Clinical trial NCT03715322: Tobramycin in Bronchiectasis Colonized With Pseudmonas Aeruginosa
Official title: Efficacy and Safety of Inhaled Tobramycin on Bronchiectasis Colonized With Pseudomonas Aeruginosa: A Randomized, Double-blind, Parallel-group Multicenter Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Bronchiectasis Adult
Pseudomonas Infections
Keywords: bronchiectasis
Pseudomonas aeruginosa
tobramycin
nebulization
bacterial load
quality of life
Lead sponsor: Guangzhou Institute of Respiratory Disease
Sponsor class: OTHER
First posted: 2018-10-23
Enrollment: 350
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized into the treatment group and control group. No cross-over of the study group will be made.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Changes in sputum load of Pseudomonas aeruginosa at day 29 compared with baseline
timeFrame: 29 days
measure: Changes in Quality of Life in Bronchiectasis-Respiratory Symptom Score at day 29 compared with baseline
timeFrame: 29 days
Secondary outcomes:
measure: The time to the first bronchiectasis exacerbation since randomization
timeFrame: 4 months
measure: The frequency of bronchiectasis exacerbation since randomization
timeFrame: 4 months
measure: The rate of isolation of Pseudomonas aeruginosa at day 85
timeFrame: 85 days
measure: Changes in the load of Pseudomonas aeruginosa at day 85 compared with baseline
timeFrame: 85 days
measure: Changes in FEV1 pred% at days 29, 57 and 85 compared with baseline
timeFrame: 85 days
measure: Changes in 24-hour sputum volume at days 29, 57 and 85 compared with baseline
timeFrame: 85 days
measure: Changes in sputum purulence at days 29, 57 and 85 compared with baseline
timeFrame: 85 days
measure: Changes in Quality of Life in Bronchiectasis-Respiratory Symptom Score at day 85 compared with baseline
timeFrame: 85 days
measure: Changes in Bronchiectasis Health Questionnaire Sore at day 29 and 85 compared with baseline
timeFrame: 85 days
measure: Peak and trough concentration of tobramycin at day 1 and 28 post-treatment
timeFrame: 29 days
measure: Changes in overall visual analogue scale at days 29 and 85 compared with baseline
timeFrame: 85 days
measure: Changes in the minimal inhibitory concentration of Pseudomonas aeruginosa at days 29 and 85 compared with baseline
timeFrame: 85 days
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University
state: Guangdong
Study officials:
affiliation: The First Affiliated Hospital of Guangzhou Medical University
name: Nan-shan Zhong, MD
role: STUDY_CHAIR
affiliation: The First Affiliated Hospital of Guangzhou Medical University
name: Wei-jie Guan, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pasteur MC, Bilton D, Hill AT; British Thoracic Society Bronchiectasis non-CF Guideline Group. British Thoracic Society guideline for non-CF bronchiectasis. Thorax. 2010 Jul;65 Suppl 1:i1-58. doi: 10.1136/thx.2010.136119.
citation: Pasteur MC, Helliwell SM, Houghton SJ, Webb SC, Foweraker JE, Coulden RA, Flower CD, Bilton D, Keogan MT. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1277-84. doi: 10.1164/ajrccm.162.4.9906120.
citation: Guan WJ, Gao YH, Xu G, Lin ZY, Tang Y, Li HM, Lin ZM, Zheng JP, Chen RC, Zhong NS. Aetiology of bronchiectasis in Guangzhou, southern China. Respirology. 2015 Jul;20(5):739-48. doi: 10.1111/resp.12528. Epub 2015 Mar 26.
citation: Angrill J, Agusti C, De Celis R, Filella X, Rano A, Elena M, De La Bellacasa JP, Xaubet A, Torres A. Bronchial inflammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med. 2001 Nov 1;164(9):1628-32. doi: 10.1164/ajrccm.164.9.2105083.
citation: Chalmers JD, Smith MP, McHugh BJ, Doherty C, Govan JR, Hill AT. Short- and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2012 Oct 1;186(7):657-65. doi: 10.1164/rccm.201203-0487OC. Epub 2012 Jun 28.
