Clinical trial NCT06093191: Tobramycin Inhalation Solution for Pseudomonas Aeruginosa Eradication in Bronchiectasis
Official title: Efficacy and Safety of tobRamycin Inhalation Solution for Pseudomonas AeruginoSa Eradication in Bronchiectasis (ERASE): a Multi-center, 2×2 Factorial Randomized, Double-blind, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Bronchiectasis Adult
Pseudomonas Aeruginosa Infection
Keywords: bronchiectasis,
Pseudomonas Aeruginosa
eradication
inhaled antibiotics
randomized controlled trial
Lead sponsor: Shanghai Pulmonary Hospital, Shanghai, China
Sponsor class: OTHER
First posted: 2023-10-23
Enrollment: 364
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized into one of the four groups. No cross-over of the study group will be made
Primary purpose: TREATMENT

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 rates of PA, defined as a negative sputum culture of PA at both 24 weeks and 36 weeks.

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.

Eligibility criteria: 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 CT scan
4. During the screening period, patients must have a positive P. aeruginosa culture in their sputum and must meet one of the following criteria: (1) they have never been isolated with P. aeruginosa from sputum or bronchoalveolar lavage fluid (BALF) before; (2) they were isolated with P. aeruginosa from sputum or BALF for the first time within 12 months before screening; (3) they had prior isolation of P. aeruginosa but not within the last 24 months (defined as having negative sputum culture results at least twice before starting antibiotic treatment)
5. During the screening period, patients must remain clinically stable (no significant changes in 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. Patients with uncontrolled asthma, physician-diagnosed cystic fibrosis, and Current diagnosis of allergic bronchopulmonary aspergillosis, hypogammaglobulinemia, common variable immunodeficiency, mycobacterial infection (including pulmonary non-tuberculous mycobacterial disease) requiring 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 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 of childbearing potential adhering to contraception requirements.
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.

