TORNASOL: Tobramycin in Bronchiectasis Colonized With Pseudmonas Aeruginosa

• Sponsor: Guangzhou Institute of Respiratory Disease (Other)
• Overall Status: Unknown status
• CT.gov ID: NCT03715322
• Collaborator: (none)
• Enrollment: 350
• Location: 1
• Arms: 3
• Anticipated Duration (Months): 31.2
• Patients Per Site Per Month: 11.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bronchiectasis Adult; Pseudomonas Infections	Drug: Tobramycin Inhalant Product; Other: usual care; Drug: Natural saline inhalation	Phase 3

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 350 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Patients will be randomized into the treatment group and control group. No cross-over of the study group will be made.Patients will be randomized into the treatment group and control group. No cross-over of the study group will be made.
• Masking: Double (Participant, Investigator)
• Masking Description: Both the investigators and the participants will be masked to the study allocation. The randonmization codes will be generated by a blinded medical statistician with the use of computerized program. Randomization will be achieved based on the permuted block design.
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Inhaled Tobramycin on Bronchiectasis Colonized With Pseudomonas Aeruginosa: A Randomized, Double-blind, Parallel-group Multicenter Trial
• Actual Study Start Date: Oct 26, 2018
• Anticipated Primary Completion Date: Apr 1, 2021
• Anticipated Study Completion Date: Jun 1, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Changes in sputum load of Pseudomonas aeruginosa at day 29 compared with baseline [29 days]

   Changes in sputum load of Pseudomonas aeruginosa at day 29 compared with baseline

2. Changes in Quality of Life in Bronchiectasis-Respiratory Symptom Score at day 29 compared with baseline [29 days]

   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.

Secondary Outcome Measures

1. The time to the first bronchiectasis exacerbation since randomization [4 months]

   The time to the first bronchiectasis exacerbation since randomization

2. The frequency of bronchiectasis exacerbation since randomization [4 months]

   The frequency of bronchiectasis exacerbation since randomization

3. The rate of isolation of Pseudomonas aeruginosa at day 85 [85 days]

   The rate of isolation of Pseudomonas aeruginosa at day 85

4. Changes in the load of Pseudomonas aeruginosa at day 85 compared with baseline [85 days]

   Changes in the load of Pseudomonas aeruginosa at day 85 compared with baseline

5. Changes in FEV1 pred% at days 29, 57 and 85 compared with baseline [85 days]

   Changes in the predicted % of forced expiratory volume in one second at days 29, 57 and 85 compared with baseline

6. Changes in 24-hour sputum volume 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

7. Changes in sputum purulence at days 29, 57 and 85 compared with baseline [85 days]

   Changes in sputum purulence at days 29, 57 and 85 compared with baseline

8. Changes in Quality of Life in Bronchiectasis-Respiratory Symptom Score at day 85 compared with baseline [85 days]

   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.

9. Changes in Bronchiectasis Health Questionnaire Sore at day 29 and 85 compared with baseline [85 days]

   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.

10. Peak and trough concentration of tobramycin at day 1 and 28 post-treatment [29 days]

    Peak and trough concentration of tobramycin at day 1 and 28 post-treatment

11. Changes in overall visual analogue scale at days 29 and 85 compared with baseline [85 days]

    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.

12. Changes in the minimal inhibitory concentration of Pseudomonas aeruginosa at days 29 and 85 compared with baseline [85 days]

    Changes in the MIC of Pseudomonas aeruginosa at days 29 and 85 compared with baseline (assessed with dilution methods for the sputum culture samples)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The First Affiliated Hospital of Guangzhou Medical University	Guangzhou	Guangdong	China	510120

Sponsors and Collaborators

• Guangzhou Institute of Respiratory Disease

Investigators

• Study Chair: Nan-shan Zhong, MD, The First Affiliated Hospital of Guangzhou Medical University
• Principal Investigator: Wei-jie Guan, PhD, The First Affiliated Hospital of Guangzhou Medical University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Angrill J, Agustí C, De Celis R, Filella X, Rañó 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.
• 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.
• 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.
• 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.
• Couch LA. Treatment With tobramycin solution for inhalation in bronchiectasis patients with Pseudomonas aeruginosa. Chest. 2001 Sep;120(3 Suppl):114S-117S.
• 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. Epub 2006 Aug 9.
• Drobnic ME, Suñé 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. Epub 2004 Nov 23.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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. Review.
• 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.
• 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.
• 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. Review.

• Responsible Party: Weijie Guan, Associated professor; principal investigator (respiratory medicine), Guangzhou Institute of Respiratory Disease
• ClinicalTrials.gov Identifier: NCT03715322
• Other Study ID Numbers: GIRH-2018-TOBRA
• First Posted: Oct 23, 2018
• Last Update Posted: Aug 2, 2019
• Last Verified: Jul 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Weijie Guan, Associated professor; principal investigator (respiratory medicine), Guangzhou Institute of Respiratory Disease: bronchiectasis; Pseudomonas aeruginosa; tobramycin; nebulization; bacterial load; quality of life
• Additional relevant MeSH terms: Pseudomonas Infections; Bronchiectasis; Tobramycin

Study Results

No Results Posted as of Aug 2, 2019