Pulmonary TB
Conditions
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.
Interventions
DRUGDelamanid
Delamanid (300 mg QD) for 17 weeks
DRUGBedaquiline
Bedaquiline (400 mg QD x 2 weeks, then 200 mg TIW) for 17 weeks
DRUGRHEZ
RHEZ (RIFAFOUR single dose combination tablets) for 8 weeks
DRUGRifampin
Rifampin tablets for 18 weeks
DRUGIsoniazid
Isoniazid tablets for 18 weeks
DRUGOPC-167832 10 mg
OPC-167832 (10 mg QD) for 17 weeks
DRUGOPC-167832 30 mg
OPC-167832 (30 mg QD) for 17 weeks
DRUGOPC-167832 90 mg
OPC-167832 (90 mg QD) for 17 weeks
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Bill and Melinda Gates Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 Electrocardiogram (ECG) Abnormalities | 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 | 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 | 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) | 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) | 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. |
| Number of Participants With Potentially Clinically Relevant Laboratory Test Abnormalities | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Acquired Drug Resistance | Baseline up to Week 52 | 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 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) | 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. |
| 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) | 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. |
| Percentage of Participants Who Achieved SCC in MGIT by the End of 8 Weeks of Treatment | Week 8 | 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 to Detection of MGIT Cultures | Baseline up to Week 52 | 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. |
Countries
South Africa
Participant flow
Recruitment details
Participants took part in the study at 8 clinical sites in South Africa from 12 April 2022 to 19 May 2024.
Pre-assignment details
A total of 306 participants were screened, of which 122 participants were randomized into the treatment arms of delamanid + bedaquiline + OPC-167832 (10 mg, 30 mg, or 90 mg) or rifampin, isoniazid, ethambutol, and pyrazinamide (RHEZ) in a ratio of 1:2:2:1.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 33.7 years STANDARD_DEVIATION 11.66 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 21 Participants |
| Race/Ethnicity, Customized Race Black or African American | 13 Participants |
| Race/Ethnicity, Customized Race Other | 39 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 1 / 42 | 0 / 38 | 0 / 21 |
| other Total, other adverse events | 17 / 20 | 31 / 42 | 25 / 38 | 20 / 21 |
| serious Total, serious adverse events | 2 / 20 | 3 / 42 | 0 / 38 | 0 / 21 |
Outcome results
None listed