Efficacy and Safety of tobRamycin Inhalation Solution for Pseudomonas AeruginoSa Eradication in Bronchiectasis (ERASE): a Multi-center, 2×2 Factorial Randomized, Double-blind, Placebo-controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 371
- 试验地点
- 74
- 主要终点
- The proportion of patients successfully eradicating PA in each group by the end of the study, defined as a negative sputum culture of PA at both 24 weeks and 36 weeks.
研究概览
简要总结
People with bronchiectasis are prone to Pseudomonas aeruginosa (PA) infections, which can become chronic and lead to increased death rates and disease severity. Studies from cystic fibrosis suggest that eradication therapy aimed at PA can successfully transition patients to a culture-negative status, providing long-term benefits. Current guidelines for managing bronchiectasis in adults recommend eradicating PA when it is first or newly isolated; however, there is a lack of randomized controlled trials supporting such recommendations. The researchers hypothesize that both oral ciprofloxacin combined with tobramycin inhalation solution and tobramycin inhalation solution alone are superior to no eradication (inhaled saline) in terms of the eradication rate of PA (with eradication defined as negative sputum culture results on two consecutive occasions separated by an interval of 12 weeks or more after the first drug administration).
详细描述
The presence of Pseudomonas aeruginosa (PA) in bronchiectasis patients is associated with a greater impairment in lung function, increased systemic and airway inflammation, more frequent exacerbations, decreased quality of life, a higher risk of hospitalization, and increased mortality. Current guidelines recommend eradicating PA when it is first isolated, but there is limited randomized controlled trial evidence to support this.
In cystic fibrosis, early infection with PA is clearly linked to worse outcomes, and eradication is associated with clinical benefits, including improved lung function and reduced hospitalization. Small sample observational studies have shown that eradication therapy following initial PA isolation is efficient, with eradication rates of 40%-57% in bronchiectasis. Therefore, a randomized control trial of PA eradication therapy is needed to determine the microbiological and clinical outcomes of this therapy.
There is also uncertainty about whether inhaled antibiotics alone are sufficient to eradicate PA in non-cystic fibrosis bronchiectasis, given the less severe nature of the disease compared to cystic fibrosis. It's unclear whether adding another antibiotic, such as oral ciprofloxacin in this study, to inhaled antibiotics at the initial stage is necessary as an enhanced treatment for eradicating PA in bronchiectasis.
To address these knowledge gaps, a multicenter, 2×2 factorial randomized, double-blind, placebo-controlled, parallel-group study is designed in bronchiectasis patients with newly or firstly isolated PA. This study aims to investigate the efficacy and safety of tobramycin inhalation solution alone or in combination with oral ciprofloxacin in eradicating PA in bronchiectasis.
Patients will be randomly assigned to one of four groups:
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)
盲法说明
Both investigators and participants were blinded to the treatment assignment throughout the study. To maintain this blinding, placebos were used, which were made indistinguishable in appearance from the inhaled tobramycin solution and oral ciprofloxacin. The taste of the inhaled tobramycin solution was not disclosed to the patients, and neither the patients nor most clinicians had prior knowledge of its taste. This blinding approach ensures that both participants and investigators remain unaware of the specific treatment each patient is receiving, thereby reducing potential biases in the study's results
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, aged 18 years and 80 years at screening
- •Signed and dated written informed consent prior to admission to the study in accordance with local legislation.
- •Clinical history consistent with bronchiectasis (cough, chronic sputum production and/or recurrent respiratory infections) and investigator-confirmed diagnosis of bronchiectasis by high-resolution CT (HRCT) scan
- •Positive sputum culture for PA during screening, and meeting one of the following three conditions:
- •① No prior isolation of PA from respiratory secretions (a positive sputum culture from the study hospital within 1 month before screening was accepted, provided that no antibiotics were used for ≥14 days before the culture);
- •② First isolated PA within 12 months prior to screening, but did not undergo eradication therapy (continuous oral/intravenous/inhaled antibiotic treatment ≥1 month, excluding macrolides);
- •③ Previously isolated PA, but respiratory secretions were negative for PA at least twice (separated by an interval of ≥3 months) for 24 months or more prior to screening (Requirement: respiratory secretion isolation results obtained while not using antibiotics for 14 days or more);
- •During the screening period, patients must remain clinically stable (no significant changes in daytime and nighttime respiratory symptoms and no upper respiratory tract infection or bronchiectasis exacerbations for 4 weeks)
- •During the screening period, P. aeruginosa is not resistant to Tobramycin and Ciprofloxacin based on the drug sensitivity test of sputum culture in vitro
- •Patient can tolerate nebulized inhalation therapy
排除标准
- •Patients who are allergic to or cannot tolerate the investigational drugs (Tobramycin, Ciprofloxacin)
- •Comorbid uncontrolled asthma (defined as ≥1 acute exacerbation within 1 week prior to screening); confirmed bronchiectasis due to cystic fibrosis; Allergic Bronchopulmonary Aspergillosis (ABPA); active pulmonary tuberculosis; or nontuberculous mycobacterial infection requiring standard anti-nontuberculous treatment;
- •Participants with unstable cardiovascular and cerebrovascular diseases, defined as those who have experienced clinically worsening symptoms (such as unstable angina, rapid atrial fibrillation, cerebral hemorrhage, acute cerebral infarction, etc.) or have been hospitalized due to these diseases within 90 days prior to the screening
- •Participants with progressive or uncontrolled systemic diseases, such as those affecting the urinary, hematological, digestive, endocrine, respiratory, circulatory, nervous, or mental systems, are not suitable for this clinical trial. This is particularly the case if these conditions are evaluated by the researcher as being unstable or potentially escalating into severe conditions during the trial.
