Cystic Fibrosis | Anti-inflammatory Pulmonal Therapy of Cystic Fibrosis (CF) Patients With Amitriptyline and Placebo
Cystic Fibrosis research study
What is the primary objective of this study?
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. Hypothesis - 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).
Who is eligible to participate?
Inclusion Criteria: - Cystic Fibrosis is verified - Patient is older than 14 years - Patients weight is more than 35 kg - FEV1 is higher than 30% and lower than 90% - The patient is pulmonal colonized with bacteria - No acute pulmonal illness is present - CRP is not elevated two fold (2 mg/dl) of normal - Lung function testing is possible - A full course of therapy is possible without any restrictions Exclusion Criteria: - FEV1 in baseline differs more than 10% from screening visit - CRP in baseline differs more than 50% from screening visit - Glaucoma, seizures, heart insufficiency or major depression are present - Intravenous antibiotic treatment was necessary in the last 4 weeks before visit 2 - High dose steroid therapy - On-off-therapy of tobramycin in the last 2 weeks - Involvement of the patient in another study - Pregnancy and - Nursing mothers
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:Amitriptyline2 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.
Drug:ManniteMannit 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
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
AmitriptylineAfter 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.
ManniteThe 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
Start Date: May 2009
Completed Date: May 2011
Phase: Phase 2
Primary Outcome: Improvement of the lung function parameter FEV1 (absolute and relative to baseline) under verum and placebo
Secondary Outcome: Increase in lung function measurements
Study sponsors, principal investigator, and references
Principal Investigator: Joachim Riethmueller, Dr
Lead Sponsor: University Children’s Hospital Tuebingen
Collaborator: Universität Duisburg-Essen