A Randomized, Blinded, Parallel Group, Multi-center Dose-finding Study, to Assess the Efficacy, Safety and Tolerability of Different Doses of Tobramycin Inhalation Powder in Patients With Non-Cystic Fibrosis Bronchiectasis and Pulmonary P. Aeruginosa Infection
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 107
- 试验地点
- 1
- 主要终点
- Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs)
研究概览
简要总结
The purpose of this study was to support the selection of a safe and tolerable tobramycin inhalation powder (TIP) dose, and regimen that exhibits effective bacterial reduction of P. aeruginosa in non-cystic fibrosis bronchiectasis (BE) patients with P. aeruginosa colonization.
详细描述
This was a blinded, randomized, dose and regimen finding trial utilizing a three treatment cohort design where active TIP and TIP/Placebo cyclical (3 capsules o.d [Cohort A], 5 capsules o.d. [Cohort B] or 4 capsules b.i.d. [Cohort C]) versus Placebo were administered for a total of 112 days.
Novartis decided to close the recruitment of new subjects into this study earlier than scheduled. Subjects who had a signed informed consent form and entered screening by 10-Sep-2018 still participated in the study. The latest possible randomization was on 08-Oct-2018. All subjects enrolled in the study (107 enrolled subjects out of 180 planned) continued as planned through to their last scheduled visit. The early recruitment halt of the study was not due to safety or lack of efficacy.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent must be obtained before any assessment is performed.
- •Male and female patients of ≥ 18 years of age at screening (Visit 1).
- •Proven diagnosis of non-CF BE as documented by computed tomography or high-resolution computed tomography
- •At least 2 or more exacerbations treated with oral antibiotics OR 1 or more exacerbation requiring intravenous antibiotic treatment within 12 months prior to screening.
- •FEV1 ≥ 30% predicted at screening (Visit 1).
- •P. aeruginosa, must be documented in a respiratory sample at least 1 time within 12 months and also present in the expectorated sputum culture at Visit
排除标准
- •Patients with a history of cystic fibrosis.
- •Patients with a primary diagnosis of bronchial asthma.
- •Patients with a primary diagnosis of COPD associated with at least a 20 pack year smoking history.
- •Any significant medical condition that is either recently diagnosed or was not stable during the last 3 months, other than pulmonary exacerbations, and that in the opinion of the investigator makes participation in the trial against the patients' best interests.
- •Clinically significant (in the opinion of the investigator) hearing loss that interferes with patients' daily activities (such as normal conversations) or chronic tinnitus. Patients with a past history of clinically significant hearing loss in the opinion of the investigator may be eligible only if their hearing threshold at screening audiometry is 25dB or lower at frequencies 0.5-4 kHz. The use of a hearing device is reflective of a clinically significant hearing loss; hence patients using hearing aids at screening are not eligible.
- •Patients with active pulmonary tuberculosis.
- •Patients currently receiving treatment for nontuberculous mycobacterial (NTM) pulmonary disease.
- •Patients who are regularly receiving inhaled anti-pseudomonal antibiotic (during the study inhaled anti-pseudomonal antibiotics are not allowed other than the study drug).
研究组 & 干预措施
Cohort B (5 capsules o.d.): PBO
Cohort B (5 capsules o.d.): inhaled placebo (PBO)
干预措施: Placebo (Drug)
Cohort C (4 capsules b.i.d.): TIP
Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)
干预措施: TIP (Drug)
Cohort A (3 capsules o.d.): TIP
Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)
干预措施: TIP (Drug)
Cohort A (3 capsules o.d.): TIP/PBO
Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical
干预措施: TIP and placebo (Drug)
Cohort A (3 capsules o.d.): PBO
Cohort A (3 capsules o.d.): Inhaled placebo (PBO)
干预措施: Placebo (Drug)
Cohort B (5 capsules o.d.): TIP
Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)
干预措施: TIP (Drug)
Cohort B (5 capsules o.d.): TIP/PBO
Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical
干预措施: TIP and placebo (Drug)
Cohort C (4 capsules b.i.d.): TIP/PBO
Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical
干预措施: TIP and placebo (Drug)
Cohort C (4 capsules b.i.d.): PBO
Cohort C (4 capsules b.i.d.): inhaled placebo (PBO)
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs)
时间窗: Baseline (Visit 101/Day 1), Visit 102 (Day 8), Visit 103 (Day 29)
Microbiological data was collected to understand the direct impact of the drug on the pathogens. Sputum samples were cultured for the presence of three Pseudomonas aeruginosa (P. aeruginosa) biotypes measured were mucoid, dry and small colony variant. Change was determined using the formula = (Post-baseline value - baseline value). If no P. aeruginosa was isolated for a visit, log10 colony forming units (CFU) was imputed with log10 (19) for all biotypes. Only values for all morphotypes presented.
次要结局
- Number of Hospitalization Due to Serious Respiratory-related Adverse Events(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Time to First Hospitalization Due to Serious Respiratory-related Adverse Events(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Serum Tobramycin Concentration(Baseline (Visit 101/Day 1), Visit 102 (Day 8) and Visits 103 (Day 29): 0-1 hours and 1-2 hours post-dose.)
- Sputum Tobramycin Concentration(Baseline (Visit 101/Day 1): 0-1 hours and 1-2 hours post-dose; Visit 102 (Day 8):0-2 hours and 5-6 hours post-dose; Visits 103 (Day 29): 5 to 6 hours post-dose, Visit 104 (Day 57) and Visit 105 (Day 85): 3-4 hours post-dose.)
- Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Physical Functioning(Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169))
- Change From Baseline to Each Post-baseline Visit in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs)(Baseline (Visit 101/Day 1), Visit 104 (Day 57), Visit 105 (Day 85), Visit 106 (Day 113), End of Treatment (EOT), Visit 201 (Day 141), Visit 202 (Day 169))
- Time to First Onset of Pulmonary Exacerbation by Exacerbation Category(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Duration of Pulmonary Exacerbation by Exacerbation Category(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Exposure Adjusted Rate of Pulmonary Exacerbations (PE) Over the Entire Study Period(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Percentage of Participants With at Least One Pulmonary Exacerbation by Exacerbation Category(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Percentage of Participants Who Permanently Discontinued Study Drug Due to Pulmonary Exacerbation(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Time to Permanent Study Drug Discontinuation Due to Pulmonary Exacerbation(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Time to First Use (Overall, Oral, and Parenteral) of Anti-pseudomonal Antibiotics Usage(From Baseline (Visit 101/Day 1) up to approximately Day 173)
- Percentage of Participants Requiring Anti-pseudomonal Antibiotics(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Duration of Anti-pseudomonal Antibiotics Usage(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Percentage of Participants Requiring Hospitalization Due to Serious Respiratory-related Adverse Events(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Duration of Hospitalization Due to Serious Respiratory-related Adverse Events(Baseline (Visit 101/Day 1) to Visit 202 (Day 169))
- Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Role Functioning(Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169))
- Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Vitality(Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169))
- Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Health Perceptions(Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169))
- Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Emotional Functioning(Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169))
- Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Social Functioning(Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169))
- Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Treatment Burden(Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169))
- Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Respiratory Symptoms(Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169))