analysis 
7.1 
Subject Disposition 
Number of patients screened, randomized, included in safety analysis or efficacy 
analysis, completed, early terminated will be summarized by count and percentage within 
each treatment group. Enrolment by country and by age group will also be summarized. 
The frequency and percentages will be presented by treatment groups for Stage 1, and 
Stage 2 with a combined RHEZ group from Stage 1 and Stage 2. 
7.2 
Demographic and Baseline Characteristics 
Summary statistics (mean, standard deviation, median, minimum and maximum) will be 
presented for continuous baseline characteristics. Frequency and percentage of discrete 
baseline variables will also be presented. Summaries will be presented by treatment 
groups based on the Randomized Analysis Set.  
Demographic and baseline characteristics variables include:  
• Age 
• Sex 
• Race 
• Ethnicity 
• Weight, Height, BMI 
• Baseline CFU/mL count (Actual X1000) 
• Baseline CFU/mL count (log10)  
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• Baseline x-ray 
• Baseline HIV Screen 
• Baseline FSH 
• Baseline Urine/Blood alcohol  
• Baseline Urine test for isoniazid (only applicable to protocol dated 26 Feb 2018) 
The baselines for lab tests, ECG, vital sign and overnight sputum culture results are 
summarized with post-baseline results and will be described in later sections. 
The analysis will be presented by treatment groups for Stage 1, and Stage 2 with a 
combined RHEZ group from Stage 1 and Stage 2. 
7.3 
Medical History 
Medical history will be presented by count and frequency for each system organ class and 
preferred term for each treatment group. The summary will be based on the Randomized 
Analysis Set. 
The frequencies and percentages will be presented by treatment groups for Stage 1, and 
Stage 2 with a combined RHEZ group from Stage 1 and Stage 2.  
7.4 
Treatment Compliance 
Plasma concentrations of rifampin and isoniazid at 2 and 6 hours postdose will be 
determined for compliance. The time and dose of IMP and RHEZ administration during 
the trial will be recorded in eCRF and be listed. No analysis will be performed on 
compliance.  
7.5 
Prior and Concomitant Medication 
The proportion of subjects taking concomitant medications will be tabulated by drug 
classification using the WHO drug dictionary WHODRUG B3G March 2019 for Safety 
Analysis Set. Concomitant medications taken prior to the study medication treatment 
period, during study medication treatment period and after the study treatment will be 
tabulated. The study medication treatment period is defined as days from first IMP till the 
last dose of OPC-167832 and/or delamanid and/or bedaquiline in non-RHEZ groups. For 
RHEZ group, Day 14 (study date – first RHEZ date +1) is used as end point for “IMP 
dosing period” period. Concomitant medications will be listed. Anti-TB concomitant 
medications and other general concomitant medications will be summarized separately.  
The analysis will be presented by treatment groups for Stage 1, and Stage 2 with a 
combined RHEZ group from Stage 1 and Stage 2. 
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7.6 
Protocol Deviations 
Frequency of protocol deviations (PDs) collected from CRF will be summarized by type 
of deviation (e.g., deviations in entry criteria, dosing, prohibited concomitant medication, 
procedural, met withdrawal criteria but was not withdrawn). The analysis will be 
presented by treatment group for Stage 1, and Stage 2 with a combined RHEZ group 
from Stage 1 and Stage 2. In addition, a subject listing for non-COVID-19 related PDs 
will be provided. COVID-19 related PDs will be listed separately. 
8 
Efficacy Analyses 
8.1 
Primary Efficacy Endpoint Analyses 
8.1.1 
Stage 1 
Overnight sputum will be collected starting from 3pm to 7am next day starting on Day -2, 
-1, 2, 4, 6, 8, 10, 12 and Day 14. Mycobacterium tuberculosis bacterial load in sputum at 
each collection time point will be measured by CFU counts on solid media culture. Two 
agar media bi-plates will be inoculated with 0.1 mL sputum sample per side (total of 0.2 
ml per whole plate) at each visit.  Each sample was diluted to 
1, 10−1, 10−2, 10−3, 10−4, 10−5  times of the original concentration, represented by the 
values of dilution factor collected from CRF in 0, 1, 2, 3, 4, 5. The number of colonies 
from each plate collected in the CRF will be converted to CFU per mL using the formula: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑜𝑙𝑜𝑛𝑖𝑒𝑠 𝑐𝑜𝑙𝑙𝑒𝑐𝑡𝑒𝑑 𝑓𝑟𝑜𝑚 𝐶𝑅𝐹 × 10𝑑𝑖𝑙𝑢𝑡𝑖𝑜𝑛 𝑓𝑎𝑐𝑡𝑜𝑟 𝑐𝑜𝑙𝑙𝑒𝑐𝑡𝑒𝑑 𝑖𝑛 𝐶𝑅𝐹+1. 
Because of the initial 10-fold dilution factor during sputum sample preparation, 1 is 
added to the power of 10. The CFU value reported from the laboratory is set to missing if 
the qualitative culture result is “Negative for MTB Complex” or “Contaminated”. 
Because two results are collected per visit, the method to derive the analysis value for 
CFU for a visit day is described as follows:  
If only one CFU result is available, then the available result is used as the  CFU/mL value 
from that visit. If both CFU results are available, the average CFU/mL is taken as the 
value for that visit. If both sputum samples have missing CFU result, then the qualitative 
test result from SOLID MICROBIAL CULTURE will be taken into consideration. If 
both of the SOLID tests are “negative for MTB Complex”, or if one of the SOLID results 
is “negative for MTB complex” and the other is “CONTAMINATED”, the CFU for that 
visit is set to 5 CFU/mL, since the lower detection limit of the agar media is 5 CFU/mL. 
If both SOLID tests are “CONTAMINATED”, then the CFU/mL for that visit is still 
treated as missing.  
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The same analysis methods as described in Section 8.1.1 will be used for the comparisons 
of (1) and (2) above mentioned. Only the data of these three treatment groups in all 
efficacy analysis set in Stage 2 will be included in this analysis (that is, Stage 2 RHEZ 
arm, and Stage 1 arms are not included in the analysis). 
  
