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
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Enrollment
- 122
- Locations
- 6
- Primary Endpoint
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Severe TEAEs, TEAEs Related to Study Drug, TEAEs Leading to Study Discontinuation, TEAEs Leading to Death, and All Grade TEAEs Based on DAIDS Criteria
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
- •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.
Arms & Interventions
Rifampin, Isoniazid, Ethambutol, and Pyrazinamide (RHEZ)
Participants will receive RHEZ, orally, QD for 8 weeks followed by 18 weeks of rifampin and isoniazid for a total of 26 weeks.
Intervention: RHEZ (Drug)
Rifampin, Isoniazid, Ethambutol, and Pyrazinamide (RHEZ)
Participants will receive RHEZ, orally, QD for 8 weeks followed by 18 weeks of rifampin and isoniazid for a total of 26 weeks.
Intervention: Isoniazid (Drug)
Delamanid + Bedaquiline + OPC-167832 30 mg
Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, QD, bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, TIW and OPC-167832, 30 mg, oral tablets, QD for a total of 17 weeks.
Intervention: Delamanid (Drug)
Delamanid + Bedaquiline + OPC-167832 10 mg
Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, once daily (QD), bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, thrice weekly (TIW) and OPC-167832, 10 mg, oral tablets, QD for a total of 17 weeks.
Intervention: Delamanid (Drug)
Delamanid + Bedaquiline + OPC-167832 90 mg
Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, QD, bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, TIW and OPC-167832, 90 mg, oral tablets, QD for a total of 17 weeks.
Intervention: Delamanid (Drug)
Rifampin, Isoniazid, Ethambutol, and Pyrazinamide (RHEZ)
Participants will receive RHEZ, orally, QD for 8 weeks followed by 18 weeks of rifampin and isoniazid for a total of 26 weeks.
Intervention: Rifampin (Drug)
Delamanid + Bedaquiline + OPC-167832 30 mg
Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, QD, bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, TIW and OPC-167832, 30 mg, oral tablets, QD for a total of 17 weeks.
Intervention: Bedaquiline (Drug)
Delamanid + Bedaquiline + OPC-167832 10 mg
Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, once daily (QD), bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, thrice weekly (TIW) and OPC-167832, 10 mg, oral tablets, QD for a total of 17 weeks.
Intervention: Bedaquiline (Drug)
Delamanid + Bedaquiline + OPC-167832 90 mg
Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, QD, bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, TIW and OPC-167832, 90 mg, oral tablets, QD for a total of 17 weeks.
Intervention: Bedaquiline (Drug)
Delamanid + Bedaquiline + OPC-167832 10 mg
Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, once daily (QD), bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, thrice weekly (TIW) and OPC-167832, 10 mg, oral tablets, QD for a total of 17 weeks.
Intervention: OPC-167832 10 mg (Drug)
Delamanid + Bedaquiline + OPC-167832 30 mg
Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, QD, bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, TIW and OPC-167832, 30 mg, oral tablets, QD for a total of 17 weeks.
Intervention: OPC-167832 30 mg (Drug)
Delamanid + Bedaquiline + OPC-167832 90 mg
Participants will receive a combination regimen of delamanid, 300 mg, oral tablets, QD, bedaquiline, 400 mg, oral tablets, QD for 2 weeks, then 200 mg, TIW and OPC-167832, 90 mg, oral tablets, QD for a total of 17 weeks.
Intervention: OPC-167832 90 mg (Drug)
Outcomes
Primary Outcomes
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Severe TEAEs, TEAEs Related to Study Drug, TEAEs Leading to Study Discontinuation, TEAEs Leading to Death, and All Grade TEAEs Based on DAIDS Criteria
Time Frame: From first dose of study drug up to end of follow up period (up to Week 52)
An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant administered an investigational medicinal product or trial treatment and which does not necessarily have a causal relationship with this treatment. TEAEs are AEs with an onset date on or after the start of treatment. Serious AE are AEs that leads to death, is life threatening, requires or prolongs hospitalization, significant disability, congenital anomaly or birth defect, and other medically important serious advent. AEs were graded on a severity 3-point scale as follows: Mild: Discomfort noticed, but no disruption to daily activity.; Moderate: Discomfort sufficient to reduce or affect normal daily activity.;Severe: Inability to work or perform normal daily activity. As pre-specified in statistical analysis plan (SAP),Division of AIDS (DAIDS v2.1) criteria was used and AEs graded as follows:Grade 1-Mild;Grade 2-Moderate;Grade 3-Severe;Grade 4-Life Threatening;Grade 5-Death.
