CotoCFII: Combined Dry Powder Tobramycin and Nebulized Colistin Inhalation in CF Patients

• Sponsor: University Hospital Tuebingen (Other)
• Overall Status: Completed
• CT.gov ID: NCT03341741
• Collaborator: (none)
• Enrollment: 26
• Arms: 2
• Actual Duration (Months): 32.5

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis With Pulmonary Manifestations	Drug: Tobramycin Powder; Drug: Colistin	Phase 3

Detailed 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: randomized, open label clinical studyrandomized, open label clinical study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Combined Dry Powder Tobramycin and Nebulized Colistin Inhalation in CF Patients
• Actual Study Start Date: Mar 11, 2014
• Actual Primary Completion Date: Dec 19, 2015
• Actual Study Completion Date: Nov 25, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tobramycin powder / Colistin TOBI®Podhaler 2 x 112 mg daily for 2 x 28 days (on/off); and Colistin solution 2 x daily 1 Mega continuously for 112 days	Drug: Tobramycin Powder; TOBI®Podhaler 2 x 112 mg daily for 2 x 28 days (on/off); Other Names: TOBI®Podhaler ; Drug: Colistin; Colistin solution 2 x daily 1 Mega continuously; Other Names: Colistin solution
Active Comparator: Colistin Colistin solution 2 x daily 1 Mega continuously for at least 30 days	Drug: Colistin; Colistin solution 2 x daily 1 Mega continuously; Other Names: Colistin solution

Outcome Measures

Primary Outcome Measures

1. Amount of P. aeruginosa in sputum [30 days]

   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.

Secondary Outcome Measures

1. Course of P.aeruginosa amount in sputum [112 days]

   Course of P. aeruginosa in sputum measured as cfu/ml during the study

2. Course of forced vital capacity (FVC) absolute amount [112 days]

   Course of FVC absolute in litres during the study

3. Course of FVC relative amount [112 days]

   Course of FVC relative (percent of expected amount for given body height and gender) during the study

4. Course of FEV1 absolute amount [112 days]

   Course of FEV1 absolute in litres during the study

5. Course of FEV1 relative amount [112 days]

   Course of FEV1 relative (percent of expected amount for given body height and gender) during the study

6. Course of MEF25-75 absolute amount [112 days]

   Course of MEF25-75 absolute in litres during the study

7. Course of MEF25-75 relative amount [112 days]

   Course of MEF25-75 relative (percent of expected amount for given body height and gender) during the study

8. Course of proinflammatory cytokine IL1ß amount [112 days]

   Course of proinflammatory cytokine IL1ß amount in sputum [pg/ml] during the study

9. Course of proinflammatory cytokine IL6 amount [112 days]

   Course of proinflammatory cytokine IL6 amount in sputum [pg/ml] during the study

10. Course of proinflammatory cytokine IL8 amount [112 days]

    Course of proinflammatory cytokine IL8 amount in sputum [pg/ml] during the study

11. Course of antiinflammatory cytokine IL10 amount [112 days]

    Course of antiinflammatory cytokine IL10 amount in sputum [pg/ml] during the study

12. Course of proinflammatory cytokine TNFa amount [112 days]

    Course of proinflammatory cytokine TNFa amount in sputum [pg/ml] during the study

13. Course of proinflammatory cytokine GM-CSF amount [112 days]

    Course of proinflammatory cytokine GM-CSF amount in sputum [pg/ml] during the study

14. Course of DNA amount in sputum [112 days]

    Course of DNA amount {pg/ml] in sputum during the study

15. Course of leukocyte amount in sputum [112 days]

    Course of leukocyte amount [pg/ml] in sputum during the study

16. Exacerbation [112 days]

    Number of exacerbations during the study

17. Antibiotics [112 days]

    Use of antibiotics during the study

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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. 1. 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• University Hospital Tuebingen

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University Hospital Tuebingen
• ClinicalTrials.gov Identifier: NCT03341741
• Other Study ID Numbers: Coto V3.0
• First Posted: Nov 14, 2017
• Last Update Posted: Nov 14, 2017
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University Hospital Tuebingen: chronic pulmonary infection
• Additional relevant MeSH terms: Cystic Fibrosis; Tobramycin; Colistin

Study Results

No Results Posted as of Nov 14, 2017