Tobramycin Inhalation Solution for Pseudomonas Aeruginosa Eradication in Bronchiectasis

Study Overview
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Brief Summary
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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 rates of PA, defined as a negative sputum culture of PA at both 24 weeks and 36 weeks.

Detailed Description
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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: Placebo group: participants will receive inhaled saline twice daily for 12 weeks and an oral ciprofloxacin placebo twice daily for 2 weeks. Oral ciprofloxacin alone group: participants will receive 750mg of oral ciprofloxacin twice daily for 2 weeks and inhaled saline twice daily for 12 weeks. Tobramycin inhalation solution alone group: participants will receive 300mg of inhaled tobramycin twice daily for 12 weeks and an oral ciprofloxacin placebo twice daily for 2 weeks. Combination group: participants will receive 300mg of inhaled tobramycin solution twice daily for 12 weeks and 750mg of oral ciprofloxacin twice daily for 2 weeks. This study will provide valuable insights into the most effective treatment strategy for eradicating PA in bronchiectasis patients.

Official Title
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Efficacy and Safety of tobRamycin Inhalation Solution for Pseudomonas AeruginoSa Eradication in Bronchiectasis (ERASE): Study Protocol for a Multi-center, 2×2 Factorial Randomized, Double-blind, Placebo-controlled Trial

Conditions
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Bronchiectasis Adult, Pseudomonas Aeruginosa Infection

