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

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ClinicalTrials.gov Identifier: NCT03341741
Recruitment Status : Completed
First Posted : November 14, 2017
Last Update Posted : November 14, 2017
Sponsor:
Information provided by (Responsible Party):
University Hospital Tuebingen

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: randomized, 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 : March 11, 2014
Actual Primary Completion Date : December 19, 2015
Actual Study Completion Date : November 25, 2016


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 Name: TOBI®Podhaler

Drug: Colistin
Colistin solution 2 x daily 1 Mega continuously
Other Name: 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 Name: Colistin solution




Primary Outcome Measures :
  1. Amount of P. aeruginosa in sputum [ Time Frame: 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 [ Time Frame: 112 days ]
    Course of P. aeruginosa in sputum measured as cfu/ml during the study

  2. Course of forced vital capacity (FVC) absolute amount [ Time Frame: 112 days ]
    Course of FVC absolute in litres during the study

  3. Course of FVC relative amount [ Time Frame: 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 [ Time Frame: 112 days ]
    Course of FEV1 absolute in litres during the study

  5. Course of FEV1 relative amount [ Time Frame: 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 [ Time Frame: 112 days ]
    Course of MEF25-75 absolute in litres during the study

  7. Course of MEF25-75 relative amount [ Time Frame: 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 [ Time Frame: 112 days ]
    Course of proinflammatory cytokine IL1ß amount in sputum [pg/ml] during the study

  9. Course of proinflammatory cytokine IL6 amount [ Time Frame: 112 days ]
    Course of proinflammatory cytokine IL6 amount in sputum [pg/ml] during the study

  10. Course of proinflammatory cytokine IL8 amount [ Time Frame: 112 days ]
    Course of proinflammatory cytokine IL8 amount in sputum [pg/ml] during the study

  11. Course of antiinflammatory cytokine IL10 amount [ Time Frame: 112 days ]
    Course of antiinflammatory cytokine IL10 amount in sputum [pg/ml] during the study

  12. Course of proinflammatory cytokine TNFa amount [ Time Frame: 112 days ]
    Course of proinflammatory cytokine TNFa amount in sputum [pg/ml] during the study

  13. Course of proinflammatory cytokine GM-CSF amount [ Time Frame: 112 days ]
    Course of proinflammatory cytokine GM-CSF amount in sputum [pg/ml] during the study

  14. Course of DNA amount in sputum [ Time Frame: 112 days ]
    Course of DNA amount {pg/ml] in sputum during the study

  15. Course of leukocyte amount in sputum [ Time Frame: 112 days ]
    Course of leukocyte amount [pg/ml] in sputum during the study

  16. Exacerbation [ Time Frame: 112 days ]
    Number of exacerbations during the study

  17. Antibiotics [ Time Frame: 112 days ]
    Use of antibiotics during the study



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
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Responsible Party: University Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT03341741    
Other Study ID Numbers: Coto V3.0
First Posted: November 14, 2017    Key Record Dates
Last Update Posted: November 14, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Cystic Fibrosis
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Tobramycin
Colistin
Anti-Bacterial Agents
Anti-Infective Agents