A Phase 1/2, Active-controlled, Randomized, Open-label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Multiple Oral Doses of OPC-167832 Tablets in Subjects With Uncomplicated, Smear-positive, Drug-susceptible Pulmonary Tuberculosis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 122
- 试验地点
- 3
- 主要终点
- Stage 1 and Stage 2: Cmax at Steady-state (Cmax,ss) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
研究概览
简要总结
This trial will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of multiple oral doses of OPC-167832 in participants with uncomplicated, smear-positive, drug-susceptible pulmonary tuberculosis (TB).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 64 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to provide written, informed consent prior to initiation of any trial-related procedures, and able, in the opinion of the investigator, to comply with all the requirements of the trial.
- •Male or female participants between 18 and 64 years of age (inclusive) at the screening visit.
- •Body mass index ≥ 16.0 and ≤ 32.0 kilograms per meters squared (kg/m^2) (inclusive) at the screening visit.
- •Newly diagnosed, uncomplicated, drug-susceptible pulmonary TB.
- •Microscopy performed on a sputum smear at screening indicates presence of acid-fast bacilli (at least 1+).
- •Able to produce an adequate volume of sputum (approximately 10 millilitres (mL) or more estimated overnight production).
- •Female participants of childbearing potential must agree to use 2 different approved methods of birth control or remain abstinent throughout the participation in the trial and for 12 weeks after the last dose of trial treatment (investigational medicinal product (IMP) or RHEZ).
- •Male participants must agree to use 2 different approved methods of birth control or remain abstinent throughout the participation in the trial and for 12 weeks after the last dose of trial treatment (IMP or RHEZ).
排除标准
- •Participants are known or suspected of having resistance to rifampicin, isoniazid, ethambutol, or pyrazinamide using any combination of Xpert Mycobacterium tuberculosis/Rifampin (MTB/RIF), line probe assay, culture, and/or epidemiologic history at screening.
- •Poor general condition where no delay in treatment can be tolerated or where immediate hospital admission is warranted.
- •Evidence of clinically significant metabolic (including ongoing or current hypokalemia), gastrointestinal, neurological, psychiatric, endocrine or liver (e.g., 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, 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 delamanid, rifampicin, isoniazid, pyrazinamide, ethambutol, or Bedaquiline is contraindicated.
- •Any prior treatment for M. tuberculosis within the past 3 years.
- •Any treatment with a drug active against M. tuberculosis (e.g., quinolones) within the 3 months prior to screening.
- •Clinical evidence of severe extrapulmonary TB (e.g., 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 serum creatinine clearance of <60 millilitres per minute (mL/min), or hepatic impairment characterized by alanine transaminase, aspartate transaminase, or total bilirubin >1.5 x upper limit of normal (ULN) of the clinical laboratory reference range at screening.
- •For Stage 1, participants who are human immunodeficiency virus (HIV) positive are excluded. For Stage 2, participants with HIV co-infection who are on antiretroviral drugs during screening or with CD4 cell count <500/ millimeters cubed (mm^3) are excluded.
- •Changes in the electrocardiogram (ECG) such as QTcF >450 milliseconds (msec), atrioventricular block II or III, bi-fasicular block, at screening or current history of clinically significant ventricular arrhythmias. Other ECG changes if considered clinically significant by the investigator.
- •Participants receiving any of the prohibited medications 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
- •History of significant drug and/or alcohol abuse within 2 years prior to screening.
- •History of or current hepatitis or carriers of HBsAg and/or anti-HCV.
- •Positive urine or blood alcohol test and/or urine drug screen for substance abuse at screening (not including cannabinoids).
- •History of having taken an investigational drug within 30 days preceding trial entry (ie, prior to screening).
- •A history of difficulty in donating blood.
- •Donation of blood or plasma within 30 days prior to dosing.
