Efficacy and Safety Evaluation of Two to Four Months of Treatment With the Combination Regimens of DBOS and PBOS in Adults With Pulmonary Tuberculosis

Inclusion Criteria:

For Stage 1:

• Able to provide written, informed consent prior to initiation of any trial-relatedprocedures or treatments, and able, in the opinion of the Investigator, to complywith all the requirements of the trial.

• Male or female participants between 18 and 65 years of age (inclusive) at thescreening visit.

• Body weight ≥35.0 kilograms (kg) and body mass index (BMI) ≥16.0 at the screeningvisit.

• Newly diagnosed within the past 8 weeks prior to informed consent, untreated (≤4days of treatment), drug-susceptible pulmonary TB, as defined by all of thefollowing:

1. Confirmation of Mtb infection: Mtb positivity on a molecular test (eg, XpertUltra, Hain Line probe assay [LPA]) conducted on a sputum specimen for trialscreening.

2. Evidence of non-paucibacillary disease: ≥1+ sputum smear positivity foracid-fast bacilli using fluorescent microscopy, as defined by the InternationalUnion Against Tuberculosis and Lung Disease (IUATLD)/World Health Organization (WHO) scale, OR a Xpert Ultra semi-quantitative result of 'medium' or 'high' onthe sputum specimen for trial screening.

3. Drug-susceptible TB: Isoniazid and rifampicin resistance not detected, asdetermined by a molecular test (eg, Hain LPA, Xpert Ultra, XpertMTB/Extensively Drug Resistant [XDR]) conducted on a sputum specimen for trialscreening.

4. Clinical signs and/or symptoms consistent with active TB in the opinion of theInvestigator.

5. Chest radiograph consistent with active TB in the opinion of the Investigator.Note, the Investigator is permitted, but not required, to incorporate aradiologist's interpretation into their assessment of a participant's chestradiograph.

• Able to spontaneously produce sputum.

• Female participants of childbearing potential (FOCBP) must agree to use 2 approvedmethods of contraception with their male sexual partners or abstain fromheterosexual intercourse throughout their participation in the trial.

• Male participants must agree to use an approved method of contraception with theirfemale sexual partners of childbearing potential or abstain from heterosexualintercourse throughout their participation in the trial.

For Stage 2:

• Newly diagnosed within the past 8 weeks of informed consent, untreated (≤4 days of treatment), drug-susceptible or rifampicin-/multi-drug resistant pulmonary TB, as defined by all of the following:

1. Confirmation of Mtb infection: Mtb positivity on a molecular test (eg, Xpert Ultra,Hain LPA) conducted on a screening sputum specimen.

2. Evidence of non-paucibacillary disease: ≥1+ sputum smear positivity for acid-fastbacilli using fluorescent microscopy, as defined on the IUATLD/WHO scale, OR XpertUltra semi-quantitative result of 'medium' or 'high' on the sputum specimen fortrial screening.

3. Resistance pattern:

i. For DS TB arm, isoniazid and rifampicin resistance not detected on a molecular test (eg, Hain LPA, Xpert Ultra, Xpert MTB/XDR) conducted on a screening sputum specimen, OR

ii. For RR/MDR TB arm, either rifampicin resistance (RR TB) OR rifampicin and isoniazid resistance (MDR TB) detected on a molecular test (eg, Hain LPA, Xpert Ultra, Xpert MTB/XDR) conducted on a screening sputum specimen.

• Participants with RR or MDR TB must also have fluoroquinolone resistance not detected, as determined by a molecular test (eg, Hain LPA second line, Xpert MTB/XDR) performed on the sputum specimen for trial screening.

d) Clinical signs and/or symptoms consistent with active TB in the opinion of the Investigator.

e) Chest radiograph consistent with active TB in the opinion of the Investigator.

The other inclusion criteria remain the same for Stage 2.

Exclusion Criteria:

• Suspected or documented extra-thoracic TB. Confirmed or suspected lymph node TB isnot considered exclusionary. The presence of a pleural effusion considered notclinically significant together with pulmonary TB is not exclusionary.

• Known, or suspected of having, resistance to a rifamycin, isoniazid, ethambutol,pyrazinamide, delamanid, pretomanid, bedaquiline, linezolid, tedizolid, or sutezolideither confirmed by the laboratory, or based on epidemiological history, such as aknown source case with said resistance.

• Received any prior treatment for active Mtb disease (>4 days) within the past 1 yearof informed consent.

• Received any treatment with a fluoroquinolone active against Mtb (ie, levofloxacin,moxifloxacin, ciprofloxacin) or an aminoglycoside for more than 14 days within the 3months prior to informed consent even if the medication was given for a differentindication than TB treatment.

• Any known prior exposure to delamanid, pretomanid, bedaquiline, OPC-167832, or anyoxazolidinone (linezolid, tedizolid, delpazolid, or sutezolid).

• Evidence of an active clinically significant/uncontrolled metabolic,gastrointestinal, neurological (including peripheral neuropathy), psychiatric,endocrine (including uncontrolled diabetes), hematologic, ophthalmologic (particularly optic neuritis), or liver disease; active malignancy; or other medicalco-morbidity considered significant enough by the Investigator that the participantshould not enter the trial.

