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

• ClinicalTrials.gov Identifier: NCT00515229
• Recruitment Status: Completed
• First Posted: August 13, 2007
• Last Update Posted: August 13, 2007
• Sponsor: University Hospital Tuebingen
• Information provided by: University Hospital Tuebingen

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis; Infection; Pseudomonas Aeruginosa	Drug: amitriptyline	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: October 2006
• Actual Study Completion Date: July 2007

Arms and Interventions

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: 0; 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

Outcome Measures

Primary Outcome Measures :

1. Increase in lung function, especially the FEV1 increase [ Time Frame: 5 months ]

Secondary Outcome Measures :

1. Increase of CO-Diffusion [ Time Frame: 5 months ]
2. Pulmonary Ceramide expression [ Time Frame: 5 months ]
3. Decrease of cytokine-concentrations [ Time Frame: 5 months ]
4. Decrease of leukocytes (sputum) [ Time Frame: 5 months ]
5. Decrease of Pseudomonas [ Time Frame: 5 months ]
6. Infection parameters in serum [ Time Frame: 5 months ]
7. Exacerbations [ Time Frame: 5 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Germany

University of Tuebingen

Tuebingen, Baden-Wuerttemberg, Germany, 72076

Sponsors and Collaborators

University Hospital Tuebingen

Investigators

• Principal Investigator: Joachim Reithmueller, Dr.; University of Tuebingen, Paediatric Department

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• ClinicalTrials.gov Identifier: NCT00515229
• Other Study ID Numbers: APA-II
• First Posted: August 13, 2007
• Last Update Posted: August 13, 2007
• Last Verified: August 2007

Keywords provided by University Hospital Tuebingen:

cystic fibrosis; ceramide; amitriptyline; Pseudomonas aeruginosa; lung function

Additional relevant MeSH terms:

Pseudomonas Infections; Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Amitriptyline; Antidepressive Agents, Tricyclic; Antidepressive Agents; Psychotropic Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Adrenergic Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Adrenergic Agents; Neurotransmitter Agents