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

A Phase 2b/c, Multi-Arm, 2-Stage, Duration Randomized Trial of the Efficacy and Safety of Two to Four Months Treatment With Regimens Containing Bedaquiline, OPC-167832, and Sutezolid, Plus Either Pretomanid or Delamanid, in Adults With Pulmonary Tuberculosis

This multicenter, two-stage, open-label, randomized trial will aim to assess the efficacy, safety, optimal duration, and pharmacokinetics (PK) of Delamanid, Bedaquiline, OPC-167832, and Sutezolid (DBOS) and Pretomanid, Bedaquiline, OPC-167832, and Sutezolid (PBOS) in adult participants with drug sensitive tuberculosis (DS-TB) and rifampicin or multi-drug resistant TB (RR/MDR-TB).

Inclusion Criteria:

For Stage 1:

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

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

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

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

  1. Confirmation of Mtb infection: Mtb positivity on a molecular test (eg, Xpert Ultra, Hain Line probe assay [LPA]) conducted on a sputum specimen for trial screening.
  2. Evidence of non-paucibacillary disease: ≥1+ sputum smear positivity for acid-fast bacilli using fluorescent microscopy, as defined by the International Union Against Tuberculosis and Lung Disease (IUATLD)/World Health Organization (WHO) scale, OR a Xpert Ultra semi-quantitative result of 'medium' or 'high' on the sputum specimen for trial screening.
  3. Drug-susceptible TB: Isoniazid and rifampicin resistance not detected, as determined by a molecular test (eg, Hain LPA, Xpert Ultra, Xpert MTB/Extensively Drug Resistant [XDR]) conducted on a sputum specimen for trial screening.
  4. Clinical signs and/or symptoms consistent with active TB in the opinion of the Investigator.
  5. Chest radiograph consistent with active TB in the opinion of the Investigator. Note, the Investigator is permitted, but not required, to incorporate a radiologist's interpretation into their assessment of a participant's chest radiograph.

• Able to spontaneously produce sputum.

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

• Male participants must agree to use an approved method of contraception with their female sexual partners of childbearing potential or abstain from heterosexual intercourse 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-fast bacilli using fluorescent microscopy, as defined on the IUATLD/WHO scale, OR Xpert Ultra semi-quantitative result of 'medium' or 'high' on the sputum specimen for trial 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 is not considered exclusionary. The presence of a pleural effusion considered not clinically 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 sutezolid either confirmed by the laboratory, or based on epidemiological history, such as a known source case with said resistance.

• Received any prior treatment for active Mtb disease (>4 days) within the past 1 year of 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 3 months prior to informed consent even if the medication was given for a different indication than TB treatment.

• Any known prior exposure to delamanid, pretomanid, bedaquiline, OPC-167832, or any oxazolidinone (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 medical co-morbidity considered significant enough by the Investigator that the participant should not enter the trial.

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

• Significant history of, or current evidence of an active clinically significant/poorly controlled pulmonary disease, such as asthma, Chronic obstructive Pulmonary disease (COPD), silicosis, or lung fibrosis (other than TB), considered as severe by the Investigator. In particular, any underlying pulmonary condition that could significantly interfere with the assessment of X-ray images, interpretation of sputum findings, or otherwise compromise the participant's participation in the trial is exclusionary based on the Investigator's judgement. Clinically significant post-Coronavirus disease-2019 (COVID-19) pulmonary sequelae should be considered exclusionary.

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

  1. Not on antiretroviral treatment at time of screening or taking antiretroviral treatment 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 to HIV other than TB that requires treatment with a prohibited concomitant medication (oral candidiasis is not exclusionary) OR
  5. HIV-infected participants enrolling at a trial site in Peru will not be eligible due to the requirement for longer TB treatment courses than the standard 6-month HRZE regimen for patients with HIV/TB co-infection as per the Peruvian national TB treatment guidelines.

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

• Current significant drug and/or alcohol abuse that is likely to result in poor adherence to trial requirements or that would pose a risk to the participant's wellbeing 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 is contraindicated.

• Positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Polymerase chain reaction (PCR) result on nasopharyngeal sample taken during screening. Prior history of COVID-19/SARS-CoV-2 infection is not exclusionary if SARS-CoV-2 PCR performed 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 limit of normal of the clinical laboratory reference range
  3. Total bilirubin >2x upper limit of normal of the clinical laboratory reference range, 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 and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria (substances of concern may include cocaine, amphetamines, opiates, barbiturates, benzodiazepines, or alcohol).

• A clinically significant Electrocardiogram (ECG) abnormality at screening as confirmed by a central ECG reading service. Examples of such include, but are not limited to, second- or third-degree atrioventricular block, complete right bundle branch block, left bundle branch block, QRS duration ≥120 millisecond (msec), QT interval 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: sinus tachycardia, mild first-degree atrioventricular block (P-R interval <0.23 sec), right or left axis deviation, incomplete right bundle branch block, and isolated left anterior fascicular block (left anterior hemiblock) in young otherwise healthy participants.

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

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

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

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