Safety and Efficacy Evaluation of 4-month Regimen of OPC-167832, Delamanid and Bedaquiline in Participants With Drug-Susceptible Pulmonary TB

Study Overview
=================
Brief Summary
-----------------
This trial will assess the safety and efficacy of OPC-167832 combined with Delamanid and Bedaquiline in subjects with DS-TB administered for 4 months compared to rifampin, isoniazid, ethambutol, pyrazinamide (RHEZ) administered for 6 months

Official Title
-----------------
A Multicenter, Phase 2b/c, Open-label, Randomized, Dose-finding Trial to Evaluate the Safety and Efficacy of a 4 Month Regimen of OPC-167832 in Combination With Delamanid and Bedaquiline in Subjects With Drug-susceptible Pulmonary Tuberculosis in Comparison With Standard Treatment

Conditions
-----------------
Pulmonary TB

Intervention / Treatment
-----------------
* Drug: Delamanid + Bedaquiline + OPC-167832 10 mg
* Drug: Delamanid + Bedaquiline + OPC-167832 30 mg
* Drug: Delamanid + Bedaquiline + OPC-167832 90 mg
* Drug: RHEZ


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 kg at the screening visit. Newly diagnosed, rifampin and isoniazid susceptible (on the screening sample) pulmonary TB. Able to spontaneously produce sputum. Females of childbearing potential (FOCBP) must agree to use 2 different approved methods of birth control or remain abstinent throughout their participation in the trial and for 12 weeks after the last dose of IMP or dose of RHEZ. Male participants must agree to use 2 different approved methods of birth control or remain abstinent throughout their participation in the trial and for 12 weeks after the last dose of IMP or RHEZ. Exclusion Criteria: Participants are known or suspected of having resistance to rifampin, isoniazid, ethambutol, pyrazinamide, DLM, or BDQ either confirmed by the laboratory, or based on epidemiological history, at screening. Evidence of clinically significant metabolic (for example, including ongoing or current hypokalemia [ie, potassium <3.5 mEq/dL at screening]), gastrointestinal, neurological, psychiatric, endocrine or liver (eg, hepatitis B and C) disease; malignancy; or other abnormalities (other than the indication being studied). History of, or current, clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, uncontrolled hypertension, arrhythmia or symptom strongly suggestive of such a problem (for example, syncope or palpitations), tachyarrhythmia or status after myocardial infarction. Known bleeding disorders or family history of bleeding disorders. Any diseases or conditions in which the use of DLM, BDQ, OPC 167832, rifampin, isoniazid, pyrazinamide, or ethambutol is contraindicated. Any prior treatment for M tuberculosis within the past 2 years. Any treatment with a drug active against M tuberculosis (eg, quinolones) within the 3 months prior to screening. Clinical evidence of severe extrapulmonary TB (eg, miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis). Evidence of pulmonary silicosis, lung fibrosis, or other lung condition considered as severe by the investigator (other than TB). In particular, any underlying condition that could interfere with the assessment of x-ray images, sputum collection, or interpretation of sputum findings, or otherwise compromise the subject's participation in the trial. Any renal impairment characterized by creatinine clearance/estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2, or hepatic impairment characterized by alanine transaminase or aspartate transaminase > 2.0 × upper limit of normal of the clinical laboratory reference range or bilirubin > 2.0 × upper limit of normal of the clinical laboratory reference range, at screening. Screening glucose (nonfasting) ≥ 200 mg/dL or glycosylated hemoglobin (HbA1c) ≥ 6.5%. QTcF > 450 msec in male participants (> 470 msec in female participants), atrioventricular block II or III, bi-fasicular block, at screening or current or history of clinically significant ventricular arrhythmias. Other ECG abnormalities, if considered clinically significant by the investigator. Participants receiving any of the prohibited medications (see Section 6.5.1) within the specified periods or who would be likely to require prohibited concomitant therapy during the trial. Female participants who are breast-feeding or who have a positive pregnancy test result prior to receiving the first dose of IMP or RHEZ on Day 1. Current history of 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 well-being during the course of the trial. History of current hepatitis or carriers of hepatitis B surface antigen (HBsAg) and/or anti hepatitis C virus (HCV). Participants who test positive for cocaine or other drugs of abuse (excluding known prescription stimulants and other prescribed medications and marijuana) at screening are excluded. Detectable levels of alcohol, marijuana, barbiturates, or opiates in the drug screen are not exclusionary if, in the investigator's documented opinion, the participant does not meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for moderate to severe substance use disorder and the positive test does not signal a clinical condition that would impact the safety of the participant or interpretation of the trial results, and participation is agreed to by the medical monitor prior to treatment. History of having taken an investigational drug within 30 days preceding trial entry. A history of difficulty in donating blood. Donation of blood or plasma within 30 days prior to dosing. History of serious mental disorders that, in the opinion of the investigator, would exclude the participant from participating in this trial. Any known prior exposure