Tobramycin in Bronchiectasis Colonized With Pseudmonas Aeruginosa

Study Overview
=================
Brief Summary
-----------------
This is a phase 3 study. Patients will be enrolled from 14 medical centers in mainland China. Eligible patients will be randomly allocated to treatment group (tobramycin nebulization, 300mg bid) and control group (natural saline nebulization, 5ml bid). A total of two 28-day on-and-off cycles will be scheduled. Both tobramycin solution and natural saline and the nebulizer will be solely provided by the sponsor.

Detailed Description
-----------------
This is a phase 3 study. All bronchiectasis patients will be enrolled from 14 medical centers located in different geographic regions of mainland China. After a three-week screening period, On the basis of usual care [ambroxool (30mg thrice daily) or N-acetylcysteine (0.2g thrice daily) and chest physiotherapy (5 min, once daily)], eligible patients will be randomly allocated to treatment group (tobramycin nebulization, 300mg bid, delivered via an ultrasonic nebulizer) and control group (natural saline nebulization, 5ml bid, delivered via an ultrasonic nebulizer). A total of two 28-day on-and-off cycles will be scheduled. At the end of each on-and-off cycle, sputum culture and other clinical assessments will be performed.

Official Title
-----------------
Efficacy and Safety of Inhaled Tobramycin on Bronchiectasis Colonized With Pseudomonas Aeruginosa: A Randomized, Double-blind, Parallel-group Multicenter Trial

Conditions
-----------------
Bronchiectasis Adult, Pseudomonas Infections

Intervention / Treatment
-----------------
* Drug: Tobramycin Inhalant Product
* Other: usual care
* Drug: Natural saline inhalation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged 18 to 75 years, had a history of chronic cough and sputum production, had physician-diagnosed bronchiectasis based on high-resolution chest computed tomography (effective within 12 months) Remaining clinically stable (no significant changes in respiratory symptoms and free from upper respiratory tract infection or bronchiectasis exacerbations for 4 weeks) Sputum culture positive to Pseudomonas aeruginosa at screening Forced expiratory volume in one second > 30% predicted and < 80% predicted Could tolerate to nebulization At least one bronchiectasis exacerbation within the past two years Can correctly nebulize the study medications and fill in the diary cards following instruction of the investigators Exclusion Criteria: Had a knwon history of allergy to tobramycin Had concomitant asthma, allergic bronchopulmonary aspergillosis, active tuberculosis, or active infection with non-tuyberculous mycobacteria that warranted regular anti-mycobacterial treatment Had moderate or major haemoptysis within 6 months Had concomitant severe cardiovascular diseases or haematopoietic diseases (congestive heart failure, clinically significant coronary heart disease, myocardial infarction or stroke, clinically arrythmia, known anurysm of the aorta, uncontroll hypertension (systolic blood pressure > 160mmHg or diastolic pressure >100mmHg at two consecutive time points) Concomitant severe psychiatric disorders Uncontrolled diabetes mellitus or fasting blood glucose >10mmol/L Active peptic or duodenal ulcer Moderate-to-severe gastroesophageal reflux diseases Malignancy Severe myasthenia gravis or Parkinson's disease Major abnormality of hepatic or renal function [ALT or AST >2-fold of the normal upper limit, creatinine > 1.5-fold- greater than the normal upper limit (excluding ALT > 1.5-fold greater than normal upper limit in patients with chronic stable hepatitis)]; concomitant infection with HBV and HCV; Hearing loss or clinically significant tinittus Use of inhaled or systemic antibiotics within 4 weeks prior to enrollment Needing oral or intravenous corticosteroids, or needing systemic corticosteroids within 30 days prior to enrollment Needing oral or intravenous anti-cholinergic medications, or needing systemic anti-cholinergic medications within 30 days prior to enrollment Needing long-term non-invasive mechanical ventilation or oxygen therapy (> 10 hrs daily) due to chronic respiratory failure Pregnancy or lactation Failure to understand or cooperate with the trial procedures Participation in other clinical trials within 3 months