LAM and TTD analyses:   
The change from baseline in LAM and TTD will be analyzed  using the same methods 
specified for CFU.  
LAM: 
More details of analysis data derivation for LAM is provided as follows.   
Two LAM assessments are available at each visit, one on raw sputum (LAM(raw)), and 
one on processed decontaminated sputum (LAM(processed)). Baseline LAM  is 
calculated as the average of Day -2 and Day -1 and the log10 of the average is used in 
EBA derivation. If one sample has a missing value then the nonmissing sample is used. 
The lower limit of quantification (LLoQ) of LAM test is 15 pg/mL. If a sample result has 
a reported value below the LLoQ (< 15 pg/mL) and does not indicate “NO RESULT”, the 
value 15 pg/mL is used in the analyses for that visit. 
TTD: 
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, is taken at each of the visits at Days -2, -1, 2, 4, 6, 8, 10, 12 
and 14.  
The TTD values  in Days will be calculated as “days + hours/24” to be used in deriving 
the analysis values of TTD. Pure MTB positive MGIT culture is MTB confirmed with no 
growth of contaminants. 
Baseline TTD will be derived using the Day -2 and Day -1 MGIT culture with a pure 
positive result for Mycobacterium tuberculosis. If both days are pure positive, the average 
of Day -2 and Day -1 will be used as baseline TTD. If only one day is pure positive, the 
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TTD from that day is used as baseline. If neither day is pure positive, the baseline TTD is 
set to missing. 
The postbaseline TTD analysis values from Day 1 and later will be derived based on the 
MGIT culture result as follows: 
1. When a MGIT culture result is negative for MTB complex, TTD is set to 42 days 
(the value for time-to-result with negative culture). 
2. If the MGIT culture is pure positive for MTB, but for some reason the TTD took 
longer than 42 days, TTD will be capped at 42 days. 
3. TTD values from MGIT cultures with the following qualitative results will be set 
to missing: 
• Contaminated 
• Positive for MTB complex and contaminated  
• No TB growth but positive for other  mycobacteria 
• Unknown. 
All analyses will be presented by treatment groups for Stage 1, and Stage 2 with a 
combined RHEZ group from Stage 1 and Stage 2. 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
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. 
9 
Safety Analyses 
Safety data will be summarized by randomized treatment using descriptive statistics 
(number, median, mean, SD, minimum, and maximum) for numeric variables and 
frequency and count for discrete variables. 
9.1 
Extent of Exposure 
In Stage 1, subjects randomized to OPC-167832 will receive once daily oral doses of 
IMP (OPC-167832) from Day 1 through Day 14. After Day 14, the subjects will receive 
treatment for pulmonary TB according to the local standard of care regimen (RHEZ). In 
subjects with no clinical indication to start RHEZ immediately, commencement of RHEZ 
can be delayed for up to 3 days (Days 15, 16, and 17) under close supervision in the trial 
site hospital ward. Subjects randomized to RHEZ will receive once daily oral doses of 
RHEZ from Day 1 through Day 20.  
In Stage 2, subjects randomized to IMP (OPC-167832 and/or delamanid and/or BDQ) 
will receive once daily oral doses of IMP from Day 1 through Day 14. After Day 14, the 
subjects will receive treatment for pulmonary TB according to the local standard of care 
regimen (RHEZ). In subjects with no clinical indication to start RHEZ immediately, 
commencement of RHEZ can be delayed for up to 3 days (Days 15, 16, and 17) under 
close supervision in the trial site hospital ward. Subjects randomized to RHEZ will 
receive once daily oral doses of RHEZ from Day 1 through Day 20. 
Exposure to IMP is considered to be the exposure of OPC, DLM or BDQ (for the three 
OPC-containing regimens) in study days 1-14. For comparison purposes, for the RHEZ 
arm also, exposure to IMP will be taken to be the exposure to any treatment with RHEZ 
in days 1-14, and will be tabulated for the first 14 days only. The total exposure to IMP or 
reference product (RHEZ) in days will be divided to time intervals (No exposure, 1-2 
days, 3-4 days, etc.) and the number and percentage of patients whose durations of 
exposure are in each interval will be presented for each treatment group. The duration of 
