Anti-Inflammatory Pulmonal Therapy of CF-Patients With Amitriptyline and Placebo

Cystic Fibrosis Clinical Trial

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 -

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00515229
• Other study ID #: APA-II
• Status: Completed
• Phase: Phase 2
• First received: August 9, 2007
• Last updated: August 10, 2007
• Start date: October 2006
• Est. completion date: July 2007

Study information

• Verified date: August 2007
• Source: University Hospital Tuebingen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: July 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cystic Fibrosis
• Infection
• Pseudomonas Aeruginosa
• Pseudomonas Infections

Intervention

Drug:
• amitriptyline
Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch

Locations

Country	Name	City	State
Germany	University of Tuebingen	Tuebingen	Baden-Wuerttemberg

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Tuebingen

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Increase in lung function, especially the FEV1 increase		5 months
Secondary	Increase of CO-Diffusion		5 months
Secondary	Pulmonary Ceramide expression		5 months
Secondary	Decrease of cytokine-concentrations		5 months
Secondary	Decrease of leukocytes (sputum)		5 months
Secondary	Decrease of Pseudomonas		5 months
Secondary	Infection parameters in serum		5 months
Secondary	Exacerbations		5 months