to OPC-167832, DLM, or BDQ. Participants with significant medical comorbidities that in the opinion of the investigator, should not participate in the trial. Participants with Karnofsky score < 60 will be excluded from the trial. Participants testing positive for active severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection at screening. Participants with HIV co infection not on a stable anti-retroviral regimen consisting of tenofovir, emtricitabine/ lamivudine, dolutegravir (ie > 3 months), or who have a detectable viral load, or who have a CD4 count < 350 cells/mm3 will be excluded from the trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Trial 323-201-00006 is a multicenter, phase 2b/c, open-label, randomized, dose-finding trial in subjects with DS-TB. Following a screening period of up to 14 days, eligible subjects will be randomized on Day -1 or predose Day 1 in a ratio of 1:2:2:1 to one of the following treatment arms: Arm 1: DLM (300 mg once daily [QD]) + BDQ (400 mg QD x 2 weeks, then 200 mg thrice-weekly [TIW]) + OPC-167832 (10 mg QD) for 17 weeks Arm 2: DLM (300 mg QD) + BDQ (400 mg QD x 2 weeks, then 200 mg TIW) + OPC-167832 (30 mg QD) for 17 weeks Arm 3: DLM (300 mg once daily [QD]) + BDQ (400 mg QD x 2 weeks, then 200 mg TIW) + OPC-167832 (90 mg QD) for 17 weeks Arm 4: RHEZ for 8 weeks followed by 18 weeks of rifampin and isoniazid (for a total of 26 weeks) Randomization will be stratified by HIV status (yes or no) and presence of bilateral cavitation on screening chest x-ray (yes or no). After the end of the treatment period, subjects will be followed until 12 months postrandomization.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Delamanid + Bedaquiline + OPC-167832 10 mg | Drug: Delamanid + Bedaquiline + OPC-167832 10 mg<br>* Delamanid (300 mg once daily [QD]) + Bedaquiline (400 mg QD x 2 weeks, then 200 mg thrice-weekly [TIW]) + OPC-167832 (10 mg QD) for 17 weeks<br>|
| Experimental: Arm 2<br>Delamanid + Bedaquiline + OPC-167832 30 mg | Drug: Delamanid + Bedaquiline + OPC-167832 30 mg<br>* Delamanid (300 mg once daily [QD]) + Bedaquiline (400 mg QD x 2 weeks, then 200 mg thrice-weekly [TIW]) + OPC-167832 (30 mg QD) for 17 weeks<br>|
| Experimental: Arm 3<br>Delamanid + Bedaquiline + OPC-167832 90 mg | Drug: Delamanid + Bedaquiline + OPC-167832 90 mg<br>* Delamanid (300 mg QD) + Bedaquiline (400 mg QD x 2 weeks, then 200 mg TIW) + OPC-167832 (90 mg QD) for 17 weeks<br>|
| Active Comparator: Arm 4<br>RHEZ | Drug: RHEZ<br>* RHEZ for 8 weeks followed by 18 weeks of rifampin and isoniazid (for a total of 26 weeks)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Emergent Adverse Events | Incidence of TEAEs: all TEAEs, TEAEs by severity, TEAEs potentially causally related to the IMP or trial medication, TEAEs with an outcome of death or trial medication, Serious TEAEs, TEAEs leading to discontinuation of the IMP or trial medication | Baseline to 12 months post randomization | 
| Incidence of potentially clinically significant changes of laboratory tests from baseline and abnormalities in the vital signs, physical examinations, electrocardiograms (ECGs) at each visit were assessed and at end of study. | Incidence of potentially clinically significant changes from baseline and abnormalities in the parameters below, at each visit were assessed and at end of study: Lab Tests: Hematology, Clinical Chemistry, CD4 Count, Urinalysis Vital Signs: systolic and diastolic blood pressure (mmHg), heart rate (beats/min), respiratory rate (breaths/min), body temperature (C), weight (kg) and body mass index (kg/m2) Physical exam include examination of the abdomen; extremities; head, eyes, ears, nose (HEENT); neurological; skin and mucosae; thorax; urogenital; audiometry assessment and visual assessment. ECGs: ECG PR interval (msec) ECG QTc interval (msec) ECG arrhythmia | Baseline to 12 months post randomization | 
| Number of participants with a grade 3 or higher AE | The proportion of subjects with a grade 3 or higher AE | Baseline to 12 months post randomization | 
| Number of all cause Treatment Discontinuation | Rate of All Cause Treatment Discontinuation | Baseline to 12 months post randomization | 
| Sputum culture conversion (SCC) in Mycobacteria Growth Indicator Tube® (MGIT) | The proportion of subjects achieving sputum culture conversion (SCC) in Mycobacteria Growth Indicator Tube® (MGIT) (Sputum culture conversion occurs when a subject has the first of 2 visits of at least 1 week apart (±4 days) with sputum cultures negative and without a positive sputum culture result in between). | Baseline to End of Treatment Period - Week 17 and Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who achieve SCC in MGIT by 8 weeks of treatment | Proportion of subjects who achieve SCC. | Baseline to Week 8 | 
| Time to detection of MGIT cultures | Change in time to detection, in days, of MGIT liquid culture results | Baseline to 12 months post randomization | 
| Proportion of participants who convert sputum LAM to negative by 8 weeks of treatment and by end of treatment | The proportion of subjects who convert sputum LAM concentrations from positive to negative by 8 weeks of treatment and by end of treatment | End of Treatment Period - Week 17 and Week 26 | 
| Proportion of participants who develop drug resistance | Proportion of subjects whose sputum cultures test resistant to any drugs in the treatment regimens during the treatment period. | Baseline to 12 months post randomization | 
| Time to Sputum Culture Conversion (SCC) of each treatment group. | To compare time to SCC, in days, of each treatment group. | Baseline to 12 months post randomization |