A Multi Center, Randomized, Double-blind, Placebo-controlled Phase 2 Trial to Evaluate the Safety, Efficacy and Pharmacokinetics of Multiple Doses of OPC 67683 in Patients With Pulmonary Sputum Culture-Positive, Multidrug-resistant Tuberculosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 481
- 试验地点
- 17
- 主要终点
- Accumulation Ratio for Cmax (Rac[Cmax]) for Delamanid
研究概览
简要总结
This is a clinical trial to evaluate the safety and efficacy of OPC-67683 in the treatment of multidrug resistant tuberculosis (MDR TB) for 56 days. In addition to an optimized background regimen (OBR), participants will be randomized to receive:
- 100 mg OPC-67683 twice daily (BID)
- 200 mg OPC-67683 BID
- Placebo BID
After 56 days participants will complete their optimized background regimen (OBR).
详细描述
This is a multi center, randomized, double-blinded, stratified, placebo-controlled clinical trial in three parallel groups. Participants will be randomized to one of the following three treatment groups:
- OBR plus 100 mg OPC-67683 BID
- OBR plus 200 mg OPC-67683 BID
- OBR plus placebo BID
The three treatment groups will comprise approximately 140 participants each (male or female). The trial will consist of the following periods:
- Pre-treatment Period (Visits 1 to 3 [Day -9 to Day -1])
- Treatment Period (Visits 4 to 59 [Days 1 to 56])
- Post-treatment Period (Visits 60 to 64 [Days 57 to 84])
Enrolled participants (those accepted into the screening period of the trial who signed an informed consent form) will be stratified at randomization by extent of pulmonary TB; an equal number of participants with and without cavities visible in the lung fields on baseline chest radiograph will be allocated to each treatment group. A total of approximately 430 male or female participants aged 18 to 64 years, inclusive, with pulmonary, sputum culture-positive MDR TB (TB caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampicin) or with sputum smears positive for acid fast bacilli (AFB) and a positive rapid test for rifampicin resistance on direct sputum within 60 days prior to the expected date of enrollment. Participants with positive AFB smears and a positive rapid rifampicin resistance test will be enrolled as presumptively culture positive and withdrawn as ineligible if they are confirmed to not have sputum culture positive MDR TB.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Provide written, informed consent prior to all trial-related procedures
- •Male and female participants aged between 18 and 64 years, inclusive.
- •Either mycobacterial culture of sputum positive for growth of Mycobacterium tuberculosis or sputum smear positive for acid fast bacilli within 60 days prior to the expected date of enrollment.
- •Participant with TB caused by isolates of Mycobacterium tuberculosis complex confirmed to be resistant to treatment with isoniazid and rifampicin, or with positive rapid test for rifampicin resistance on direct sputum positive for acid fast bacilli within 60 days prior to the expected date of enrollment.
- •Findings on chest radiograph consistent with TB.
- •Able to produce sputum for mycobacterial culture.
- •Female participants of childbearing potential must have a negative urine pregnancy test and agree to use a highly effective method of birth control (for example, two of the following precautions: tubal ligation, vaginal diaphragm, intrauterine device, oral contraceptives, contraceptive implant, combined hormonal patch, combined injectable contraceptive or depot-medroxyprogesterone acetate) throughout the participation in the trial and for 22 weeks after last dose (to cover duration of ovulation).
- •Male participants must agree to use an adequate method of contraception (double barrier) throughout the participation in the trial and for 30 weeks after last dose (to cover duration of spermatogenesis).
排除标准
- •A history of allergy to any nitro-imidazoles or nitro-imidazole derivates at any time.
- •Use of the medications including: use of amiodarone at any time during the previous 12 months, use of other anti-arrhythmics for the previous 30 days, and use of certain other medications, including certain anti-depressants, anti-histamines, and macrolides, for the previous 14 days.
- •Any current serious concomitant conditions or renal impairment characterized by serum creatinine levels ≥265 micromol/L or hepatic impairment characterized by alanine transaminase (ALT) and/or aspartate transferase (AST) levels 3 times the upper limit of the laboratory reference range.
- •Current clinically relevant changes in the electrocardiogram (ECG) such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 milliseconds (in both male and female participants), or of either the QT interval corrected by Fridericia's formula (QTcF) or QT interval corrected by Bazett's formula (QTcB) interval over 430 milliseconds in male participants and 450 milliseconds in female participants.