- •Consumption of alcohol and/or grapefruit, grapefruit juice, Seville oranges, or Seville orange juice and related products within 72 hours prior to the first dose of IMP or RHEZ on Day
- •History of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial.
- •Any known prior exposure to OPC-167832, delamanid or Bedaquiline.
- •Participants with significant medical comorbidities that in the opinion of the investigator, should not participate in the trial.
研究组 & 干预措施
Stage 1: RHEZ
Participants received a single dose of RHEZ (each tablet containing 150 milligrams (mg) rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol), orally, once daily (QD) from Day 1 through Day 20.
干预措施: RHEZ (Drug)
Stage 1: 10 mg OPC-167832
Participants received OPC-167832, 10 mg, orally, QD, from Day 1 through Day 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.
干预措施: 10 mg OPC-167832 (Drug)
Stage 1: 30 mg OPC-167832
Participants received OPC-167832, 30 mg, orally, QD from Day 1 through Day 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.
干预措施: 30 mg OPC-167832 (Drug)
Stage 1: 90 mg OPC-167832
Participants received OPC-167832, 90 mg, orally, QD from Day 1 through Day 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.
干预措施: 90 mg OPC-167832 (Drug)
Stage 1: 3 mg OPC-167832
Participants received OPC-167832, 3 mg, orally, QD from Day 1 through Day 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.
干预措施: 3 mg OPC-167832 (Drug)
Stage 2: 30 mg OPC-167832 + 300 mg Delamanid
Participants received OPC-167832, 30 mg, in combination with delamanid, 300 mg, orally, QD from Day 1 through Day 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.
干预措施: 30 mg OPC-167832 + 300 mg delamanid (Drug)
Stage 2: 30 mg OPC-167832 + 400 mg Bedaquiline (BDQ)
Participants received OPC-167832, 30 mg, in combination with BDQ, orally, QD, from Day 1 through Day 14. Participants received a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. BDQ was then administered at a dose of 400 mg, QD, orally from Days 3 to 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.
干预措施: 30 mg OPC-167832 + 400 mg BDQ (Drug)
Stage 2: 30 mg OPC-167832 + 300 mg Delamanid + 400 mg BDQ
Participants received OPC-167832, 30 mg, in combination with delamanid, 300 mg and BDQ, 400 mg, orally, QD, from Day 1 through Day 14. Participants received a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. BDQ was then administered at a dose of 400 mg, orally, QD from Days 3 to 14. After Day 14, participants received RHEZ according to the local standard of care regimen up to Day 20.
干预措施: 30 mg OPC-167832 + 300 mg delamanid + 400 mg BDQ (Drug)
Stage 2: RHEZ
Participants received a single dose of RHEZ (each tablet containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol), orally, QD, from Day 1 through Day 20.
干预措施: RHEZ (Drug)
结局指标
主要结局
Stage 1 and Stage 2: Cmax at Steady-state (Cmax,ss) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: AUC Calculated Over the Dosing Interval at Steady-state (AUCτ) for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Accumulation Ratio of AUC (RAUC) for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Cmax of Delamanid
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 1: Change From Baseline in TB Bacterial Load in Sputum as a Measure of Early Bactericidal Activity (EBA)
时间窗: Baseline to Day 14
Bacterial load in sputum at each collection time point was measured by CFU counts on agar media culture. EBA was determined by the rate of decline per day in log10CFU/mL during the first 14 days of treatment. Change from baseline in log 10 CFU was calculated as post-baseline minus baseline. A larger EBA in positive direction indicates a better drug effect.
Stage 1 and Stage 2: Maximum (Peak) Plasma Concentration (Cmax) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: AUCτ of Delamanid
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUCτ/Dose of Delamanid
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Tmax of Bedaquiline
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Cmax/Dose of Bedaquiline
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs)
时间窗: From first dose of study drug to end of follow up period (up to 34 days)
An AE is defined as any untoward medical occurrence in a clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAEs were all AEs which started after the start of randomized study drug treatment or if the event was continuous from baseline and was serious, study drug-related, or resulted in death, discontinuation, interruption, or reduction of study therapy.