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized into the treatment group and control group. No cross-over of the study group will be made.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: tobramycin inhalation<br>300mg tobramycin dissolved in 5ml saline will be nebulized with an ultrasonic nebulizer within 15-20 minutes. | Drug: Tobramycin Inhalant Product<br>* Tobramycin will be nebulized (300mg twice daily) with an ultrasonic nebulizer. A total of two 28-day on-and-off cycles will be scheduled.<br>Other: usual care<br>* ambroxool (30mg thrice daily), or N-acetylcysteine (0.2g thrice daily) plus chest physiotherapy (5 min, once daily)<br>|
| Placebo Comparator: natural saline inhalation<br>5ml saline will be nebulized with an ultrasonic nebulizer within 15-20 minutes. | Other: usual care<br>* ambroxool (30mg thrice daily), or N-acetylcysteine (0.2g thrice daily) plus chest physiotherapy (5 min, once daily)<br>Drug: Natural saline inhalation<br>* Natural saline will be nebulized (5ml twice daily) with an ultrasonic nebulizer. A total of two 28-day on-and-off cycles will be scheduled.<br>|
| Other: usual care<br>ambroxool (30mg thrice daily), or N-acetylcysteine (0.2g thrice daily) plus chest physiotherapy (5 min, once daily) | Drug: Tobramycin Inhalant Product<br>* Tobramycin will be nebulized (300mg twice daily) with an ultrasonic nebulizer. A total of two 28-day on-and-off cycles will be scheduled.<br>Drug: Natural saline inhalation<br>* Natural saline will be nebulized (5ml twice daily) with an ultrasonic nebulizer. A total of two 28-day on-and-off cycles will be scheduled.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in sputum load of Pseudomonas aeruginosa at day 29 compared with baseline | Changes in sputum load of Pseudomonas aeruginosa at day 29 compared with baseline | 29 days | 
| Changes in Quality of Life in Bronchiectasis-Respiratory Symptom Score at day 29 compared with baseline | Changes in QoL-B-RSS at day 29 compared with baseline. The respiratory symptom domain contains 9 items describing patient's self assessment of her/his respiratory symptoms that affect the daily life. The total score for this domain is 100, with higher scores indicating better quality of life. No summation was made for the total score. | 29 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time to the first bronchiectasis exacerbation since randomization | The time to the first bronchiectasis exacerbation since randomization | 4 months | 
| The frequency of bronchiectasis exacerbation since randomization | The frequency of bronchiectasis exacerbation since randomization | 4 months | 
| The rate of isolation of Pseudomonas aeruginosa at day 85 | The rate of isolation of Pseudomonas aeruginosa at day 85 | 85 days | 
| Changes in the load of Pseudomonas aeruginosa at day 85 compared with baseline | Changes in the load of Pseudomonas aeruginosa at day 85 compared with baseline | 85 days | 
| Changes in FEV1 pred% at days 29, 57 and 85 compared with baseline | Changes in the predicted % of forced expiratory volume in one second at days 29, 57 and 85 compared with baseline | 85 days | 
| Changes in 24-hour sputum volume at days 29, 57 and 85 compared with baseline | Changes in 24-hour sputum volume at days 29, 57 and 85 compared with baseline | 85 days | 
| Changes in sputum purulence at days 29, 57 and 85 compared with baseline | Changes in sputum purulence at days 29, 57 and 85 compared with baseline | 85 days | 
| Changes in Quality of Life in Bronchiectasis-Respiratory Symptom Score at day 85 compared with baseline | Changes in QoL-B-RSS at day 85 compared with baseline. The respiratory symptom domain contains 9 items describing patient's self assessment of her/his respiratory symptoms that affect the daily life. The total score for this domain is 100, with higher scores indicating better quality of life. No summation was made for the total score. | 85 days | 
| Changes in Bronchiectasis Health Questionnaire Sore at day 29 and 85 compared with baseline | Changes in BHQ Sore at day 29 and 85 compared with baseline. Theb BHQ contains 10 items, with higher scores indicating better quality of life. The total score was calculated as the weighted summation of the scores for the 10 individual items. | 85 days | 
| Peak and trough concentration of tobramycin at day 1 and 28 post-treatment | Peak and trough concentration of tobramycin at day 1 and 28 post-treatment | 29 days | 
| Changes in overall visual analogue scale at days 29 and 85 compared with baseline | Changes in overall VAS at days 29 and 85 compared with baseline. The VAS ranged from 0 to 10, with higher scores indicating poorer status. No summation of the score was made. | 85 days | 
| Changes in the minimal inhibitory concentration of Pseudomonas aeruginosa at days 29 and 85 compared with baseline | Changes in the MIC of Pseudomonas aeruginosa at days 29 and 85 compared with baseline (assessed with dilution methods for the sputum culture samples) | 85 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
bronchiectasis, Pseudomonas aeruginosa, tobramycin, nebulization, bacterial load, quality of life