- •AST and/or ALT >2 ULN and/or Total Bilirubin (TBIL) at screening period
- •Serum creatinine >ULN at screening period
- •Participants with a history of hearing loss or those who are determined by the researcher to have clinically significant chronic tinnitus
- •Participants with a history of prolonged QT intervals or those whose electrocardiograms show prolonged QT intervals during the screening period
- •Participants who have used drugs that are prohibited according to the plan during the screening period.
- •Women who are pregnant or lactating, or women of childbearing potential preparing for pregnancy
- •Patients with FEV1% of predicted value<30%
- •Participants who have participated in other clinical trials (defined as those where medication has been administered) within the 4 weeks prior to the screening
- •Participants who have experienced moderate or severe hemoptysis (defined as expectorating 100-500ml of blood in 24 hours for moderate hemoptysis; and expectorating more than 500ml in 24 hours, or a single instance of expectorating more than 100ml of blood for severe hemoptysis) due to bronchiectasis within the past 6 months.
- •Participants who are deemed unsuitable for inclusion in the study due to other reasons, as determined by the researcher.
研究组 & 干预措施
Placebo group
Participants will receive inhaled saline twice daily for 12 weeks and oral ciprofloxacin placebo twice daily for 2 weeks
干预措施: Oral ciprofloxacin placebo (Drug)
Oral ciprofloxacin alone group
Participants will receive oral 750mg of ciprofloxacin twice daily for 2 weeks and inhaled saline twice daily for 12 weeks
干预措施: Ciprofloxacin 750 MG (Drug)
Oral ciprofloxacin alone group
Participants will receive oral 750mg of ciprofloxacin twice daily for 2 weeks and inhaled saline twice daily for 12 weeks
干预措施: Natural saline inhalation (Drug)
Tobramycin inhalation solution alone group
Participants will receive inhaled 300mg of tobramycin twice daily for 12 weeks and oral ciprofloxacin placebo twice daily for 2 weeks
干预措施: Oral ciprofloxacin placebo (Drug)
Placebo group
Participants will receive inhaled saline twice daily for 12 weeks and oral ciprofloxacin placebo twice daily for 2 weeks
干预措施: Natural saline inhalation (Drug)
Combination group
Participants will receive inhaled 300mg of tobramycin solution twice daily for 12 weeks and oral 750mg of ciprofloxacin twice daily for 2 weeks
干预措施: Tobramycin Inhalant Product (Drug)
Combination group
Participants will receive inhaled 300mg of tobramycin solution twice daily for 12 weeks and oral 750mg of ciprofloxacin twice daily for 2 weeks
干预措施: Ciprofloxacin 750 MG (Drug)
Tobramycin inhalation solution alone group
Participants will receive inhaled 300mg of tobramycin twice daily for 12 weeks and oral ciprofloxacin placebo twice daily for 2 weeks
干预措施: Tobramycin Inhalant Product (Drug)
结局指标
主要结局
The proportion of patients successfully eradicating PA in each group by the end of the study, defined as a negative sputum culture of PA at both 24 weeks and 36 weeks.
时间窗: 36 weeks
The proportion of patients with negative PA from sputum samples, either spontaneous or induced, in each group by the end of the study, at both 24 and 36 weeks post-randomization
The proportion of subjects with sustained negative sputum cultures for Pseudomonas aeruginosa (defined as negative sputum culture results on two consecutive occasions separated by an interval of 12 weeks or more) after first drug administration.
