Anti-inflammatory Pulmonal Therapy of Cystic Fibrosis (CF) Patients With Amitriptyline and Placebo

Summary

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).

Conditions

• Cystic Fibrosis
• Pneumonia

Interventions

DRUG

Amitriptyline

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.

DRUG

Mannite

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

Sponsors & Collaborators

• Universität Duisburg-Essen

  collaborator OTHER

• University of Ulm

  collaborator OTHER

• University Children's Hospital Tuebingen

  lead OTHER

Principal Investigators

• Joachim Riethmueller, Dr · University Children´s Hospital Tubeingen, Germany

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

14 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2009-05-31

Primary Completion

2011-05-31

Completion

2011-05-31

Countries

• Germany

Study Locations