Tobramycin in Bronchiectasis Colonized With Pseudmonas Aeruginosa

NCT03715322 | Unknown Phase 3 DMC

• 1 other identifier: GIRH-2018-TOBRA
• Study Type: interventional
• Target: 350
• Locations: 1 country
• Sites: 1

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.

Conditions

Bronchiectasis Adult; Pseudomonas Infections

Keywords

bronchiectasis; Pseudomonas aeruginosa; tobramycin; nebulization; bacterial load; quality of life

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (12)

• The time to the first bronchiectasis exacerbation since randomization

  4 months

• The frequency of bronchiectasis exacerbation since randomization

  4 months

• 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

  85 days

• Changes in FEV1 pred% at days 29, 57 and 85 compared with baseline

  85 days

Study Arms (3)

tobramycin inhalation

ACTIVE COMPARATOR

300mg tobramycin dissolved in 5ml saline will be nebulized with an ultrasonic nebulizer within 15-20 minutes.

Drug: Tobramycin Inhalant Product; Other: usual care

natural saline inhalation

PLACEBO COMPARATOR

5ml saline will be nebulized with an ultrasonic nebulizer within 15-20 minutes.

Other: usual care; Drug: Natural saline inhalation

usual care

OTHER

ambroxool (30mg thrice daily), or N-acetylcysteine (0.2g thrice daily) plus chest physiotherapy (5 min, once daily)

Drug: Tobramycin Inhalant Product; Drug: Natural saline inhalation

Interventions

Tobramycin Inhalant Product DRUG

Tobramycin will be nebulized (300mg twice daily) with an ultrasonic nebulizer. A total of two 28-day on-and-off cycles will be scheduled.

tobramycin inhalation; usual care

usual care OTHER

ambroxool (30mg thrice daily), or N-acetylcysteine (0.2g thrice daily) plus chest physiotherapy (5 min, once daily)

natural saline inhalation; tobramycin inhalation

Natural saline inhalation DRUG

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.

natural saline inhalation; usual care

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Guangzhou Institute of Respiratory Disease: lead

Study Sites (1)

The First Affiliated Hospital of Guangzhou Medical University

Guangzhou, Guangdong, 510120, China

RECRUITING

Related Publications (17)

• 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.

  PMID: 20627931 BACKGROUND

• 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.

  PMID: 11029331 BACKGROUND

• 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.

  PMID: 25819403 BACKGROUND

• 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.

  PMID: 11719301 BACKGROUND

• 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.

  PMID: 22744718 BACKGROUND

• 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.

  PMID: 16899482 BACKGROUND

• 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.

  PMID: 25973228 BACKGROUND

• 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.

  PMID: 27492530 BACKGROUND

• 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.

  PMID: 26340658 BACKGROUND

• 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.

  PMID: 26959239 BACKGROUND

• 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.

  PMID: 17099030 BACKGROUND

• 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.

  PMID: 15821224 BACKGROUND

• 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.

  PMID: 15562142 BACKGROUND

• 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.

  PMID: 11555565 BACKGROUND

• 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.

  PMID: 10464834 BACKGROUND

• 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.

  PMID: 10934074 BACKGROUND

• 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.

  PMID: 35863486 DERIVED

MeSH Terms

Conditions

Pseudomonas Infections; Bronchiectasis

Condition Hierarchy (Ancestors)

Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Bronchial Diseases; Respiratory Tract Diseases

Study Officials

• Nan-shan Zhong, MD

  The First Affiliated Hospital of Guangzhou Medical University

  STUDY CHAIR

• Wei-jie Guan, PhD

  The First Affiliated Hospital of Guangzhou Medical University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nan-shan Zhong, MD

CONTACT

13609003622; nanshan@vip.163.com

Wei-jie Guan, PhD

CONTACT

+86-13826042052; battery203@163.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associated professor; principal investigator (respiratory medicine)

Model Details: Patients will be randomized into the treatment group and control group. No cross-over of the study group will be made.

Study Record Dates

• First Submitted: October 19, 2018
• First Posted: October 23, 2018
• Study Start: October 26, 2018
• Primary Completion: April 1, 2021
• Study Completion: June 1, 2021
• Last Updated: August 2, 2019

Record last verified: 2019-07

Locations

CN (1)