Stage 2: CLss/F of BDQ From Plasma
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUCτ/Dose of Bedaquiline
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: RCmax of Delamanid
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Cmax of Bedaquiline
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: Cmax,ss of Bedaquiline
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: T1/2,z of Bedaquiline
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
T1/2,z is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose. Half-life (T1/2) is determined in the terminal phase after drug administration, which is calculated from the relationship T1/2 = ln2/λz where λz is the terminal-phase slope obtainable using the NCA method. The values reported for this OM are estimates and not actual observed data. Hence, the value might not lie within the sampling timepoints provided in the timeframe.
Stage 1 and Stage 2: Time to Cmax (Tmax) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 1 and Stage 2: Area Under the Concentration-Time Curve (AUC) From Time Zero to Time t (the Last Observable Concentration, Here t=24) (AUC0-24), for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 1 and Stage 2: Terminal-phase Elimination Half-life (t1/2,z) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
T1/2,z is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose. Half-life (T1/2) is determined in the terminal phase after drug administration, which is calculated from the relationship T1/2 = ln2/λz where λz is the terminal-phase slope obtainable from non-compartmental analysis (NCA). The values reported for this outcome measure (OM) are estimates and not actual observed data.
Stage 1 and Stage 2: Apparent Clearance From Plasma at Steady-state (CLss/F) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Accumulation Ratio of Cmax (RCmax) for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Cmax Normalized to Dose (Cmax/Dose) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUCτ Normalized to Dose (AUCτ/Dose) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: Tmax of Delamanid
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: CLss/F of Delamanid From Plasma
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: RAUC of Delamanid
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUC0-24 of Bedaquiline
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: AUCτ of Bedaquiline
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: AUC0-24 of Delamanid
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
Stage 2: Cmax,ss of Delamanid
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 2: T1/2,z of Delamanid
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
T1/2,z is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose. Half-life (T1/2) is determined in the terminal phase after drug administration, which is calculated from the relationship T1/2 = ln2/λz where λz is the terminal-phase slope obtainable using the NCA method. The values reported for this OM are estimates and not actual observed data.
Stage 2: Cmax/Dose of Delamanid
时间窗: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values
时间窗: From first dose of study drug to end of follow up period (up to 34 days)
Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters
时间窗: From first dose of study drug to end of follow up period (up to 34 days)
次要结局
- Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System(Baseline to Day 14)
- Stage 1: Plasma Concentration of Isoniazid(2 hours and 6 hours post-dose on Day 14)
- Stage 2: Cmax,ss of DM-6705(Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14)
- Stage 2: Tmax of DM-6705(Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14)
- Stage 2: Cmax of DM-6705(Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1)
- Stage 2: T1/2,z of DM-6705(Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14)
- Stage 2: Cmax,ss of N-Desmethyl Bedaquiline(Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14)
- Stage 2: Tmax of N-Desmethyl Bedaquiline(Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours (±15 minutes) postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14)
- Stage 2: Cmax of N-Desmethyl Bedaquiline(Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1)
- Stage 2: Plasma Concentration of Rifampin(2 hours and 6 hours post-dose on Day 14)
- Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline(From first dose of study drug to end of follow up period (up to 34 days))
- Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System(Day 1 to Day 14 of treatment period + 42 days of inoculation period (up to 56 days))
- Stage 2: Change From Baseline in TB Bacterial Load in Sputum as a Measure of EBA(Baseline to Day 14)
- Stage 2: AUC0-24 for DM-6705(Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14)
- Stage 2: Number of Participants With TEAEs on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline(From first dose of study drug to end of follow up period (up to 34 days))
- Stage 2: AUC0-24 for N-Desmethyl Bedaquiline(Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14)
- Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline(From first dose of study drug to end of follow up period (up to 34 days))