Primary outcomes:
measure: The proportion of patients successfully eradicating PA in each group by the end of the study, defined as a negative sputum culture of PA at both 24 weeks and 36 weeks.
timeFrame: 36 weeks
Secondary outcomes:
measure: The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 12 weeks after randomization
timeFrame: 12 weeks
measure: The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 24 weeks after randomization
timeFrame: 24 weeks
measure: The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 36 weeks after randomization
timeFrame: 36 weeks
measure: Time to the first bronchiectasis exacerbation since randomization
timeFrame: 36 weeks
measure: Frequency of bronchiectasis exacerbation since randomization
timeFrame: 36 weeks
measure: Frequency of bronchiectasis exacerbation since randomization
timeFrame: 12 weeks
measure: Frequency of hospitalization due to bronchiectasis exacerbation since randomization
timeFrame: 36 weeks
measure: Frequency of hospitalization due to bronchiectasis exacerbation since randomization
timeFrame: 12 weeks
measure: Time to reoccurrence of P. aeruginosa infection since randomization
timeFrame: 36 weeks
measure: Quality-of-Life-Bronchiectasis Respiratory Symptom Scale, that measures health-related quality of life
timeFrame: Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
measure: St.George Respiratory Questionnaire, that measures health-related quality of life
timeFrame: Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
measure: Euroqual-5 Dimensions questionnaire
timeFrame: Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
measure: Changes in forced expiratory volume in 1 second [FEV1] at 12, 24, and 36 weeks compared with baseline
timeFrame: Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
measure: Changes in forced vital capacity [FVC] at 12, 24, and 36 weeks compared with baseline
timeFrame: Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
measure: Changes in forced expiratory flow at 25-75% of forced vital capacity at 12, 24, and 36 weeks compared with baseline
timeFrame: Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
measure: The cost of hospitalization
timeFrame: 36 weeks
measure: Other sputum microbiology during the whole study period.
timeFrame: 36 weeks
measure: Resistant P. aeruginosa during the whole study period
timeFrame: 36 weeks
measure: Number of adverse events
timeFrame: 36 weeks
Other outcomes:
Locations:
city: Haikou
country: China
facility: Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University
state: Hainan
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
state: Shangdong
city: Shanghai
country: China
facility: Ruijin Hospital
state: Shanghai
city: Shanghai
country: China
facility: The Shanghai Fifth People's Hospital
state: Shanghai
city: Shanghai
country: China
facility: Shanghai pulmonary hospital
state: Shanghai
city: Taiyuan
country: China
facility: Shanxi Bethune Hospital
state: Shanxi
city: Kunming
country: China
facility: The First Affiliated Hospital of Kunming Medical University
state: Yunnan
city: Hangzhou
country: China
facility: The Affiliated Hospital of Hangzhou Normal University
state: Zhejiang
city: Anning
country: China
facility: The First People's Hospital of Anning City Affiliated to Kunming University of Science and Technology
city: Beijing
country: China
facility: Beijing Chao-Yang Hospital, Capital Medical University
city: Beijing
country: China
facility: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
city: Beijing
country: China
facility: Peking University Third Hospital
city: Changchun
country: China
facility: The First Affiliated Hospital of Jilin University
city: Changsha
country: China
facility: The Second Xiangya Hospital of Central South University
city: Changsha
country: China
facility: Xiangya Hospital, Central South University
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
city: Chongqing
country: China
facility: The Second Affiliated Hospital of Chongqing Medical University
city: Chongqing
country: China
facility: The Third Affiliated Hospital of Chongqing Medical University
city: Dalian
country: China
facility: The Second Affiliated Hospital of Dalian Medical University
city: Fuzhou
country: China
facility: Fujian Provincial Hospital
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine
city: Guiyang
country: China
facility: Guizhou Provincial People's Hospital
city: Hangzhou
country: China
facility: The Second Affiliated Hospital of Zhengjiang University
city: Hefei
country: China
facility: Anhui Chest Hospital
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University
city: Huzhou
country: China
facility: Huzhou Central Hospital
city: Jiaxing
country: China
facility: The First Hospital of Jiaxing City
city: Jiaxing
country: China
facility: The Second Hospital of Jiaxing City
city: Jinan
country: China
facility: The First Affiliated Hospital of Shandong First Medical University
city: Jinan
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University
city: Nanjing
country: China
facility: The Affiliated Sir Run Run Hospital of Nanjing Medical University
city: Nanjing
country: China
facility: The Second Affiliated Hospital of Nanjing Medical University
city: Nanning
country: China
facility: The First Affiliated Hospital of Guangxi Medical University
city: Nantong
country: China
facility: Affiliated Hospital, Nantong University
city: Nantong
country: China
facility: The Sixth People's Hospital of Nantong City
city: Ningbo
country: China
facility: Fenghua District People's Hospital of Ningbo City
city: Ningbo
country: China
facility: Ningbo Medical Center Lihuili Hospital
city: Ningbo
country: China
facility: The First Affiliated Hospital of Ningbo University
city: Qingdao
country: China
facility: Qingdao Municipal Hospital
city: Shanghai
country: China
facility: Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine
city: Shanghai
country: China
facility: Shanghai Eighth People's Hospital
city: Shanghai
country: China
facility: Shanghai General Hospital
city: Shanghai
country: China
facility: Shanghai Putuo District People's Hospital
city: Shanghai
country: China
facility: Shanghai Shidong Hospital of Yangpu District
city: Shanghai
country: China
facility: Shanghai Sixth People's Hospital
city: Shanghai
country: China
facility: Shanghai Songjiang District Central Hospital
city: Shanghai
country: China
facility: Shanghai Yangpu District Central Hospital
city: Shanghai
country: China
facility: Zhongshan Hospital, Fudan University
city: Shangrao
country: China
facility: Shangrao People's Hospital
city: Shenyang
country: China
facility: Shengjing Hospital of China Medical University
city: Shenyang
country: China
facility: The First Affiliated Hospital of China Medical University
city: Shenzhen
country: China
facility: Shenzhen Institute of Respiratory Diseases
city: Shenzhen
country: China
facility: The Eighth Affiliated Hospital of Sun Yat-Sen University
city: Suzhou
country: China
facility: Suzhou Science and Technology Town Hospital
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
city: Wuhan
country: China
facility: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
city: Wuhan
country: China
facility: Union Hospital,Tongji Medical College, Huazhong University of Science and Technology
city: Yangzhou
country: China
facility: Subei People's Hospital
city: Zhanjiang
country: China
facility: Affiliated Hospital, Guangdong Medical College
city: Zhengzhou
country: China
facility: Henan Provincial People's Hospital
city: Zhengzhou
country: China
facility: Zhengzhou People's Hospital
Study officials:
affiliation: Shanghai Pulmonary Hospital, Shanghai, China
name: Jin-Fu Xu, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Polverino E, Goeminne PC, McDonnell MJ, Aliberti S, Marshall SE, Loebinger MR, Murris M, Canton R, Torres A, Dimakou K, De Soyza A, Hill AT, Haworth CS, Vendrell M, Ringshausen FC, Subotic D, Wilson R, Vilaro J, Stallberg B, Welte T, Rohde G, Blasi F, Elborn S, Almagro M, Timothy A, Ruddy T, Tonia T, Rigau D, Chalmers JD. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J. 2017 Sep 9;50(3):1700629. doi: 10.1183/13993003.00629-2017. Print 2017 Sep.
citation: Hill AT, Sullivan AL, Chalmers JD, De Soyza A, Elborn SJ, Floto AR, Grillo L, Gruffydd-Jones K, Harvey A, Haworth CS, Hiscocks E, Hurst JR, Johnson C, Kelleher PW, Bedi P, Payne K, Saleh H, Screaton NJ, Smith M, Tunney M, Whitters D, Wilson R, Loebinger MR. British Thoracic Society Guideline for bronchiectasis in adults. Thorax. 2019 Jan;74(Suppl 1):1-69. doi: 10.1136/thoraxjnl-2018-212463. No abstract available.
citation: Aliberti S, Masefield S, Polverino E, De Soyza A, Loebinger MR, Menendez R, Ringshausen FC, Vendrell M, Powell P, Chalmers JD; EMBARC Study Group. Research priorities in bronchiectasis: a consensus statement from the EMBARC Clinical Research Collaboration. Eur Respir J. 2016 Sep;48(3):632-47. doi: 10.1183/13993003.01888-2015. Epub 2016 Jun 10.
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citation: Vallieres E, Tumelty K, Tunney MM, Hannah R, Hewitt O, Elborn JS, Downey DG. Efficacy of Pseudomonas aeruginosa eradication regimens in bronchiectasis. Eur Respir J. 2017 Apr 12;49(4):1600851. doi: 10.1183/13993003.00851-2016. Print 2017 Apr. No abstract available.
citation: Blanco-Aparicio M, Saleta Canosa JL, Valino Lopez P, Martin Egana MT, Vidal Garcia I, Montero Martinez C. Eradication of Pseudomonas aeruginosa with inhaled colistin in adults with non-cystic fibrosis bronchiectasis. Chron Respir Dis. 2019 Jan-Dec;16:1479973119872513. doi: 10.1177/1479973119872513.
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: Pieters A, Bakker M, Hoek RAS, Altenburg J, van Westreenen M, Aerts JGJV, van der Eerden MM. The clinical impact of Pseudomonas aeruginosa eradication in bronchiectasis in a Dutch referral centre. Eur Respir J. 2019 Apr 11;53(4):1802081. doi: 10.1183/13993003.02081-2018. Print 2019 Apr. No abstract available.