Number of Participants With Potentially Clinically Relevant Laboratory Test Abnormalities
Time Frame: Baseline up to end of follow up period (up to Week 52)
Laboratory assessments included clinical chemistry (Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Total Bilirubin, Calcium, Creatinine, estimated Glomerular Filtration Rate (eGFR), Glucose, Fasting and Non-Fasting, Cholesterol, Inorganic Phosphorus, Magnesium, Potassium, Sodium, Triglycerides and Uric Acid), hematology (Activated Partial Thromboplastin Time, Prothrombin Time, Partial Thromboplastin Time, International Normalized Ratio (INR), Absolute CD4+ Count, Absolute Lymphocytes, Absolute Neutrophil Count, Hemoglobin, Platelet Count, White Blood Cell), and urinalysis (Urine Glucose, Blood and Protein). As pre-specified in statistical analysis plan (SAP), Division of AIDS (DAIDS) criteria was used and abnormalities were graded as follows:Grade 1 - Mild; Grade 2 - Moderate; Grade 3 - Severe; Grade 4 - Life Threatening; Grade 5 - Death. Laboratory values with DAIDS Grade ≥3 were considered as potentially clinically relevant abnormalities and are reported here.
Number of Participants With Potentially Clinically Relevant Abnormalities in the Vital Signs
Time Frame: Baseline up to end of follow up period (up to Week 52)
Vital signs measurements included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, body weight, and body temperature. Blood pressure (i.e., SBP, DBP) and heart rate were measured in the supine and sitting positions after the participant had been in each position for at least 3 minutes. The participants were categorized based on the clinically relevant vital sign values as per DAIDS criteria pre-specified in SAP. Each vital sign parameter was graded using the DAIDS criteria as follows: Grade 1 - Mild; Grade 2 - Moderate; Grade 3 - Severe; Grade 4 - Potentially Life Threatening; Grade 5 - Death. The categories with at least one participant with clinically significant value of any grade for vital signs are reported here.
Number of Participants With Potentially Clinically Relevant Electrocardiogram (ECG) Abnormalities
Time Frame: Baseline up to end of follow up period (up to Week 52)
3 ECGs were performed at baseline (Day -1) spaced 5 to 10 minutes apart, and 3 ECGs at all subsequent visits during the treatment and follow-up periods. The categories with at least one participant with clinically relevant ECG abnormalities are reported here.
Number of Participants With an AE Reported as DAIDS Grade 3 or Higher
Time Frame: From first dose of study drug up to end of follow up period (up to approximately Week 52)
An AE was defined as any untoward medical occurrence in a clinical trial participant administered a treatment that does not necessarily have a causal relationship with the treatment. All AEs were graded on a 5-point scale according to DAIDS Table for Grading the Severity of Adult and Pediatric AEs as follows: Grade 1 - Mild; Grade 2 - Moderate; Grade 3 - Severe; Grade 4 - Life Threatening; Grade 5 - Death.
Number of Participants With TEAEs Leading to Discontinuation of Treatment
Time Frame: From first dose of the study drug up to end of follow up period (up to approximately Week 52)
An AE was defined as any untoward medical occurrence in a clinical trial participant administered an investigational medicinal product or trial treatment and which does not necessarily have a causal relationship with this treatment. TEAEs are AEs with an onset date on or after the start of treatment.
Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) in Mycobacteria Growth Indicator Tube® (MGIT) by End of Treatment (Week 17)
Time Frame: Week 17
A participant was classified as having achieved SCC if the participant achieved first 2 consecutive sputum cultures negative for growth of mycobacterium tuberculosis at least 1 week apart (±4 days) after his/her last sputum culture that was positive for growth, and did not have a positive sputum culture result in between, and by the end of the treatment. Efficacy was assessed by using the MGIT liquid culture system. 95% confidence interval (CI) was calculated using Clopper Pearson (exact) confidence interval model.
Percentage of Participants Who Achieved SCC in MGIT by End of Treatment (Week 26)
Time Frame: Week 26
A participant was classified as having achieved SCC if the participant achieved first 2 consecutive sputum cultures negative for growth of mycobacterium tuberculosis at least 1 week apart (±4 days) after his/her last sputum culture that was positive for growth, and did not have a positive sputum culture result in between, and by the end of the treatment. Efficacy was assessed by using the MGIT liquid culture system. 95% CI is calculated using Clopper Pearson (exact) confidence interval model.
Secondary Outcomes
- Percentage of Participants Who Achieved SCC in MGIT by the End of 8 Weeks of Treatment(Week 8)
- Time to Detection of MGIT Cultures(Baseline up to Week 52)
- Percentage of Participants Achieving Negative Sputum Lipoarabinomannan (LAM) by 8 Weeks of Treatment and by End of Treatment(Week 8, and End of Treatment Period - Week 17 (for OPC-167832 arms) and Week 26 (for RHEZ arm))
- Percentage of Participants With Acquired Drug Resistance(Baseline up to Week 52)
- Time to Sputum Culture Conversion (SCC)(From the first dose of the study up to the end of the follow-up period (up to Week 52))