Combined Dry Powder Tobramycin and Nebulized Colistin Inhalation in CF Patients

Cystic Fibrosis With Pulmonary Manifestations Clinical Trial

— CotoCFII  

Official title:

Combined Dry Powder Tobramycin and Nebulized Colistin Inhalation in CF Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03341741
• Other study ID #: Coto V3.0
• Status: Completed
• Phase: Phase 3
• First received: November 3, 2017
• Last updated: November 8, 2017
• Start date: March 11, 2014
• Est. completion date: November 25, 2016

Study information

• Verified date: October 2017
• Source: University Hospital Tuebingen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To assess whether the inhalative combination of Tobramycin/Colistin is more effective in reducing Pseudomonas colony forming units (CFUs) and improvement of lung function than Colistin in mono-therapy.

Description:

Cystic fibrosis (CF), the most common autosomal recessive disorder in Western countries, is caused by mutations of the cystic fibrosis transmembrane conductance regulator molecule (CFTR) and affects approximately 40.000 patients in Europe. The majority of CF patients develop chronic pulmonary infections with Pseudomonas aeruginosa. These are normally treated with single antibiotics, administered orally, intravenously or inhalatively. Once the infection becomes chronic, eradication of the pathogen is not any more possible due to biofilm formation of the pathogen and increasing resistance. However, inhalative antibiotic combination therapy might be more efficient than single antibiotic therapy in chronically infected CF patients. This notion is supported by previous in vitro and animal studies using Tobramycin/Colistin combination therapy. Importantly, a pilot study in five CF patients who inhaled consecutively Colistin and Tobramycin solutions for 4 week, revealed a decrease of log10 2.52 ± 2.5 cfu of P. aeruginosa in sputum specimens during the course of the treatment compared to baseline values (p=0.027). The treatment was shown to be safe and well tolerated. However, forced expiratory volume in 1 sec (FEV1) did not differ significantly.

Taking advantage of the new development of dry powder inhalation (DPI) antibiotics, specifically TOBI© Podhaler, a larger randomised trial has been performed in which the combined TOBI© Podhaler and Colistin treatment is compared to the monotherapy with Colistin.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: November 25, 2016
• Est. primary completion date: December 19, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

1. Cystic Fibrosis is verified;

2. Patient is 12 years or older;

3. FEV1 is higher than 25% and lower than 100%;

4. The patients' lung is colonised with P. aeruginosa chronically (=6 months);

5. P. aeruginosa must be sensitive for Tobramycin or Colistin;

6. Pretreated with Colistin >2 months;

7. Last i.v. antibiotic treatment =2 weeks;

8. Informed consent is given by patients/legal representatives

Exclusion Criteria:

1. Clinical deterioration is present (exacerbation symptoms);

2. Last Tobramycin inhalation treatment = 2 weeks;

3. Renal dysfunction (creatinine <1.5 fold of normal, glomerular filtration rate (GFR) <80%) at baseline

4. auditoria or vestibular dysfunction, hearing loss

5. Intolerances against Tobramycin, Colistin or Polymyxin B

6. Myasthenia gravis

7. Porphyria

8. Pregnancy and nursing

Related Conditions & MeSH terms

• Cystic Fibrosis
• Cystic Fibrosis With Pulmonary Manifestations

Intervention

Drug:
• Tobramycin Powder
TOBI®Podhaler 2 x 112 mg daily for 2 x 28 days (on/off);
• Colistin
Colistin solution 2 x daily 1 Mega continuously

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Tuebingen

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Amount of P. aeruginosa in sputum	The primary endpoint will be the difference of P. aeruginosa cfu/ml in sputum with combined therapy with Tobramycin/Colistin compared to colistin mono-therapy. The analysis will be adjusted for baseline values of each cycle and parametric (paired t-Test) or non-parametric (sign test) methods will be used as appropriate.	30 days
Secondary	Course of P.aeruginosa amount in sputum	Course of P. aeruginosa in sputum measured as cfu/ml during the study	112 days
Secondary	Course of forced vital capacity (FVC) absolute amount	Course of FVC absolute in litres during the study	112 days
Secondary	Course of FVC relative amount	Course of FVC relative (percent of expected amount for given body height and gender) during the study	112 days
Secondary	Course of FEV1 absolute amount	Course of FEV1 absolute in litres during the study	112 days
Secondary	Course of FEV1 relative amount	Course of FEV1 relative (percent of expected amount for given body height and gender) during the study	112 days
Secondary	Course of MEF25-75 absolute amount	Course of MEF25-75 absolute in litres during the study	112 days
Secondary	Course of MEF25-75 relative amount	Course of MEF25-75 relative (percent of expected amount for given body height and gender) during the study	112 days
Secondary	Course of proinflammatory cytokine IL1ß amount	Course of proinflammatory cytokine IL1ß amount in sputum [pg/ml] during the study	112 days
Secondary	Course of proinflammatory cytokine IL6 amount	Course of proinflammatory cytokine IL6 amount in sputum [pg/ml] during the study	112 days
Secondary	Course of proinflammatory cytokine IL8 amount	Course of proinflammatory cytokine IL8 amount in sputum [pg/ml] during the study	112 days
Secondary	Course of antiinflammatory cytokine IL10 amount	Course of antiinflammatory cytokine IL10 amount in sputum [pg/ml] during the study	112 days
Secondary	Course of proinflammatory cytokine TNFa amount	Course of proinflammatory cytokine TNFa amount in sputum [pg/ml] during the study	112 days
Secondary	Course of proinflammatory cytokine GM-CSF amount	Course of proinflammatory cytokine GM-CSF amount in sputum [pg/ml] during the study	112 days
Secondary	Course of DNA amount in sputum	Course of DNA amount {pg/ml] in sputum during the study	112 days
Secondary	Course of leukocyte amount in sputum	Course of leukocyte amount [pg/ml] in sputum during the study	112 days
Secondary	Exacerbation	Number of exacerbations during the study	112 days
Secondary	Antibiotics	Use of antibiotics during the study	112 days