citation: Davies G, Wells AU, Doffman S, Watanabe S, Wilson R. The effect of Pseudomonas aeruginosa on pulmonary function in patients with bronchiectasis. Eur Respir J. 2006 Nov;28(5):974-9. doi: 10.1183/09031936.06.00074605. Epub 2006 Aug 9.
citation: Guan WJ, Gao YH, Xu G, Lin ZY, Tang Y, Li HM, Li ZM, Zheng JP, Chen RC, Zhong NS. Effect of airway Pseudomonas aeruginosa isolation and infection on steady-state bronchiectasis in Guangzhou, China. J Thorac Dis. 2015 Apr;7(4):625-36. doi: 10.3978/j.issn.2072-1439.2015.04.04.
citation: Wilson R, Aksamit T, Aliberti S, De Soyza A, Elborn JS, Goeminne P, Hill AT, Menendez R, Polverino E. Challenges in managing Pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis. Respir Med. 2016 Aug;117:179-89. doi: 10.1016/j.rmed.2016.06.007. Epub 2016 Jun 7.
citation: Orriols R, Hernando R, Ferrer A, Terradas S, Montoro B. Eradication Therapy against Pseudomonas aeruginosa in Non-Cystic Fibrosis Bronchiectasis. Respiration. 2015;90(4):299-305. doi: 10.1159/000438490. Epub 2015 Sep 5.
citation: Hoppentocht M, Akkerman OW, Hagedoorn P, Alffenaar JW, van der Werf TS, Kerstjens HA, Frijlink HW, de Boer AH. Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Tobramycin Free Base in Non-Cystic Fibrosis Bronchiectasis Patients. PLoS One. 2016 Mar 9;11(3):e0149768. doi: 10.1371/journal.pone.0149768. eCollection 2016.
citation: Bilton D, Henig N, Morrissey B, Gotfried M. Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis. Chest. 2006 Nov;130(5):1503-10. doi: 10.1378/chest.130.5.1503.
citation: Scheinberg P, Shore E. A pilot study of the safety and efficacy of tobramycin solution for inhalation in patients with severe bronchiectasis. Chest. 2005 Apr;127(4):1420-6. doi: 10.1378/chest.127.4.1420.
citation: Drobnic ME, Sune P, Montoro JB, Ferrer A, Orriols R. Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa. Ann Pharmacother. 2005 Jan;39(1):39-44. doi: 10.1345/aph.1E099. Epub 2004 Nov 23.
citation: Couch LA. Treatment With tobramycin solution for inhalation in bronchiectasis patients with Pseudomonas aeruginosa. Chest. 2001 Sep;120(3 Suppl):114S-117S. doi: 10.1378/chest.120.3_suppl.114s.
citation: Orriols R, Roig J, Ferrer J, Sampol G, Rosell A, Ferrer A, Vallano A. Inhaled antibiotic therapy in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection by Pseudomonas aeruginosa. Respir Med. 1999 Jul;93(7):476-80. doi: 10.1016/s0954-6111(99)90090-2.
citation: Barker AF, Couch L, Fiel SB, Gotfried MH, Ilowite J, Meyer KC, O'Donnell A, Sahn SA, Smith LJ, Stewart JO, Abuan T, Tully H, Van Dalfsen J, Wells CD, Quan J. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):481-5. doi: 10.1164/ajrccm.162.2.9910086.
citation: Guan WJ, Xu JF, Luo H, Xu XX, Song YL, Ma WL, Liang ZA, Liu XD, Zhang GJ, Zhang XJ, Li RK, Zhu SY, Zhang YJ, Cai XJ, Wei LP, Tian DB, Zhao H, Chen PY, Qu JM, Zhong NS; TORNASOL Study Group. A Double-Blind Randomized Placebo-Controlled Phase 3 Trial of Tobramycin Inhalation Solution in Adults With Bronchiectasis With Pseudomonas aeruginosa Infection. Chest. 2023 Jan;163(1):64-76. doi: 10.1016/j.chest.2022.07.007. Epub 2022 Jul 19.