- •Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction.
- •For participants with human immunodeficiency virus (HIV) infection, cluster of differentiation 4 helper/inducer T cell[s] (CD4) cell count < 350/mm3 or on treatment with anti-retroviral medication for HIV infection.
- •Karnofsky score < 60%.
- •Any diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.
- •Evidence of clinically significant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).
- •Known or suspected alcohol abuse, that is, abuse sufficient enough to compromise the safety or cooperation of the participant in the opinion of the investigator.
- •Administered an investigational medicinal product (IMP) within 1 month prior to Visit 1 (Screening [Days -9 to -3]).
- •Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the informed consent form.
- •Recent use of methadone, benzodiazepines, cocaine, amphetamine/metamphetamine, tetrahydrocannabinol, barbiturates, tricyclic antidepressants, and opiates as determined by a urine drug screen unless evidence is provided that the positive drug screen is the result of authorized medications products prescribed by a physician for a non-abuse-related indication.
- •Any disorder that in the judgment of the investigator makes the participant not a good candidate for the trial or may prevent the participant from reliably participating in the entire course of the trial.
研究组 & 干预措施
Delamanid 100 mg BID + OBR
Participants received delamanid 100 milligrams (mg) (two 50 mg tablets), orally, BID with two matching placebo tablets plus optimized background regimen (OBR) for 56 consecutive days (from Day 1 to Day 56).
Participants were administered OBR as directed by the given investigator based on World Health Organization (WHO) guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
干预措施: Delamanid (Drug)
Delamanid 100 mg BID + OBR
Participants received delamanid 100 milligrams (mg) (two 50 mg tablets), orally, BID with two matching placebo tablets plus optimized background regimen (OBR) for 56 consecutive days (from Day 1 to Day 56).
Participants were administered OBR as directed by the given investigator based on World Health Organization (WHO) guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
干预措施: Optimized Background Regimen (OBR) (Drug)
Delamanid 100 mg BID + OBR
Participants received delamanid 100 milligrams (mg) (two 50 mg tablets), orally, BID with two matching placebo tablets plus optimized background regimen (OBR) for 56 consecutive days (from Day 1 to Day 56).
Participants were administered OBR as directed by the given investigator based on World Health Organization (WHO) guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
干预措施: Placebo (Drug)
Delamanid 200 mg BID + OBR
Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56).
Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
干预措施: Delamanid (Drug)
Delamanid 200 mg BID + OBR
Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56).
Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
干预措施: Optimized Background Regimen (OBR) (Drug)
Placebo + OBR
Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56).
Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
干预措施: Optimized Background Regimen (OBR) (Drug)
Placebo + OBR
Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56).
Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
干预措施: Placebo (Drug)
结局指标
主要结局
Accumulation Ratio for Cmax (Rac[Cmax]) for Delamanid
时间窗: Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Data for Rac (Cmax) up to Day 56 was collected on Days 14, 28 and 56. Rac (Cmax) on Days 14, 28 or 56 compared to Cmax on Day 1 was computed.
Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using the Mycobacteria Growth Indicator Tube (MGIT) System
时间窗: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)
Sputum culture conversion was defined to occur at the time of the collection of a sputum specimen with mycobacterial culture negative for growth of Mycobacterium tuberculosis (MTB) followed by at least one additional sputum specimen with mycobacterial culture negative for growth at least 27 days after the first negative specimen and not followed by any sputum specimens positive for growth in the MGIT system at any point during the remainder of the 84-day trial after the first negative culture.
Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for Delamanid
时间窗: Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.
Elimination Half-life (t1/2) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
时间窗: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose on Day 56
Tmax 1 and 2: Time to Maximal Peak Concentration (Tmax) for Delamanid Following First and Second Daily Dose
时间窗: Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Time to maximum (peak) plasma concentration following the first daily dose (Cmax1) was reported as tmax1 and time to maximum (peak) plasma concentration following the second daily dose (Cmax2) was reported as tmax2. Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.
Cmax 1 and 2: Maximal Peak Concentration (Cmax) for Delamanid Following First and Second Daily Dose
时间窗: Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Maximum (peak) plasma concentration following the first daily dose was reported as Cmax1 and maximum (peak) plasma concentration following the second daily dose was reported as Cmax2. Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.
Time to Maximal Peak Concentration (Tmax) for Delamanid Metabolite (DM)-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
时间窗: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.
