Clinical trial NCT05221502: Safety and Efficacy Evaluation of 4-month Regimen of OPC-167832, Delamanid and Bedaquiline in Participants With Drug-Susceptible Pulmonary TB
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary TB
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Bill and Melinda Gates Foundation
First posted: 2022-02-03
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial will assess the safety and efficacy of OPC-167832 combined with delamanid and bedaquiline in participants with drug-susceptible tuberculosis (DS-TB) administered for 17 weeks compared to rifampin, isoniazid, ethambutol, pyrazinamide (RHEZ) administered for 26 weeks.

Detailed description: Eligible participants for this study have a diagnosis of pulmonary DS-TB.

This is a Phase 2b/c multicenter, open-label, randomized, dose-finding study, consisting of up to 26 weeks of treatment period.

Following a screening period of up to 14 days, eligible participants will be randomized in the study.

Randomization will be stratified by presence of bilateral cavitation on screening chest x-ray (yes or no). After the end of the treatment period, participants will be followed until 12 months post randomization.

Eligibility criteria: Inclusion Criteria:

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.
2. Male or female participants between 18 and 65 years of age (inclusive) at the screening visit.
3. Body weight ≥ 35.0 kg at the screening visit.
4. Newly diagnosed, rifampin and isoniazid susceptible (on the screening sample) pulmonary TB.
5. Able to spontaneously produce sputum.
6. 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.
7. 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:

1. 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.
2. 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).
3. 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.
4. Known bleeding disorders or family history of bleeding disorders.
5. Any diseases or conditions in which the use of DLM, BDQ, OPC 167832, rifampin, isoniazid, pyrazinamide, or ethambutol is contraindicated.
6. Any prior treatment for M tuberculosis within the past 2 years.
7. Any treatment with a drug active against M tuberculosis (eg, quinolones) within the 3 months prior to screening.
8. Clinical evidence of severe extrapulmonary TB (eg, miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis).
9. 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.
10. 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.
11. Screening glucose (nonfasting) ≥ 200 mg/dL or glycosylated hemoglobin (HbA1c) ≥ 6.5%.
12. 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.
13. 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.
14. 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.
15. 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.
16. History of current hepatitis or carriers of hepatitis B surface antigen (HBsAg) and/or anti hepatitis C virus (HCV).
17. 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.
18. History of having taken an investigational drug within 30 days preceding trial entry.
19. A history of difficulty in donating blood.
20. Donation of blood or plasma within 30 days prior to dosing.
21. History of serious mental disorders that, in the opinion of the investigator, would exclude the participant from participating in this trial.
22. Any known prior exposure to OPC-167832, DLM, or BDQ.
23. Participants with significant medical comorbidities that in the opinion of the investigator, should not participate in the trial.
24. Participants with Karnofsky score \< 60 will be excluded from the trial.
25. Participants testing positive for active severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection at screening.
26. 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.

Primary outcomes:
measure: Incidence of Treatment Emergent Adverse Events
timeFrame: Baseline to 12 months post randomization
measure: 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.
timeFrame: Baseline to 12 months post randomization
measure: Number of participants with a grade 3 or higher AE
timeFrame: Baseline to 12 months post randomization
measure: Number of all cause Treatment Discontinuation
timeFrame: Baseline to 12 months post randomization
measure: Sputum culture conversion (SCC) in Mycobacteria Growth Indicator Tube® (MGIT)
timeFrame: Baseline to End of Treatment Period - Week 17 and Week 26
Secondary outcomes:
measure: Proportion of participants who achieve SCC in MGIT by 8 weeks of treatment
timeFrame: Baseline to Week 8
measure: Time to detection of MGIT cultures
timeFrame: Baseline to 12 months post randomization
measure: Proportion of participants who convert sputum LAM to negative by 8 weeks of treatment and by end of treatment
timeFrame: End of Treatment Period - Week 17 and Week 26
measure: Proportion of participants who develop drug resistance
timeFrame: Baseline to 12 months post randomization
measure: Time to Sputum Culture Conversion (SCC) of each treatment group.
timeFrame: Baseline to 12 months post randomization
Other outcomes:
measure: Assess the positron emission tomography/computerized axial tomography (PET/CT) imaging response over the course of treatment
timeFrame: Baseline to Week 26
measure: Evaluate the ribosomal ribonucleic acid synthesis ratio (RS ratio) decline in sputum
timeFrame: Baseline to 12 months post randomization
measure: Assess whole blood transcriptomic signatures previously associated with TB cure from serum
timeFrame: Screening to 12 months post randomization
measure: The proportion of participants with favorable outcome at 12 months post randomization
timeFrame: Baseline to 12 months post randomization
measure: Number of participants with relapse at 12 months post randomization
timeFrame: Baseline to 12 months post randomization
Locations:
city: Tembisa
country: South Africa
facility: Aurum Institute - Tembisa Clinical Research Centre
state: Gauteng
city: Cape Town
country: South Africa
facility: TASK Applied Science, Brooklyn Chest Hospital Premises
city: Cape Town
country: South Africa
facility: University of CapeTown Lung Center Institute
city: Johannesburg
country: South Africa
facility: Themba Lethu Clinic Clinical HIV Research Unit (CHRU)
city: Klerksdorp
country: South Africa
facility: Perinatal HIV Research Unit Tshepong Hospital Complex
city: Pretoria
country: South Africa
facility: Setshaba Research Center
Study officials:
References: