A Phase 2/3, Multicenter, Randomized, Open-label, Active-controlled Study to Evaluate the Efficacy and Safety of Bedaquiline Administered as Part of a Treatment Regimen With Clarithromycin and Ethambutol in Adult Patients With Treatment-refractory Mycobacterium Avium Complex-lung Disease (MAC-LD)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 129
- 试验地点
- 103
- 主要终点
- Percentage of Participants with Sputum Culture Conversion in Mycobacteria Growth Indicator Tube (MGIT) at Week 24
研究概览
简要总结
The purpose of the study is to evaluate the efficacy of bedaquiline (BDQ) compared with rifamycin when administered as part of a treatment regimen with clarithromycin (CAM) and ethambutol (EB) in adult participants with treatment-refractory Mycobacterium avium complex-lung disease (MAC-LD) at Week 24 for microbiological assessment in mycobacteria growth indicator tube (MGIT).
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
- None
入排标准
- 年龄范围
- 20 Years 至 79 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Has body weight greater than or equal to (>=) 40 kilograms (kg) at screening and on Day 1
- •Has radiological evidence consistent with nontuberculous mycobacterial lung disease (NTM-LD) based on a chest Computed Tomography (CT) scan taken within 6 months prior to screening or at screening
- •Has at least 2 positive sputum cultures of Mycobacterium avium complex (MAC) (sputum cultures to be taken at least 4 weeks apart): one obtained within 12 months prior to screening, which was documented while being treated for Mycobacterium avium complex lung disease (MAC-LD) for a total of at least 6 months; and one at screening (by central microbiology laboratory)
- •Received at least 6 months of consecutive MAC-LD treatment (at least 2 antibiotics for MAC, including a macrolide), that is either ongoing or has stopped within 12 months prior to screening
- •No presence of cognitive dysfunction that would impact the completion of the patient reported outcome (PRO) assessments
排除标准
- •Had previous exposure to bedaquiline (BDQ)
- •Has active Tuberculosis (TB) disease
- •Has cystic fibrosis, medically unstable respiratory disease (for example, chronic obstructive pulmonary disease, bronchiectasis, asthma)
- •Has one or more cavities >=2 centimeter (cm) in diameter on a chest CT scan taken within 6 months prior to screening or at screening
- •Treatment already includes an injectable/inhaled aminoglycoside within 3 months prior to screening or the investigator deems the participant to be a candidate for an injectable/inhaled aminoglycoside during screening period or at Day 1
研究组 & 干预措施
Group B: Rifampicin (RFP) or Rifabutin (RBT) + CAM + EB
Participants will receive maximum of 4 capsules of RFP 450 mg daily (or maximum daily dose of 600 mg), CAM 400 mg or 500 mg (2*200 mg tablets) twice a day along with EB 500-750 mg daily or 15 mg/kg once a day or maximum daily dose of 1.0 gram for up to Week 48, followed by 2 capsules of RBT 300 mg or 150 mg once a day.
干预措施: Rifampicin (Drug)
Group A: Bedaquiline (BDQ) + Clarithromycin (CAM) + Ethambutol (EB)
Participants will receive BDQ 400 milligrams (mg) (4*100 mg tablets) once daily (qd) from Week 1-2 (loading phase), BDQ 200 mg (2*100mg tablets) bi-weekly (biw) from Week 3 to 48 (maintenance phase) and CAM 400 mg or 500 mg twice daily (2*200 mg tablets) along with EB 500-750 mg or 15 mg/kg once a day or maximum daily dose of 1.0 gram for up to Week 48.
干预措施: Bedaquiline (Drug)
Group A: Bedaquiline (BDQ) + Clarithromycin (CAM) + Ethambutol (EB)
Participants will receive BDQ 400 milligrams (mg) (4*100 mg tablets) once daily (qd) from Week 1-2 (loading phase), BDQ 200 mg (2*100mg tablets) bi-weekly (biw) from Week 3 to 48 (maintenance phase) and CAM 400 mg or 500 mg twice daily (2*200 mg tablets) along with EB 500-750 mg or 15 mg/kg once a day or maximum daily dose of 1.0 gram for up to Week 48.
干预措施: Ethambutol (Drug)
Group A: Bedaquiline (BDQ) + Clarithromycin (CAM) + Ethambutol (EB)
Participants will receive BDQ 400 milligrams (mg) (4*100 mg tablets) once daily (qd) from Week 1-2 (loading phase), BDQ 200 mg (2*100mg tablets) bi-weekly (biw) from Week 3 to 48 (maintenance phase) and CAM 400 mg or 500 mg twice daily (2*200 mg tablets) along with EB 500-750 mg or 15 mg/kg once a day or maximum daily dose of 1.0 gram for up to Week 48.
干预措施: Clarithromycin (Drug)
Group B: Rifampicin (RFP) or Rifabutin (RBT) + CAM + EB
Participants will receive maximum of 4 capsules of RFP 450 mg daily (or maximum daily dose of 600 mg), CAM 400 mg or 500 mg (2*200 mg tablets) twice a day along with EB 500-750 mg daily or 15 mg/kg once a day or maximum daily dose of 1.0 gram for up to Week 48, followed by 2 capsules of RBT 300 mg or 150 mg once a day.
干预措施: Clarithromycin (Drug)
Group B: Rifampicin (RFP) or Rifabutin (RBT) + CAM + EB
Participants will receive maximum of 4 capsules of RFP 450 mg daily (or maximum daily dose of 600 mg), CAM 400 mg or 500 mg (2*200 mg tablets) twice a day along with EB 500-750 mg daily or 15 mg/kg once a day or maximum daily dose of 1.0 gram for up to Week 48, followed by 2 capsules of RBT 300 mg or 150 mg once a day.
干预措施: Ethambutol (Drug)
Group B: Rifampicin (RFP) or Rifabutin (RBT) + CAM + EB
Participants will receive maximum of 4 capsules of RFP 450 mg daily (or maximum daily dose of 600 mg), CAM 400 mg or 500 mg (2*200 mg tablets) twice a day along with EB 500-750 mg daily or 15 mg/kg once a day or maximum daily dose of 1.0 gram for up to Week 48, followed by 2 capsules of RBT 300 mg or 150 mg once a day.
干预措施: Rifabutin (Drug)
结局指标
主要结局
Percentage of Participants with Sputum Culture Conversion in Mycobacteria Growth Indicator Tube (MGIT) at Week 24
时间窗: Week 24
Percentage of participant with sputum culture conversion (defined as 3 consecutive negative sputum cultures taken at least 25 days apart) in MGIT at Week 24 will be assessed.
Number of Participants With Sputum Culture Conversion in Mycobacteria Growth Indicator Tube (MGIT) at Week 24
时间窗: At Week 24
Number of participants with sputum culture conversion in MGIT at Week 24 was reported. Sputum culture conversion was defined as 3 consecutive negative sputum cultures taken at least 25 days apart.
次要结局
- Percentage of Participants with Sputum Culture Conversion in 7H10 or 7H11 agar media at Week 24(Up to Week 24)
- Time to Sputum Culture Conversion in MGIT up to Week 48(Up to Week 48)
- Change From Baseline in Patient Reported Health Status on Total Score of SGRQ at Weeks 48 and 60(From baseline to Week 48 and Week 60)
- Change From Baseline in Lung Function Parameters (Forced Vital Capacity) at Weeks 24, 48, and 60(At Weeks 24, 48, and 60)
- Change From Baseline in Lung Function Parameters (Inspiratory Capacity) at Weeks 24, 48, and 60(At Weeks 24, 48, and 60)
- Number of Participants with Physical Examination Abnormalities(Up to Week 60)
- Number of Participants with Visual Examination Abnormalities(Up to Week 60)
- Area Under the Plasma Concentration-time Curve From Time Zero to End of Dosing Interval (tau) (AUC [0-tau]) of Bedaquiline and its Metabolite M2(Day 1, Weeks 2, 8, 12, 24 and Week 48)
- Change from Baseline in Patient-reported Health Status on Total Score of St. George's Respiratory Questionnaire (SGRQ) at Week 24(Baseline and Week 24)
- Percentage of Participants with Sputum Culture Negativity in MGIT and 7H10 or 7H11 at each visit after Week 2(From Week 2 to Week 60)
- Number of Participants with 12-Lead Electrocardiogram (ECG) Abnormalities(Up to Week 60)
- Minimum Plasma Concentration Between 0 Hour and the Dosing Interval (tau) (Ctrough) of Bedaquiline and its Metabolite M2(Day 1, Weeks 2, 8, 12, 24 and Week 48)
- Percentage of Participants with Sputum Culture Conversion in MGIT and 7H10 or 7H11 agar media at Week 48 and Week 60(Up to Week 48 and Week 60)
- Number of Participants with Adverse Events (AE)(Up to Week 60)
- Number of Participants with Clinical Laboratory Abnormalities(Up to Week 60)
- Number of Participants with Vital Signs Abnormalities(Up to Week 60)
- Maximum Plasma Concentration (Cmax) of Bedaquiline and its Metabolite M2(Day 1, Weeks 2, 8, 12, 24 and Week 48)
- AUC (0-tau) of Clarithromycin and its Metabolite 4-OH CAM(Day 1, Weeks 2, 8, 12 and 24)
- Time to Positivity in MGIT up to Week 48(Up to Week 48)
- Percentage of Participants who Undergo a Change in Their Mycobacterium Avium Complex-lung Disease (MAC-LD) Treatment Regimen by Week 24 and by Week 48 in Group A and by Week 60 in Group B(Week 24 and Week 48 (Group A) and by week 60 (Group B))
- Change From Baseline in Lung Function Parameters (Functional Residual Capacity and Total Lung Capacity) at Weeks 24, 48, and 60(At Weeks 24, 48, and 60)
- Cmax of Clarithromycin and its Metabolite 4-OH CAM(Day 1, Weeks 2, 8, 12 and 24)
- C (0-trough) of Clarithromycin and its Metabolite 4-OH CAM(Day 1, Weeks 2, 8, 12 and 24)
- Change From Baseline in Patient-Reported Health Status on Total Score of SGRQ at Weeks 48 and 60(Baseline (Day 1), Week 48 and Week 60)
- Percentage of Participants With Sputum Culture Negativity in MGIT(From Week 2 to Week 60)
- Percentage of Participants With Sputum Culture Negativity in 7H10 or 7H11 Agar Media(From Week 2 to Week 60)
- Time to Sputum Culture Conversion in MGIT up to Week 48(From baseline (Day 1) up to Week 48)
- Time to Positivity in MGIT up to Week 48(From baseline (Day 1) up to Week 48)
- Number of Participants With Sputum Culture Conversion in 7H11 Agar Media at Week 24(At week 24)
- Change From Baseline in Patient Reported Health Status on Total Score of St. George's Respiratory Questionnaire (SGRQ) at Week 24(Baseline (Day 1), Week 24)
- Percentage of Participants With Sputum Culture Conversion in MGIT at Week 48(At Week 48)
- Percentage of Participants With Sputum Culture Conversion in 7H10 or 7H11 Agar Media at Week 48(At Week 48)
- Change From Baseline in Lung Function Parameters at Week 24(Baseline (Day 1), Week 24)
- Change From Baseline in Lung Function Parameters at Weeks 48 and 60(Baseline (Day 1), Week 48 and Week 60)
- Percentage of Participants Who Underwent a Change in Their Mycobacterium Avium Complex-lung Disease (MAC-LD) Treatment Regimen by Week 24(Baseline (Day 1) up to Week 24)
- Percentage of Participants Who Underwent a Change in Their Mycobacterium Avium Complex-lung Disease (MAC-LD) Treatment Regimen by Week 48 and Week 60(Baseline (Day 1), Week 48 and Week 60)
- Percentage of Participants With Sputum Culture Conversion in MGIT at Week 60(At Week 60)
- Percentage of Participants With Sputum Culture Conversion in 7H10 or 7H11 Agar Media at Week 60(At Week 60)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)(From Baseline (Day 1) up to Week 60)
- Number of Participants With Clinically Significant Changes in Laboratory Tests(From Baseline (Day 1) up to Week 60)
- Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)(From Baseline (Day 1) up to Week 60)
- Number of Participants With Clinically Significant Changes in Vital Signs(From Baseline (Day 1) up to Week 60)
- Number of Participants With Clinically Significant Changes in Physical Examination(From Baseline (Day 1) up to Week 60)
- Number of Participants With Clinically Significant Changes in Visual Examination(From Baseline (Day 1) up to Week 60)
- Number of Participants With Clinically Significant Changes in Audiology(From Baseline (Day 1) up to Week 60)
- Minimum Plasma Concentration Between 0 Hour and the Dosing Interval (Tau) (Ctrough) of BDQ and Its Metabolite M2(Day 1, Weeks 2, 8, 12, 24 and Week 48)
- Minimum Plasma Concentration Between 0 Hour and the Dosing Interval (Tau) (Ctrough) of Clarithromycin and Its Metabolite 4-OH CAM(Day 1, Weeks 2, 8, 12 and 24)