exposure is calculated as the last date of IMP (within 14 study days)  – first date of IMP 
+1. For patients who are lost to follow-up, the last known date of taking IMP or RHEZ 
(within 14 study days) will be used for missing last date.  
Patients randomized to RHEZ will receive once daily oral doses of RHEZ from Day 1 
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through Day 20. For the RHEZ group, the exposure table will summarize the exposure to 
RHEZ within the first 14 days of treatment only  
All analyses will be presented by treatment groups for Stage 1,  and Stage 2 with a 
combined RHEZ group from Stage 1 and Stage 2.  
The summaries will be based on the Randomized Analysis Set. IMP dosing will be listed. 
The dosing of RHEZ will be listed in the anti-TB concomitant medication listing.  
9.2 
Adverse Events 
All AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA; 
Version 22 or newest available) system organ class and preferred term. Treatment-
emergent AEs (TEAE) are defined as AEs that occurs after the initiation of trial 
treatment; or an event or pre-existing medical problem that has changed adversely in 
nature or severity from baseline in a subject while receiving trial treatment.The frequency 
and percentage of subjects with the following events will be summarized by SOC, 
MedDRA preferred term, severity and treatment: 
• Treatment-emergent AEs (TEAEs) 
• TEAEs potentially causally related to the IMP or RHEZ 
• TEAEs with an outcome of death 
• Serious TEAEs 
• TEAEs leading to discontinuations of the IMP  
• TEAEs by DAIDS grading 
• non-serious TEAEs (NSAE)  
All AEs will be presented in a listing. The listing of death due to AE, serious AE and 
TEAE leading to discontinuation will also be provided. In addition, the number and 
frequency of TEAE incidences will be summarized for serious TEAE, serious study 
medication related TEAE and non-serious TEAE. The analyses on AEs will be performed 
separately for Stage 1, and Stage 2 with a combined RHEZ group from Stage 1 and Stage 
2. 
9.3 
Clinical Laboratory Data 
Clinical hematology, chemistry, coagulation and urinalysis are tested at screening, Day -
1, Day 4, Day 7, Day 14 and Day 20/ET for both Stage 1 and Stage 2.  
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For clinical laboratory tests data, baseline is defined as the last non-missing value 
obtained on or before Day −1.  
The incidence of clinical laboratory test abnormalities, as defined in the “Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events1will be summarized by grade and treatment group and listed by test. The DAIDS 
criteria for laboratory test results are listed in Appendix 1.  
Shift tables assessing status (low, normal, or high based on the clinical laboratory normal 
ranges) changes from baseline will be presented by treatment group based on the Safety 
Analysis Set. All cases  of lab results where ALT (alanine aminotransferase) or AST 
(aspartate aminotransferase) are  3 times the normal upper limit and at the same time the 
total bilirubin is  2 times normal upper limit. All clinical laboratory test data will be 
listed. 
In case of a repeated lab test, the last repeat test on the same visit will be used for the 
value at that visit. Unscheduled lab test data will not be included in the mean change 
from baseline summary but will be included when searching for laboratory test 
abnormalities in the incidence and shift analyses. 
When lab parameter values are recorded as < or > a cutoff value, then the lab value is set 
as 50% of the cutoff value in the case of < and 150% in the case of > when used as a 
continuous variable. In data listing the originally collected format will be presented.   
All analyses will be presented by treatment groups for Stage 1, and Stage 2 with a 
combined RHEZ group from Stage 1 and Stage 2.  
9.4 
Vital Sign Data  
Vital signs (blood pressure, heart rate, temperature, and respiratory rate) will be assessed 
at screening and on Day −1, Day 1 (predose and at 1, 2, 4, 8, and 12 hours postdose), 
Days 2 through 6 (predose and 2 and 4 hours postdose), Day 7 (predose and 1, 2, 4, 8, 
and 12 hours postdose), Days 8 through 13 (predose and 2 and 4 hours postdose), Day 14 
(predose and 1, 2, 4, 8, and 12 hours postdose), and Days 15 through 20 or at ET. At 
screening, blood pressure and heart rate will be taken with the subject in the supine 