Accumulation Ratio for Cmax (Rac[Cmax]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
时间窗: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Data for Rac (Cmax) up to Day 56 was to be collected on Days 1, 14, 28 and 56. Rac (Cmax) on Days 14, 28 or 56 compared to Cmax on Day 1 was to be computed. Due to limited measurable data on Day 1 for delamanid metabolites, pharmacokinetic (PK) analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (Cmax) was not available.
Accumulation Ratio for AUC From Time 0 to 24 Hours (Rac[AUC0-24h]) for Delamanid
时间窗: Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Data for Rac (AUC) up to Day 56 was collected on Days 14, 28 and 56. Rac (AUC) on Days 14, 28 or 56 compared to AUC0-24h on Day 1 was computed.
Maximal Peak Concentration (Cmax) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
时间窗: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.
Accumulation Ratio for AUC (Rac[AUC]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
时间窗: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Data for Rac (AUC) up to Day 56 was to be collected on Days 1, 14, 28 and 56. Rac (AUC) on Days 14, 28 or 56 compared to AUC0-24h on Day 1 was to be computed. Due to limited measurable data on Day 1 for delamanid metabolites, PK analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (AUC) was not available.
Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
时间窗: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.
次要结局
- Change From Baseline in Time to Culture Positivity Using the MGIT System(Baseline, Day 84)
- Percentage of Participants With Sputum Culture Negative at Day 57 Using Solid Culture Media Without Respect to Subsequent Culture Results(Day 57)
- Percentage of Participants With Sputum Culture Negative at Day 57 and Day 84 Using Solid Culture Media Without Respect to Interim Culture Results(Day 57 and Day 84)
- Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using Solid Culture Media(From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84))
- Percentage of Participants With Sputum Culture Negative at Day 57 Using the MGIT System Without Consideration of Subsequent Culture Results(Day 57)
- Area Under the Curve (AUC) of Change From Baseline in Time to Culture Positivity in the MGIT System(Baseline to Day 57)
- Percentage of Participants With Sputum Culture Negative at Day 57 and Day 84 Using the MGIT System Without Respect to Interim Culture Results(Day 57 and Day 84)
- Percentage of Participants Who Achieved SCC From the MGIT System Analyzed by Cochran-Armitage Linear Trend Test for Dose-response Relationship(From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84))
- Percentage of Participants Who Achieved Initial SCC Using the Solid Culture Media(Day 57)
- Percentage of Participants Who Achieved Initial SCC Using the MGIT System(Day 57)
- Percentage of Participants Who Achieved Final SCC Using MGIT(Day 57)
- Percentage of Participants With Clinically Significant Physical Examination Findings, Including Vision and Neuropsychiatric Assessments(From first dose of study drug up to post treatment period (Day 84))
- Percentage of Participants Who Achieved Final SCC Using Solid Culture Media(Day 57)
- Percentage of Participants With Clinically Significant Vital Sign Abnormalities(From first dose of study drug up to post treatment period (Day 84))
- Percentage of Participants With Categorical Changes in 12-lead Electrocardiogram Results at Day 56(Baseline up to Day 56)
- Percentage of Participants With Clinically Significant Laboratory Test Abnormalities(From first dose of study drug up to post treatment period (Day 84))
- Percentage of Participants With Clinically Significant Audiometry Findings(From first dose of study drug up to post treatment period (Day 84))
- Percentage of Participants Using Concomitant Medications(From first dose of study drug up to post treatment period (Day 84))
- Percentage of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs)(From first dose of study drug up to post treatment period (Day 84))
- Time-matched Change From Baseline (Day -1) in QTcF at Day 56(Baseline, and 2, 3, 4, 10, 12, and 24 hours post dose on Day 56)
- Mean Change From Baseline in QTcF(Baseline, Days 1, 14, 28 and 56)
- Mean Change From Baseline in QTcB(Baseline, Days 1, 14, 28 and 56)
- Mean Change From Baseline in Ventricular Rate(Baseline, Days 1, 14, 28 and 56)
- Mean Change From Baseline in PR Interval(Baseline, Days 1, 14, 28 and 56)
- Mean Change From Baseline in QRS Interval(Baseline, Days 1, 14, 28 and 56)
- Mean Change From Baseline in QT Interval(Baseline, Days 1, 14, 28 and 56)
- Percentage of Participants With Change in ECG Morphological Patterns From Baseline(Baseline, Days 1, 14, 28 and 56)