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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
122
Delamanid (300 mg QD) for 17 weeks
Bedaquiline (400 mg QD x 2 weeks, then 200 mg TIW) for 17 weeks
RHEZ (RIFAFOUR single dose combination tablets) for 8 weeks
Aurum Institute - Tembisa Clinical Research Centre
Tembisa, Gauteng, South Africa
TASK Applied Science, Brooklyn Chest Hospital Premises
Cape Town, South Africa
University of CapeTown Lung Center Institute
Cape Town, South Africa
Themba Lethu Clinic Clinical HIV Research Unit (CHRU)
Johannesburg, South Africa
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
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.
Time frame: From first dose of study drug up to end of follow up period (up to Week 52)
Number of Participants With Potentially Clinically Relevant Laboratory Test Abnormalities
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.
Time frame: Baseline up to end of follow up period (up to Week 52)
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Rifampin tablets for 18 weeks
Isoniazid tablets for 18 weeks
OPC-167832 (10 mg QD) for 17 weeks
OPC-167832 (30 mg QD) for 17 weeks
OPC-167832 (90 mg QD) for 17 weeks
Perinatal HIV Research Unit Tshepong Hospital Complex
Klerksdorp, South Africa
Setshaba Research Center
Pretoria, South Africa
Number of Participants With Potentially Clinically Relevant Abnormalities in the Vital Signs
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.
Time frame: Baseline up to end of follow up period (up to Week 52)
Number of Participants With Potentially Clinically Relevant Electrocardiogram (ECG) Abnormalities
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.
Time frame: Baseline up to end of follow up period (up to Week 52)
Number of Participants With an AE Reported as DAIDS Grade 3 or Higher
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.
Time frame: From first dose of study drug up to end of follow up period (up to approximately Week 52)
Number of Participants With TEAEs Leading to Discontinuation of Treatment
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.
Time frame: From first dose of the study drug up to end of follow up period (up to approximately Week 52)
Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) in Mycobacteria Growth Indicator Tube® (MGIT) by End of Treatment (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.
Time frame: Week 17
Percentage of Participants Who Achieved SCC in MGIT by End of Treatment (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.
Time frame: Week 26
Percentage of Participants Who Achieved SCC in MGIT by the End of 8 Weeks of Treatment
A participant was classified as having achieved SCC if he/she 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 8 weeks of treatment. Efficacy was assessed by using the MGIT liquid culture system. 95% CI is calculated using Clopper Pearson (exact) confidence interval model.
Time frame: Week 8
Time to Detection of MGIT Cultures
Time to detection of MGIT cultures was the time assessed, in days, when a sputum culture result was positive using the MGIT system during the routine 42-day incubation period. A longer time to detection represented a lower burden of mycobacterium tuberculosis (MTB) organisms present in the sputum.
Time frame: Baseline up to Week 52
Percentage of Participants Achieving Negative Sputum Lipoarabinomannan (LAM) by 8 Weeks of Treatment and by End of Treatment
Sputum LAM concentrations were measured on up to 3 samples collected at baseline and postbaseline at Week 8 and at end of treatment. A participant was classified as having achieved negative sputum conversion in LAM if the participant has the first of 2 visits of at least 1 week apart with sputum LAM negative (below the lower limit of quantification) and without a positive sputum LAM result in between. Numeric sputum LAM concentration data was converted to a binary variable using the rule: if the sputum LAM concentration was less than 10 picograms per milliliter (pg/mL) then it was interpreted as a negative result. If the sputum LAM concentration was greater than or equal to 10 pg/mL then it was interpreted as positive result. SCC for LAM was considered to have been achieved if there were negative results at two consecutive visits with non-missing results. 95% CI was calculated using Clopper Pearson (exact) confidence interval model.
Time frame: 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
Acquired resistance was defined as a post-baseline resistant result at any timepoint after a baseline susceptible result. Baseline was defined as Day -1, if Day -1 was missing then Day 1 was used, if day 1 was missing then Week 1 was used. Resistance data was collected for streptomycin, isoniazid, rifampicin, ethambutol, pyrazinamide, bedaquiline and delamanid. Susceptibility testing (DST) for anti-TB medications was performed on positive M tuberculosis isolates from Day -1 or Day 1 cultures, and on the end of treatment sputum specimen. Percentage of participants who were susceptible at baseline and developed resistance to the indicated drug (class) at any post-baseline visits was summarized.
Time frame: Baseline up to Week 52
Time to Sputum Culture Conversion (SCC)
Sputum culture conversion occurs when a participant has the first of 2 consecutive visits of at least 7 days apart with sputum cultures negative and without a positive sputum culture result in between, as well as no positive sputum culture after the negative results. If a participant had a positive MGIT culture result throughout the study period, then the participant was considered as not having achieved SCC within the period under consideration. The time to SCC in this case was censored. Time to SCC was calculated from date of first dose using MGIT cultures without the mitigation method measures.
Time frame: From the first dose of the study up to the end of the follow-up period (up to Week 52)