(performed first) and sitting position after remaining for  3 minutes in each position and 
temperature and respiratory rate will be taken with the subject in the supine position for 
at least 1 minute. At all other time points, vital signs will be obtained after the subject has 
been at rest in the supine position for 1 to 3 minutes. Vital signs will be obtained prior to 
the ECG and PK blood draw at the nominal time points, where applicable. The post-dose 
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vital signs could be performed within 15 minutes earlier than the expected post-dose 
timepoints. 
The baseline of vital sign is defined as data collected at Day 1 predose. If Day 1 predose 
is missing, then baseline can be taken from Day -1 or screening.  
Change from baseline in vital signs will be summarized for each post-baseline 
timepoints. The “last visit” in the summaries includes last observed non-missing data 
collected at post-baseline visits. The incidence of vital signsas based on the tablein 
Appendix 2, specifying potentially clinically relevant abnormalities, will be summarized 
for all visits. Also incidence of vital signs based on the “Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events” as listed out in 
Appendix 3 will also be summarized by grade and treatment group and will  be listed.  
When vital sign is repeated, the last repeat value will be used in the summary for that 
visit. Unscheduled vital sign data will not be summarized in the change from baseline 
analysis, but will be included in incidence of clinical relevance analysis. 
All analyses will be presented by treatment groups for Stage 1, and Stage 2 with a 
combined RHEZ group from Stage 1 and Stage 2.  
9.5 
Physical Examination Data 
Complete physical examinations will be performed at screening and on Day −1. Targeted 
physical examinations will be performed on Days 1 through 14 (predose and 4 hours 
postdose) and Days 15 through 20 or at ET. The 4-hour post-dose targeted physical 
examination could be performed ±30 minutes around the expected post-dose timepoint. 
Baseline is defined as Day 1 predose. If Day 1 predose is missing, then Day -1 or 
screening can be used as baseline.                                                                                                                  
Frequency of percentage of subjects for each physical examination outcome will be 
presented by visit and treatment group.  
All analyses will be presented by treatment groups for Stage 1 and Stage 2 separately, 
and with a combined RHEZ group from Stage 1 and Stage 2.  
9.6 
Electrocardiogram Data 
Standard 12-lead ECGs will be collected in triplicate (5 minutes apart) at screening and 
on Day −1, Day 7 (predose), and Day 14 (predose). The ECGs will be recorded after the 
subject has been supine and at rest for ≥ 10 minutes prior to the first ECG and subjects 
will remain supine through the final ECG. Electrocardiograms will be obtained prior to 
the PK blood draw and after vital signs at the nominal time points, where applicable. 
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Heart rate, ventricular rate, RR interval, PR interval, QRS duration, and QT intervals will 
be recorded. The QTcF and corrected QT interval using Bazett’s method (QTcB) will be 
calculated. 
ECGs are available in triplicates at each nominal timepoint, but may appear as a single or 
duplicate assessment. All (single, duplicate or triplicate) ECGs at each nominal time 
point will be averaged and the average will be used in descriptive summary statistics and 
frequency and percentages. Baseline of ECG is defined as the averaged measurement on 
Day -1. If the measurement from Day -1 is missing, the screening ECG is taken as 
baseline.  
Summary and change from baseline for ECG will be presented for continuous ECG 
parameters by visit and treatment group.  
Incidence and percentage of potentially clinically significant ECG parameters as defined 
in Appendix 4 will be presented for each treatment group. All post baseline visit till end 
of study will be included in incidences of significant change or value. For criteria that 
involves change from baseline, the subject must have a baseline value to be included in 
the analysis. For absolute criteria the complete Safety Set will be included.  
