Bronchiectasis Adult, Pseudomonas Aeruginosa Infection
Conditions
Keywords
bronchiectasis,, Pseudomonas Aeruginosa, eradication, inhaled antibiotics, randomized controlled trial
Brief summary
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).
Detailed description
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: 1. Placebo group: participants will receive inhaled saline twice daily for 12 weeks and an oral ciprofloxacin placebo twice daily for 2 weeks. 2. Oral ciprofloxacin alone group: participants will receive 750mg of oral ciprofloxacin twice daily for 2 weeks and inhaled saline twice daily for 12 weeks. 3. 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. 4. 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.
Interventions
Tobramycin will be nebulized (300mg twice daily) with an ultrasonic nebulizer. A total of 12 weeks therapy will be scheduled.
Oral ciprofloxacin 750mg twice daily will be prescribed for 2 weeks.
DRUGOral ciprofloxacin placebo
Oral ciprofloxacin placebo twice daily will be prescribed for 2 weeks.
Natural saline will be nebulized (5ml twice daily) with an ultrasonic nebulizer. A total of 12 weeks therapy will be scheduled.
Sponsors
Jin-Fu Xu
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
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
Intervention model description
Patients will be randomized into one of the four groups. No cross-over of the study group will be made
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, aged 18 years and 80 years at screening 2. Signed and dated written informed consent prior to admission to the study in accordance with local legislation. 3. 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 4. 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); 5. 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) 6. During the screening period, P. aeruginosa is not resistant to Tobramycin and Ciprofloxacin based on the drug sensitivity test of sputum culture in vitro 7. Patient can tolerate nebulized inhalation therapy
Exclusion criteria
1. Patients who are allergic to or cannot tolerate the investigational drugs (Tobramycin, Ciprofloxacin) 2. 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; 3. 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 4. 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. 5. AST and/or ALT \>2 ULN and/or Total Bilirubin (TBIL) at screening period 6. Serum creatinine \>ULN at screening period 7. Participants with a history of hearing loss or those who are determined by the researcher to have clinically significant chronic tinnitus 8. Participants with a history of prolonged QT intervals or those whose electrocardiograms show prolonged QT intervals during the screening period 9. Participants who have used drugs that are prohibited according to the plan during the screening period. 10. Women who are pregnant or lactating, or women of childbearing potential preparing for pregnancy 11. Patients with FEV1% of predicted value\<30% 12. Participants who have participated in other clinical trials (defined as those where medication has been administered) within the 4 weeks prior to the screening 13. 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. 14. Participants who are deemed unsuitable for inclusion in the study due to other reasons, as determined by the researcher.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 12 weeks after the first drug administration. |
| 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 24 weeks after the first drug administration. |
| Proportion of patients with a negative Pseudomonas aeruginosa sputum culture at 36 weeks after the first drug administration. | 36 weeks | Proportion of patients with a negative Pseudomonas aeruginosa sputum culture at 36 weeks after the first drug administration. |
| Time to first pulmonary exacerbation of bronchiectasis after the first drug administration. | 36 weeks | Time to first pulmonary exacerbation of bronchiectasis after the first drug administration. |
| Frequency of pulmonary exacerbations of bronchiectasis after the first drug administration. | 12 weeks | Frequency of pulmonary exacerbations of bronchiectasis after the first drug administration. |
| Time to reoccurrence of Pseudomonas aeruginosa infection since randomization. | 36 weeks | Time to reoccurrence of Pseudomonas aeruginosa infection since randomization. |
| 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 1 second \[FEV1\] at 12, 24, and 36 weeks. |
| 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 vital capacity \[FVC\] at 12, 24, and 36 weeks |
| 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. | Absolute change from baseline in forced expiratory flow between 25 and 75% of forced vital capacity \[FEF25%-75%\] at 12, 24, and 36 weeks. |
| Proportion of hospitalisations due to bronchiectasis after the first drug administration. | 24 weeks | Proportion of hospitalisations due to bronchiectasis after the first drug administration. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| Number of hospitalisations per person. | 36 weeks. | Number of hospitalisations per person. |
| Cost per hospitalisation per person. | 36 weeks | Cost per hospitalisation per person. |
| 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. | The number of participants who yielded at least one positive culture for other pathogenic microorganisms was calculated. |
| Proportion of subjects developing resistance to tobramycin or ciprofloxacin after enrolment. | 36 weeks | Sputum cultures were performed at intervals of baseline, 2 weeks, 8 weeks, 12 weeks, 24 weeks, and 36 weeks. Drug sensitivity testing was conducted to assess the resistance of the current Pseudomonas 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. |
| Incidence of adverse events and serious adverse events. | 36 weeks | Assessed by the investigator via patient interview, spontaneous reporting, and clinical evaluation. |
Countries
China
Contacts
PRINCIPAL_INVESTIGATORJin-Fu Xu, MD, PhD
Tongji Hospital, School of Medicine, Tongji University; Shanghai Pulmonary Hospital, School of Medicine, Tongji University; Huadong Hospital, School of Medicine, Fudan University
Outcome results
None listed