时间窗: 36 weeks
The proportion of subjects with sustained negative sputum cultures for Pseudomonas aeruginosa after first drug administration. This is defined as negative sputum culture results on two consecutive occasions separated by an interval of 12 weeks or more.
次要结局
- The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 36 weeks after randomization(36 weeks)
- The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 12 weeks after randomization(12 weeks)
- The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 24 weeks after randomization(24 weeks)
- Frequency of bronchiectasis exacerbation since randomization(12 weeks)
- Frequency of hospitalization due to bronchiectasis exacerbation since randomization(12 weeks)
- Time to reoccurrence of P. aeruginosa infection since randomization(36 weeks)
- Quality-of-Life-Bronchiectasis Respiratory Symptom Scale, that measures health-related quality of life(Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.)
- Euroqual-5 Dimensions questionnaire(Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.)
- Changes in forced vital capacity [FVC] at 12, 24, and 36 weeks compared with baseline(Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.)
- The cost of hospitalization(36 weeks)
- Number of adverse events(36 weeks)
- Time to the first bronchiectasis exacerbation since randomization(36 weeks)
- St.George Respiratory Questionnaire, that measures health-related quality of life(Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.)
- Changes in forced expiratory volume in 1 second [FEV1] at 12, 24, and 36 weeks compared with baseline(Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.)
- Changes in forced expiratory flow at 25-75% of forced vital capacity at 12, 24, and 36 weeks compared with baseline(Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.)
- Other sputum microbiology during the whole study period.(36 weeks)
- Resistant P. aeruginosa during the whole study period(36 weeks)
- Proportion of patients with a negative Pseudomonas aeruginosa sputum culture at 12 weeks after the first drug administration.(12 weeks)
- Proportion of patients with a negative Pseudomonas aeruginosa sputum culture at 24 weeks after the first drug administration.(24 weeks)
- Proportion of patients with a negative Pseudomonas aeruginosa sputum culture at 36 weeks after the first drug administration.(36 weeks)
- Time to first pulmonary exacerbation of bronchiectasis after the first drug administration.(36 weeks)
- Frequency of pulmonary exacerbations of bronchiectasis after the first drug administration.(12 weeks)
- Frequency of pulmonary exacerbations of bronchiectasis after the first drug administration.(36 weeks)
- Time to reoccurrence of Pseudomonas aeruginosa infection since randomization.(36 weeks)
- Absolute change from baseline in 1 second [FEV1] at 12, 24, and 36 weeks.(Assessed at 12 weeks, 24 weeks and 36 weeks after the first drug administration.)
- Absolute change from baseline in forced vital capacity [FVC] at 12, 24, and 36 weeks(Assessed at 12 weeks, 24 weeks and 36 weeks after the first drug administration.)
- Absolute change from baseline in forced expiratory flow between 25 and 75% of forced vital capacity [FEF25%-75%] at 12, 24, and 36 weeks.(Assessed at 12 weeks, 24 weeks and 36 weeks after the first drug administration.)
- Proportion of hospitalisations due to bronchiectasis after the first drug administration.(24 weeks)
- Proportion of hospitalisations due to bronchiectasis after the first drug administration.(36 weeks)
- Absolute change from baseline in health-related quality of life, as measured by the Quality-of-Life Bronchiectasis Respiratory Symptom Scale (QOL-B-RSS) score at 12, 24, and 36 weeks.(Assessed at 12 weeks, 24 weeks and 36 weeks after the first drug administration.)
- Absolute change from baseline in health-related quality of life, as measured by the St George's Respiratory Questionnaire (SGRQ) score at 12, 24, and 36 weeks.(Assessed at 12 weeks, 24 weeks and 36 weeks after the first drug administration.)
- Absolute change from baseline in health-related quality of life, as measured by the EuroQol Five Dimensions Questionnaire (EQ-5D-5L) score at 12, 24, and 36 weeks.(Assessed at 12 weeks, 24 weeks and 36 weeks after the first drug administration.)
- Number of hospitalisations per person.(36 weeks.)
- Cost per hospitalisation per person.(36 weeks)
- Isolation rate of other pathogenic microorganisms at 12 weeks, 24 weeks, and 36 weeks.(Assessed at 12 weeks, 24 weeks and 36 weeks after the first drug administration.)
- Proportion of subjects developing resistance to tobramycin or ciprofloxacin after enrolment.(36 weeks)
- Incidence of adverse events and serious adverse events.(36 weeks)
研究者
Jin-Fu Xu
Professor
Shanghai Tongji Hospital, Tongji University School of Medicine