Incidence of potentially clinically significant QT increases will also be summarized by 
treatment groups. 
In summarizing the incidence of abnormalities, a patient must have had an evaluation that 
met abnormality criteria by the end of trial, i.e. last contact date.  Incidence rate is 
calculated as the number of patients having at least one abnormality within a trial period 
divided by the number of patients who are both exposed to trial medication and have an 
on-treatment evaluation within that trial period.     
When the ECG is repeated, the last repeat value will be used in the summary for that 
visit. Unscheduled ECG data will not be summarized in the change from baseline 
descriptive analysis but will be included in the incidence of clinically relevant table. 
All analyses will be presented by treatment groups for Stage 1, and Stage 2 with a 
combined RHEZ group from Stage 1 and Stage 2.  
9.7 
Other Safety Data 
NA. 
10 
Pharmacokinetic Analyses 
In general, pharmacokinetic concentrations and parameters will be summarized by 
treatment using descriptive statistics (number, median, mean, standard deviation (SD), 
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percent coefficient of variation, minimum, and maximum). Pharmacokinetic 
concentrations and parameters will also be listed by subject. The individual, mean, and 
median plots of plasma concentrations and other PK analyses will be detailed in the 
clinical pharmacology report. 
In Stage 1, dose proportionality for steady-state (eg, Day 14) PK exposure (Cmax,ss and 
AUCτ) of OPC-167832 will be analyzed using the random intercept power model, with 
subjects as a random effect, using the following equation:xx 
ln (AUCτ or Cmax,ss) = α + β ln (dose) 
where α is the intercept and β is the slope parameter. Dose proportionality will be 
assumed if β is close to 1 and its 90% confidence interval (CI) is entirely contained 
within the 80% to 125% interval corrected for dose range.xx 
Population PK modeling will be performed on OPC-167832 PK data from both stages, 
and the details can be found in a separate Population PK/PD analysis plan.  
11 
Pharmacokinetic/Pharmacodynamic Analyses 
Exposure-response modeling will be performed in both stages for OPC-167832 PK 
measures versus bacterial load using LAM and CFU counts on agar media.  
The relationship between QT interval (Holter data) and plasma concentrations of OPC-
167832 (stage 1) and OPC-167832 when administered with delamanid and/or BDQ 
(stage 2) will be examined using an exposure-response analysis.  
The details can be found in a separate population PK/PD analysis plan. 
12 
Pharmacogenomic Analyses 
There were no pharmacogenomic analyses in this trial. 
13 
Interim Analysis 
An interim analysis of safety, tolerability, PK and efficacy of OPC-167832 is planned 
after the end of stage 1. All analyses specified in this SAP for Stage 1 will be provided at 
the interim analysis. 
14 
Changes in Planned Analysis 
There is no deviation from the planned analysis. 
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15 
Document History 
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16 
References 
1. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events. Version 2.1. July 2017  
2. Ratios: A short guide to confidence limits and proper use. Franz, Volker H. 
http://www.ecogsci.cs.uni-
tuebingen.de/pub/publications_abstracts.php#Franz_fieller_07, 2007. 
3. Gough K, Hutchison M, Keene O, Byron B, Ellis S, Lacey L, et al. Assessment of 
dose proportionality: Report from the statisticians in the pharmaceutical 
industry/pharmacokinetics UK joint working party. Drug Inf J. 
1995;29(3):1039-1048. 
4. Smith BP, Vandenhende FR, Desarte KA, Farid NA, Welch PA, Callaghan JT, et 
al. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 
2000;17(10):1278-1283. 
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Appendix 2 
Criteria for Potentially Clinical Significant Vital Sign 
Abnormalities 
Variable 
Criterion Valuea 
Change Relative to Baselinea 
Heart Rateb 
> 120 bpm 
< 50 bpm 
 15 bpm increase 
 15 bpm decrease 
Systolic Blood Pressureb 
> 160 mmHg 
< 90 mmHg 
 20 mmHg increase 
 20 mmHg decrease 
Diastolic Blood Pressureb 
> 105 mmHg 
< 50 mmHg 
 15 mmHg increase 
 15 mmHg decrease 
Weight 
- 
 5% increase 
 5% decrease 
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column. 
 