Intervention / Treatment
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* Drug: Tobramycin Inhalant Product
* Drug: Ciprofloxacin 750 MG
* Drug: Oral ciprofloxacin placebo
* Drug: Natural saline inhalation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 CT scan During the screening period, patients must have a positive P. aeruginosa culture in their sputum and must meet one of the following criteria: (1) they have never been isolated with P. aeruginosa from sputum or bronchoalveolar lavage fluid (BALF) before; (2) they were isolated with P. aeruginosa from sputum or BALF for the first time within 12 months before screening; (3) they had prior isolation of P. aeruginosa but not within the last 24 months (defined as having negative sputum culture results at least twice before starting antibiotic treatment) During the screening period, patients must remain clinically stable (no significant changes in 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 Exclusion criteria Patients who are allergic to or cannot tolerate the investigational drugs (Tobramycin, Ciprofloxacin) Patients with uncontrolled asthma, physician-diagnosed cystic fibrosis, and Current diagnosis of allergic bronchopulmonary aspergillosis, hypogammaglobulinemia, common variable immunodeficiency, mycobacterial infection (including pulmonary non-tuberculous mycobacterial disease) requiring 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 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 of childbearing potential adhering to contraception requirements. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized into one of the four groups. No cross-over of the study group will be made
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Combination group<br>Participants will receive inhaled 300mg of tobramycin solution twice daily for 12 weeks and oral 750mg of ciprofloxacin twice daily for 2 weeks | Drug: Tobramycin Inhalant Product<br>* Tobramycin will be nebulized (300mg twice daily) with an ultrasonic nebulizer. A total of 12 weeks therapy will be scheduled.<br>* Other names: Inhaled antibiotics;Drug: Ciprofloxacin 750 MG<br>* Oral ciprofloxacin 750mg twice daily will be prescribed for 2 weeks.<br>* Other names: Oral antibiotics;|
| Active Comparator: Tobramycin inhalation solution alone group<br>Participants will receive inhaled 300mg of tobramycin twice daily for 12 weeks and oral ciprofloxacin placebo twice daily for 2 weeks | Drug: Tobramycin Inhalant Product<br>* Tobramycin will be nebulized (300mg twice daily) with an ultrasonic nebulizer. A total of 12 weeks therapy will be scheduled.<br>* Other names: Inhaled antibiotics;Drug: Oral ciprofloxacin placebo<br>* Oral ciprofloxacin placebo twice daily will be prescribed for 2 weeks.<br>* Other names: Oral antibiotics;|
| Active Comparator: Oral ciprofloxacin alone group<br>Participants will receive oral 750mg of ciprofloxacin twice daily for 2 weeks and inhaled saline twice daily for 12 weeks | Drug: Ciprofloxacin 750 MG<br>* Oral ciprofloxacin 750mg twice daily will be prescribed for 2 weeks.<br>* Other names: Oral antibiotics;Drug: Natural saline inhalation<br>* Natural saline will be nebulized (5ml twice daily) with an ultrasonic nebulizer. A total of 12 weeks therapy will be scheduled.<br>* Other names: Inhaled saline;|
| Placebo Comparator: Placebo group<br>Participants will receive inhaled saline twice daily for 12 weeks and oral ciprofloxacin placebo twice daily for 2 weeks | Drug: Oral ciprofloxacin placebo<br>* Oral ciprofloxacin placebo twice daily will be prescribed for 2 weeks.<br>* Other names: Oral antibiotics;Drug: Natural saline inhalation<br>* Natural saline will be nebulized (5ml twice daily) with an ultrasonic nebulizer. A total of 12 weeks therapy will be scheduled.<br>* Other names: Inhaled saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 12 weeks after randomization | 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 | The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 24 weeks after randomization | 24 weeks | 
| The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 36 weeks after randomization | The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 36 weeks after randomization | 36 weeks | 
| Time to the first bronchiectasis exacerbation since randomization | Time to the first bronchiectasis exacerbation since randomization | 36 weeks | 
| Frequency of bronchiectasis exacerbation since randomization | Frequency of bronchiectasis exacerbation since randomization | 36 weeks | 
| Frequency of bronchiectasis exacerbation since randomization | Frequency of bronchiectasis exacerbation since randomization | 12 weeks | 
| Frequency of hospitalization due to bronchiectasis exacerbation since randomization | Frequency of hospitalization due to bronchiectasis exacerbation since randomization | 36 weeks | 
| Frequency of hospitalization due to bronchiectasis exacerbation since randomization | Frequency of hospitalization due to bronchiectasis exacerbation since randomization | 12 weeks | 
| Time to reoccurrence of P. aeruginosa infection since randomization | 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 | The Quality-of-Life-Bronchiectasis (QoL-B) questionnaire is a disease-specific survey designed for patients with bronchiectasis. The Respiratory Symptoms scale is a component of the QoL-B questionnaire, with a scale range from 0 to 100. Higher scores on this scale signify a better health status. | Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization. | 
| St.George Respiratory Questionnaire, that measures health-related quality of life | St.George Respiratory Questionnaire (SGRQ): a validated questionnaire for use in bronchiectasis population. This questionnaire is structured into 3 main components: symptoms, activity and impacts. Scale range is 0-100, where lower scores correspond to the better health status. Each questionnaire response has a unique empirically derived weight. Each component of the questionnaire is scored separately in three steps: i. The weights for all items with a positive responses are summed. ii. The weights for missed items are deducted from the maximum possible weight for each component. The weights for all missed items are deducted from the maximum possible weight for the Total score. iii. The score is calculated by dividing the summed weights by the adjusted maximum possible weight for that component and expressing the result as a percentage The Total score is calculated in similar way. | Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization. | 
| Euroqual-5 Dimensions questionnaire | The Euroqual-5 Dimensions questionnaire (EQ-5D) consists of two parts: health state description and evaluation. In the description part, health status is measured across five dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Respondents rate their severity level for each dimension using a five-level (EQ-5D-5L) scale. In the evaluation part, respondents assess their overall health status using the visual analogue scale (EQ-VAS), which ranges from 0 to 100, with higher scores indicating a better health status. Health states defined by the EQ-5D-5L descriptive system are converted into index values. This facilitates the calculation of Quality-Adjusted Life Years (QALYs), which are used to inform economic evaluations of healthcare interventions, according to guidelines found at https://euroqol.org. | 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 | 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 vital capacity [FVC] at 12, 24, and 36 weeks compared with baseline | 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. | 
| Changes in forced expiratory flow at 25-75% of forced vital capacity at 12, 24, and 36 weeks compared with baseline | 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. | 
| The cost of hospitalization | The cost of hospitalization during the whole study period | 36 weeks | 
| Other sputum microbiology during the whole study period. | Sputum cultures were conducted at baseline, 2 weeks, 8 weeks, 12 weeks, 24 weeks, and 36 weeks. Other sputum microbiology, including Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Burkholderia cepacia complex, Stenotrophomonas, Aspergillus, and Candida spp. were documented throughout the entire study period. The number of participants who yielded at least one positive culture for these microorganisms was calculated. | 36 weeks | 
| Resistant P. aeruginosa during the whole study period | Sputum cultures were performed at intervals of 2 weeks, 8 weeks, 12 weeks, 24 weeks, and 36 weeks. Drug sensitivity testing was conducted to assess the resistance of the current P. aeruginosa sample to antibiotics such as ciprofloxacin and tobramycin. The number of participants who showed growth of Pseudomonas aeruginosa resistant to ciprofloxacin and/or tobramycin was calculated. | 36 weeks | 
| Number of adverse events | Reported by the PI or designee via interview with patients. | 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pseudomonas Aeruginosa, eradication, bronchiectasis,, randomized controlled trial, inhaled antibiotics