Tobramycin Inhalation Solution for Pseudomonas Aeruginosa Eradication in Bronchiectasis

Bronchiectasis Adult Clinical Trial

— ERASE  

Official title:

Efficacy and Safety of tobRamycin Inhalation Solution for Pseudomonas AeruginoSa Eradication in Bronchiectasis (ERASE): Study Protocol for a Multi-center, 2×2 Factorial Randomized, Double-blind, Placebo-controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06093191
• Other study ID #: 20230329
• Status: Recruiting
• Phase: Phase 4
• Start date: September 25, 2023
• Est. completion date: December 30, 2025

Study information

• Verified date: April 2024
• Source: Shanghai Pulmonary Hospital, Shanghai, China
• Contact: Jin-Fu Xu, PhD
• Phone: +8613321922898
• Email: jfxucn[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 364
• Est. completion date: December 30, 2025
• Est. primary completion date: May 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Bronchiectasis
• Bronchiectasis Adult
• Pseudomonas Aeruginosa Infection
• Pseudomonas Infections

Intervention

Drug:
• Tobramycin Inhalant Product
Tobramycin will be nebulized (300mg twice daily) with an ultrasonic nebulizer. A total of 12 weeks therapy will be scheduled.
• Ciprofloxacin 750 MG
Oral ciprofloxacin 750mg twice daily will be prescribed for 2 weeks.
• Oral ciprofloxacin placebo
Oral ciprofloxacin placebo twice daily will be prescribed for 2 weeks.
• Natural saline inhalation
Natural saline will be nebulized (5ml twice daily) with an ultrasonic nebulizer. A total of 12 weeks therapy will be scheduled.

Locations

Country	Name	City	State
China	The First People's Hospital of Anning City Affiliated to Kunming University of Science and Technology	Anning
China	Beijing Chao-Yang Hospital, Capital Medical University	Beijing
China	Peking Union Medical College Hospital, Chinese Academy of Medical Sciences	Beijing
China	Peking University Third Hospital	Beijing
China	The First Affiliated Hospital of Jilin University	Changchun
China	The Second Xiangya Hospital of Central South University	Changsha
China	Xiangya Hospital, Central South University	Changsha
China	West China Hospital of Sichuan University	Chengdu
China	The Second Affiliated Hospital of Chongqing Medical University	Chongqing
China	The Third Affiliated Hospital of Chongqing Medical University	Chongqing
China	The Second Affiliated Hospital of Dalian Medical University	Dalian
China	Fujian Provincial Hospital	Fuzhou
China	The First Affiliated Hospital of Guangzhou Medical University	Guangzhou
China	The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine	Guangzhou
China	Guizhou Provincial People's Hospital	Guiyang
China	The Affiliated Hospital of Hangzhou Normal University	Hangzhou	Zhejiang
China	The Second Affiliated Hospital of Zhengjiang University	Hangzhou
China	Anhui Chest Hospital	Hefei
China	The First Affiliated Hospital of Anhui Medical University	Hefei
China	Huzhou Central Hospital	Huzhou
China	The First Hospital of Jiaxing City	Jiaxing
China	The Second Hospital of Jiaxing City	Jiaxing
China	Qilu Hospital of Shandong University	Jinan	Shangdong
China	The First Affiliated Hospital of Shandong First Medical University	Jinan
China	The First Affiliated Hospital of Wenzhou Medical University	Jinan
China	The First Affiliated Hospital of Nanchang University	Nanchang
China	The Affiliated Sir Run Run Hospital of Nanjing Medical University	Nanjing
China	The Second Affiliated Hospital of Nanjing Medical University	Nanjing
China	The First Affiliated Hospital of Guangxi Medical University	Nanning
China	Affiliated Hospital, Nantong University	Nantong
China	The Sixth People's Hospital of Nantong City	Nantong
China	Fenghua District People's Hospital of Ningbo City	Ningbo
China	Ningbo Medical Center Lihuili Hospital	Ningbo
China	The First Affiliated Hospital of Ningbo University	Ningbo
China	Qingdao Municipal Hospital	Qingdao
China	Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine	Shanghai
China	Ruijin Hospital	Shanghai	Shanghai
China	Shanghai Eighth People's Hospital	Shanghai
China	Shanghai General Hospital	Shanghai
China	Shanghai pulmonary hospital	Shanghai	Shanghai
China	Shanghai Putuo District People's Hospital	Shanghai
China	Shanghai Shidong Hospital of Yangpu District	Shanghai
China	Shanghai Sixth People's Hospital	Shanghai
China	Shanghai Songjiang District Central Hospital	Shanghai
China	Shanghai Yangpu District Central Hospital	Shanghai
China	The Shanghai Fifth People's Hospital	Shanghai	Shanghai
China	Zhongshan Hospital, Fudan University	Shanghai
China	Shangrao People's Hospital	Shangrao
China	Shengjing Hospital of China Medical University	Shenyang
China	The First Affiliated Hospital of China Medical University	Shenyang
China	Shenzhen Institute of Respiratory Diseases	Shenzhen
China	The Eighth Affiliated Hospital of Sun Yat-Sen University	Shenzhen
China	Suzhou Science and Technology Town Hospital	Suzhou
China	The First Affiliated Hospital of Soochow University	Suzhou
China	Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology	Wuhan
China	Union Hospital,Tongji Medical College, Huazhong University of Science and Technology	Wuhan
China	Subei People's Hospital	Yangzhou
China	Affiliated Hospital, Guangdong Medical College	Zhanjiang
China	Henan Provincial People's Hospital	Zhengzhou
China	Zhengzhou People's Hospital	Zhengzhou