 
 
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Appendix 4 
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance 
 
Category 
 
Diagnosis 
Criterion Valuea 
Change Relative to 
Baselinea 
Rate 
 
 
 
Tachycardia 
 120 bpm 
increase of   15 bpm 
 
Bradycardia 
 50 bpm 
decrease of  15 bpm 
Rhythm 
 
 
 
Sinus tachycardiab 
 120 bpm 
increase of  15 bpm 
 
Sinus bradycardiac 
 50 bpm 
decrease of  15 bpm 
 
Supraventricular premature beat 
all 
not present → present 
 
Ventricular premature beat 
all 
not present → present 
 
Supraventricular tachycardia 
all 
not present → present 
 
Ventricular tachycardia 
all 
not present → present 
 
Atrial fibrillation 
all 
not present → present 
 
Atrial flutter 
all 
not present → present 
Conduction 
 
 
 
1 atrioventricular block 
PR  0.20 second 
increase of   0.05 second 
 
2 atrioventricular block 
all 
not present → present 
 
3 atrioventricular block 
all 
not present → present 
 
Left bundle-branch block 
all 
not present → present 
 
Right bundle-branch block 
all 
not present → present 
 
Pre-excitation syndrome 
all 
not present → present 
 
Other intraventricular conduction 
 
blockd 
QRS  0.12 second 
increase of  0.02 second 
Infarction 
 
 
 
Acute or subacute 
all 
not present → present 
 
Old 
 
all 
 
not present → present 
 12 weeks post trial entry 
ST/T Morphological 
 
 
 
Myocardial Ischemia 
all 
not present → present 
 
Symmetrical T-wave inversion 
all 
not present → present 
 
Increase in QTc 
QTc > 450 msec 
(males and females) 
 
              QT 
> 500 msec 
 
 
Increase in QTcF 
QTc > 450 msec 
(males and females) 
 
  
QTc > 500 msec 
(males and females) 
 
 
  
  
Increase of  30 msec and 
 60 msec 
 
  
  
Increase of > 60 msec 
             Increase in QTcB 
QTc > 450 msec 
(males and females) 
 
  
QTc > 500 msec 
(males and females) 
 
 
  
  
Increase of  30 msec and 
 60 msec 
 
  
  
Increase of > 60 msec 
 
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column. 
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Appendix 6 
Technical Details  
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Appendix 7 
List of Proposed Summary Tables  
                      
                     
                     
  
                     
  
       
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Protocol 323-201-00003 
Statistical Analysis Plan                                        56 of 58 
Version Date: 16 May 2022 
 
Appendix 8 
List of Proposed Subject Data Listings 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
56


Protocol 323-201-00003 
Statistical Analysis Plan                                        57 of 58 
Version Date: 16 May 2022 
 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
57


Protocol 323-201-00003 
Statistical Analysis Plan                                        58 of 58 
Version Date: 16 May 2022 
 
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
58


This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: SAP_32320100003_18May2022
Document Number: 
Document Version: 2.0
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Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
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Clinical Pharmacology
Approval
19-May-2022
18:10:41
Clinical Approval
19-May-2022
15:07:16
Biostatistics Approval
18-May-2022
15:55:14
Clinical Study Report 323-201-00003
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
59