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

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 -

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis; Infection; Pseudomonas Aeruginosa
• Intervention / Treatment: Drug: amitriptyline

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Baden-Wuerttemberg
    • Tuebingen, Baden-Wuerttemberg, Germany, 72076
      • University of Tuebingen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 1; Verum 1: Each individual capsule has a filling volume of 25 mg amitriptyline, given once an day in the evening over 28 days	Drug: amitriptyline; Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch
ACTIVE_COMPARATOR: 2; Verum 1: Each individual capsule has a filling volume of 50 mg amitriptyline, given once an day in the evening over 28 days	Drug: amitriptyline; Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch
ACTIVE_COMPARATOR: 3; Verum 3: Each individual capsule has a filling volume of 75 mg amitriptyline, given once an day in the evening over 28 days	Drug: amitriptyline; Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch
PLACEBO_COMPARATOR; Placebo: Each individual capsule has a filling volume of 25 mg placebo (corn starch), given once an day in the evening over 28 days	Drug: amitriptyline; Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Increase in lung function, especially the FEV1 increase	5 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Increase of CO-Diffusion	5 months
Pulmonary Ceramide expression	5 months
Decrease of cytokine-concentrations	5 months
Decrease of leukocytes (sputum)	5 months
Decrease of Pseudomonas	5 months
Infection parameters in serum	5 months
Exacerbations	5 months

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Investigators: Principal Investigator: Joachim Reithmueller, Dr., University of Tuebingen, Paediatric Department

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Study Completion (ACTUAL): July 1, 2007

Study Registration Dates

• First Submitted: August 9, 2007
• First Submitted That Met QC Criteria: August 10, 2007
• First Posted (ESTIMATE): August 13, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): August 13, 2007
• Last Update Submitted That Met QC Criteria: August 10, 2007
• Last Verified: August 1, 2007

More Information

Terms related to this study

• Keywords: lung function; cystic fibrosis; Pseudomonas aeruginosa; amitriptyline; ceramide
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Pseudomonas Infections; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Antidepressive Agents, Tricyclic; Adrenergic Uptake Inhibitors; Amitriptyline
• Other Study ID Numbers: APA-II