Clinical trial NCT00515229: Anti-Inflammatory Pulmonal Therapy of CF-Patients With Amitriptyline and Placebo
Official title: Protocol for a Phase II-Study Anti-Inflammatory Pulmonal Therapy of CF-Patients With Amitriptyline and Placebo - Randomised, Double-Blinded, Placebo-Controlled, Cross Over - Study -
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cystic Fibrosis
Infection
Pseudomonas Aeruginosa
Keywords: cystic fibrosis
ceramide
amitriptyline
Pseudomonas aeruginosa
lung function
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
First posted: 2007-08-13
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Our data indicate that the CFTR-molecule functions as a transporter for sphingosine-1-phosphate and sphingosine or regulates the uptake of these sphingolipids by epithelial cells. The disturbed uptake of sphingosine and sphingosine-1-phosphate over the cell membrane results in an accumulation of ceramide in the cell membrane, which finally triggers a pro-inflammatory and pro-apoptotic status in the respiratory tract of cystic fibrosis patients. Amitriptyline reduces the cera-mide levels in the lung tissue, normalises the activity of cytokines and prevents constitutive cell death of epithelial cells observed in CFTR-deficient mice. Most important, amitriptyline prevents pulmonary infections of CFTR-deficient mice with P. aeruginosa. These effects of amitriptyline may result in an improved lung function of cystic fibrosis patients.

Detailed description: Cystic fibrosis (CF), the most common autosomal recessive disorder at least in western countries, is caused by mutations of the cystic fibrosis transmembrane conductance regulator molecule (CFTR) and affects approximately 40 000 patients in Europe. Most, if not all, CF-patients develop a chronic pulmonary infection with Pseudomonas aeruginosa (P. aeruginosa). At present it is un-known why CF-patients are highly sensitive to P. aeruginosa infections and, most important, no curative treatment for cystic fibrosis is available.

Our data on CFTR-deficient mice demonstrate that the CFTR-molecule does not only function as a chloride-channel, but also as a transporter for sphingolipids, in particular sphingosine and sphingosine-1-phosphate. Deficiency of functional CFTR in CFTR-knock-out mice results in an alteration of the sphingolipid metabolism in pulmonary epithelial cells and an accumulation of cellular ceramide in these cells.

Inhibition of ceramide release in the lung was achieved by pharmacological and genetic inhibition of the acid sphingomyelinase (ASM) that generates ceramide from sphingomyelin. Amitriptyline was employed to pharmacologically block the ASM genetic inhibition of the ASM was achieved by crossing CFTR- and ASM-deficient mice. Although the ASM is not affected in cystic fibrosis, an inhibition of the enzyme should block the formation of ceramide and, thus, normalize the increase of pulmonary ceramide caused by CFTR-deficiency.

Eligibility criteria: Inclusion Criteria:

1. Cystic Fibrosis is proved
2. The patient are older than 18 years (\<50 years)
3. No sec discrimination
4. The patient is pulmonal colonized with bacteria
5. Signs of pulmonary exacerbation are not present
6. A full course of therapy is possible without any restrictions
7. Lung function measurement is possible

Exclusion Criteria:

1. Poor metabolizer for amitriptyline (CYP2D6 genotyping)
2. Glaucoma, seizures, heart insufficiency or depression is present
3. Signs of acute pulmonary illness (bronchial or tracheal stenosis, tuberculosis, thorax trauma, acute pneumonia, pneumothorax, bronchial haemorrhage, ARDS) are present
4. intravenous antibiotic treatment was necessary in the last 4 weeks
5. Involvement of the patient in another study
6. Pregnancy

Primary outcomes:
measure: Increase in lung function, especially the FEV1 increase
timeFrame: 5 months
Secondary outcomes:
measure: Increase of CO-Diffusion
timeFrame: 5 months
measure: Pulmonary Ceramide expression
timeFrame: 5 months
measure: Decrease of cytokine-concentrations
timeFrame: 5 months
measure: Decrease of leukocytes (sputum)
timeFrame: 5 months
measure: Decrease of Pseudomonas
timeFrame: 5 months
measure: Infection parameters in serum
timeFrame: 5 months
measure: Exacerbations
timeFrame: 5 months
Other outcomes:
Locations:
city: Tuebingen
country: Germany
facility: University of Tuebingen
state: Baden-Wuerttemberg
Study officials:
affiliation: University of Tuebingen, Paediatric Department
name: Joachim Reithmueller, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Becker KA, Riethmuller J, Luth A, Doring G, Kleuser B, Gulbins E. Acid sphingomyelinase inhibitors normalize pulmonary ceramide and inflammation in cystic fibrosis. Am J Respir Cell Mol Biol. 2010 Jun;42(6):716-24. doi: 10.1165/rcmb.2009-0174OC. Epub 2009 Jul 27.