Anti-inflammatory Pulmonal Therapy of Cystic Fibrosis (CF) Patients With Amitriptyline and Placebo (APA-IIb)
Recruitment status was: Recruiting
Cystic fibrosis patients suffer from a chronic destruction of the lung, frequent and finally chronic pneumonia and a reduced life expectancy. Unfortunately, no curative treatment for cystic fibrosis is available, neither are treatments established that prevent the disease. Our data identify ceramide as a potential novel target to treat cystic fibrosis.
Two smaller trials support the notion that inhibition of the acid sphingomyelinase by amitriptyline improves the lung function of CF-patients even at a dose that is low enough to avoid adverse effects.
In the present proposal the investigators, therefore, aim to test in a larger cystic fibrosis patient population whether an inhibition of ceramide release in the lung caused by the lack of functional CFTR improves the lung function of cystic fibrosis patients. Inhibition of ceramide-release in the lung will be achieved by treatment with amitriptyline, which is used as an anti-depressant drug for almost 50 years. Although it is not absolutely specific, it seems to be relatively specific for the degradation of acid sphingomyelinase (typically 60-80% of cellular acid sphingomyelinase are degraded), which releases ceramide from sphingomyelin.
If the data confirm the beneficial effect of amitriptyline already observed in our preliminary studies, the present clinical study may establish a novel treatment to improve clinical symptoms of cystic fibrosis and, moreover, to prevent or at least delay the onset of cystic fibrosis.
- Amitriptyline reduces ceramide concentrations in respiratory epithelial cells (measured in nasal epithelial cells obtained by brushing nasal mucosa).
- Amitriptyline treatment reduces cell death in bronchi and deposition of DNA on the respiratory epithelium, which permits elimination of P. aeruginosa from the lung (measured as P. aeruginosa counts in tracheal fluid).
- Amitriptyline treatment results in normalization of the function of leukocytes (number determined in serum and tracheal fluid)
- Amitriptyline reduces systemic and local inflammation (measured as cytokines in plasma and tracheal fluid).
Based on these effects amitriptyline increases the lung function of cystic fibrosis patients (measured by FEV1).
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Anti-inflammatory Pulmonal Therapy of CF Patients With Amitriptyline and Placebo - a Randomised, Double-blind, Placebo-controlled, Multicenter, Cohort - Study|
- Improvement of the lung function parameter FEV1 (absolute and relative to baseline) under verum and placebo [ Time Frame: in 4 weeks ] [ Designated as safety issue: No ]The primary aim is the change of the lung function parameter Forced Expiratory Volume in 1 second (FEV1) relative to baseline under verum and placebo
- Increase in lung function measurements [ Time Frame: in 2 and 4 weeks ] [ Designated as safety issue: No ]Increase (absolute and relative to baseline) in lung function (FVC, FEV1, MEF 25, LCI, CO-Diffusion) in 2 and 4 weeks
- Ceramide concentration in epithelial cells [ Time Frame: in 4 weeks ] [ Designated as safety issue: No ]Decrease of Ceramide concentration in epithelial cells detected in sputum
- Inflammation status [ Time Frame: in 4 weeks ] [ Designated as safety issue: No ]Reduction of IL-8 (facultatively IL-1ß, IL-6, IL-8, TNFα) as well as an increase of anti-inflammatory IL-10 in tracheal mucus
- Bacteriological and cell status [ Time Frame: in 4 weeks ] [ Designated as safety issue: No ]Reduction of the DNA-content and granulocyte concentration and decrease of chronic bacterial colonization (P. aerug., S. aureus, etc.) in tracheal mucus.
- Side effects [ Time Frame: in 4 weeks ] [ Designated as safety issue: Yes ]Number of upper and lower respiratory tract infections pulmonary exacerbations)
|Study Start Date:||May 2009|
|Estimated Study Completion Date:||May 2011|
|Estimated Primary Completion Date:||May 2011 (Final data collection date for primary outcome measure)|
Active Comparator: Amitriptyline
After the experience with the treatment of 18 CF-patients phase IIa study), the medication will be therefore 25 mg daily in two doses (2 x 12,5 mg). Because of a higher rate of side effects (tiredness, dry mucous membrane) the higher dose of 50 mg (2 x 25 mg) is not chosen first, but will be adapted after 2 weeks of treatment.
2 x 12,5 mg capsules for oral use in the first two weeks, the higher dose of 50 mg (2 x 25 mg) will be adapted after 2 weeks of treatment.
Other Name: Amitriptylinhydrochlorid
Placebo Comparator: Mannite
The placebo will be given 25 mg daily in two doses (2 x 12,5 mg). After 2 weeks of treatment the higher dose of 50 mg (2 x 25 mg) will be given
Mannit capsules daily in two doses (2 x 12,5 mg). After 2 weeks of treatment the higher dose of 50 mg (2 x 25 mg) will be given
Other Name: Mannite Ph. Eur.
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01309178
|Giessen, Germany, 35385|
|Jena, Germany, 07740|
|Tuebingen, Germany, 72076|
|Study Director:||Joachim Riethmueller, Dr||University Children´s Hospital Tubeingen, Germany|