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Pulmonary Hospital, Shanghai, China

Country where clinical trial is conducted

China, 

References & Publications (8)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

White L, Mirrani G, Grover M, Rollason J, Malin A, Suntharalingam J. Outcomes of Pseudomonas eradication therapy in patients with non-cystic fibrosis bronchiectasis. Respir Med. 2012 Mar;106(3):356-60. doi: 10.1016/j.rmed.2011.11.018. Epub 2011 Dec 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	The proportion of patients with negative PA from sputum samples, either spontaneous or induced, in each group by the end of the study, at both 24 and 36 weeks post-randomization	36 weeks
Secondary	The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 12 weeks after randomization	The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 12 weeks after randomization	12 weeks
Secondary	The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 24 weeks after randomization	The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 24 weeks after randomization	24 weeks
Secondary	The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 36 weeks after randomization	The proportion of patients in each group who have a negative Pseudomonas aeruginosa (PA) culture 36 weeks after randomization	36 weeks
Secondary	Time to the first bronchiectasis exacerbation since randomization	Time to the first bronchiectasis exacerbation since randomization	36 weeks
Secondary	Frequency of bronchiectasis exacerbation since randomization	Frequency of bronchiectasis exacerbation since randomization	36 weeks
Secondary	Frequency of bronchiectasis exacerbation since randomization	Frequency of bronchiectasis exacerbation since randomization	12 weeks
Secondary	Frequency of hospitalization due to bronchiectasis exacerbation since randomization	Frequency of hospitalization due to bronchiectasis exacerbation since randomization	36 weeks
Secondary	Frequency of hospitalization due to bronchiectasis exacerbation since randomization	Frequency of hospitalization due to bronchiectasis exacerbation since randomization	12 weeks
Secondary	Time to reoccurrence of P. aeruginosa infection since randomization	Time to reoccurrence of P. aeruginosa infection since randomization	36 weeks
Secondary	Quality-of-Life-Bronchiectasis Respiratory Symptom Scale, that measures health-related quality of life	The Quality-of-Life-Bronchiectasis (QoL-B) questionnaire is a disease-specific survey designed for patients with bronchiectasis. The Respiratory Symptoms scale is a component of the QoL-B questionnaire, with a scale range from 0 to 100. Higher scores on this scale signify a better health status.	Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
Secondary	St.George Respiratory Questionnaire, that measures health-related quality of life	St.George Respiratory Questionnaire (SGRQ): a validated questionnaire for use in bronchiectasis population. This questionnaire is structured into 3 main components: symptoms, activity and impacts.; Scale range is 0-100, where lower scores correspond to the better health status.; Each questionnaire response has a unique empirically derived "weight".; Each component of the questionnaire is scored separately in three steps: i. The weights for all items with a positive responses are summed. ii. The weights for missed items are deducted from the maximum possible weight for each component. The weights for all missed items are deducted from the maximum possible weight for the Total score.; iii. The score is calculated by dividing the summed weights by the adjusted maximum possible weight for that component and expressing the result as a percentage The Total score is calculated in similar way.	Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
Secondary	Euroqual-5 Dimensions questionnaire	The Euroqual-5 Dimensions questionnaire (EQ-5D) consists of two parts: health state description and evaluation. In the description part, health status is measured across five dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Respondents rate their severity level for each dimension using a five-level (EQ-5D-5L) scale.; In the evaluation part, respondents assess their overall health status using the visual analogue scale (EQ-VAS), which ranges from 0 to 100, with higher scores indicating a better health status.; Health states defined by the EQ-5D-5L descriptive system are converted into index values. This facilitates the calculation of Quality-Adjusted Life Years (QALYs), which are used to inform economic evaluations of healthcare interventions, according to guidelines found at https://euroqol.org.	Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
Secondary	Changes in forced expiratory volume in 1 second [FEV1] at 12, 24, and 36 weeks compared with baseline	Changes in forced expiratory volume in 1 second [FEV1] at 12, 24, and 36 weeks compared with baseline	Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
Secondary	Changes in forced vital capacity [FVC] at 12, 24, and 36 weeks compared with baseline	Changes in forced vital capacity [FVC] at 12, 24, and 36 weeks compared with baseline	Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
Secondary	Changes in forced expiratory flow at 25-75% of forced vital capacity at 12, 24, and 36 weeks compared with baseline	Changes in forced expiratory flow at 25-75% of forced vital capacity at 12, 24, and 36 weeks compared with baseline	Assessed at baseline, 12 weeks, 24 weeks and 36 weeks post-randomization.
Secondary	The cost of hospitalization	The cost of hospitalization during the whole study period	36 weeks
Secondary	Other sputum microbiology during the whole study period.	Sputum cultures were conducted at baseline, 2 weeks, 8 weeks, 12 weeks, 24 weeks, and 36 weeks. Other sputum microbiology, including Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Burkholderia cepacia complex, Stenotrophomonas, Aspergillus, and Candida spp. were documented throughout the entire study period. The number of participants who yielded at least one positive culture for these microorganisms was calculated.	36 weeks
Secondary	Resistant P. aeruginosa during the whole study period	Sputum cultures were performed at intervals of 2 weeks, 8 weeks, 12 weeks, 24 weeks, and 36 weeks. Drug sensitivity testing was conducted to assess the resistance of the current P. aeruginosa sample to antibiotics such as ciprofloxacin and tobramycin. The number of participants who showed growth of Pseudomonas aeruginosa resistant to ciprofloxacin and/or tobramycin was calculated.	36 weeks
Secondary	Number of adverse events	Reported by the PI or designee via interview with patients.	36 weeks