• Significant history of, or current clinically relevant cardiovascular disorder, suchas heart failure, coronary artery disease, uncontrolled hypertension, arrhythmia,tachyarrhythmia, prolonged QT syndrome, or presence of symptom(s) stronglysuggestive of such a problem, such as exertional chest pressure/pain or unexplainedsyncope.

• Significant history of, or current evidence of an active clinicallysignificant/poorly controlled pulmonary disease, such as asthma, Chronic obstructivePulmonary disease (COPD), silicosis, or lung fibrosis (other than TB), considered assevere by the Investigator. In particular, any underlying pulmonary condition thatcould significantly interfere with the assessment of X-ray images, interpretation ofsputum findings, or otherwise compromise the participant's participation in thetrial is exclusionary based on the Investigator's judgement. Clinically significantpost-Coronavirus disease-2019 (COVID-19) pulmonary sequelae should be consideredexclusionary.

• If HIV-infected, having any of the following present:

1. Not on antiretroviral treatment at time of screening or taking antiretroviraltreatment for <3 months prior to screening, OR

2. Cluster of differentiation (CD)4+ T-cell count <200 cells/microliter (μL)during the screening period, OR

3. HIV viral load >200 copies/milliliter (mL) during the screening period, OR

4. Evidence of a currently active opportunistic malignancy or infection related toHIV other than TB that requires treatment with a prohibited concomitantmedication (oral candidiasis is not exclusionary) OR

5. HIV-infected participants enrolling at a trial site in Peru will not beeligible due to the requirement for longer TB treatment courses than thestandard 6-month HRZE regimen for patients with HIV/TB co-infection as per thePeruvian national TB treatment guidelines.

• If female, currently pregnant or breastfeeding, OR having a positive serum or urinepregnancy test during the screening period, OR planning to become pregnant withinthe 12-month period after the screening period.

• Current significant drug and/or alcohol abuse that is likely to result in pooradherence to trial requirements or that would pose a risk to the participant'swellbeing during the trial.

• Karnofsky Performance Status scale score at screening of <60.

• Having a disease or condition where the use of delamanid, pretomanid, bedaquiline,OPC-167832, sutezolid, rifampicin, isoniazid, pyrazinamide, or ethambutol iscontraindicated.

• Positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Polymerasechain reaction (PCR) result on nasopharyngeal sample taken during screening. Priorhistory of COVID-19/SARS-CoV-2 infection is not exclusionary if SARS-CoV-2 PCRperformed on screening sample is negative.

• Any of the following laboratory results during screening:

1. Estimated creatinine clearance <60 mL/minute

2. Alanine transaminase (ALT) or aspartate transaminase (AST) >2.5 × upper limitof normal of the clinical laboratory reference range

3. Total bilirubin >2x upper limit of normal of the clinical laboratory referencerange, at screening

4. Hemoglobin <8.0 grams per deciliter (g/dL)

5. Platelet count <100 x 10^9/liter (L)

6. White blood cell count <2.0 x 10^9/L

7. Screening glycosylated hemoglobin (HbA1c) ≥10.0%

8. Positive hepatitis B surface antigen

9. Positive hepatitis C antibody.

• Moderate to severe substance use disorder according to the Diagnostic andStatistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria (substancesof concern may include cocaine, amphetamines, opiates, barbiturates,benzodiazepines, or alcohol).

• A clinically significant Electrocardiogram (ECG) abnormality at screening asconfirmed by a central ECG reading service. Examples of such include, but are notlimited to, second- or third-degree atrioventricular block, complete right bundlebranch block, left bundle branch block, QRS duration ≥120 millisecond (msec), QTinterval corrected using Fridericia's formula (QTcF) interval >450 msec in males or >470 msec in females, atrial fibrillation or flutter, supraventricular tachycardia,and ventricular tachycardia or multiple multifocal premature ventricular complexes.The following ECG findings are not considered clinically significant: sinustachycardia, mild first-degree atrioventricular block (P-R interval <0.23 sec),right or left axis deviation, incomplete right bundle branch block, and isolatedleft anterior fascicular block (left anterior hemiblock) in young otherwise healthyparticipants.

• Participants receiving any of the prohibited medications within the specifiedperiods or who would be likely to require prohibited concomitant therapy during thetrial.

• History of having taken another investigational drug within 30 days preceding trialentry or participates in another clinical study during the duration of this trial.

• Prospective approvals of protocol deviations to enrollment criteria, also known asprotocol waivers or exemptions, are not permitted.

• Participants with baseline culture results (defined as collected during screeningperiod through up to Week 1) that are all negative for growth of Mtb will not beincluded in efficacy analyses. DS-TB participants whose baseline phenotypic DSTresults demonstrate resistance to isoniazid and/or rifampicin will not be includedin efficacy analyses. Their treatment will be modified accordingly based on theirresistance profile, relevant local/national guidelines, and the participant'sinterest to continue in the trial after discussion with the Investigator.