Clinical trial NCT03341741: Combined Dry Powder Tobramycin and Nebulized Colistin Inhalation in CF Patients
Official title: Combined Dry Powder Tobramycin and Nebulized Colistin Inhalation in CF Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cystic Fibrosis With Pulmonary Manifestations
Keywords: chronic pulmonary infection
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
First posted: 2017-11-14
Enrollment: 26
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized, open label clinical study
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Amount of P. aeruginosa in sputum
timeFrame: 30 days
Secondary outcomes:
measure: Course of P.aeruginosa amount in sputum
timeFrame: 112 days
measure: Course of forced vital capacity (FVC) absolute amount
timeFrame: 112 days
measure: Course of FVC relative amount
timeFrame: 112 days
measure: Course of FEV1 absolute amount
timeFrame: 112 days
measure: Course of FEV1 relative amount
timeFrame: 112 days
measure: Course of MEF25-75 absolute amount
timeFrame: 112 days
measure: Course of MEF25-75 relative amount
timeFrame: 112 days
measure: Course of proinflammatory cytokine IL1ß amount
timeFrame: 112 days
measure: Course of proinflammatory cytokine IL6 amount
timeFrame: 112 days
measure: Course of proinflammatory cytokine IL8 amount
timeFrame: 112 days
measure: Course of antiinflammatory cytokine IL10 amount
timeFrame: 112 days
measure: Course of proinflammatory cytokine TNFa amount
timeFrame: 112 days
measure: Course of proinflammatory cytokine GM-CSF amount
timeFrame: 112 days
measure: Course of DNA amount in sputum
timeFrame: 112 days
measure: Course of leukocyte amount in sputum
timeFrame: 112 days
measure: Exacerbation
timeFrame: 112 days
measure: Antibiotics
timeFrame: 112 days
Other outcomes:
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