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

Purpose

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	Intervention	Phase
Cystic Fibrosis Infection Pseudomonas Aeruginosa	Drug: amitriptyline	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Caregiver, 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 -

Resource links provided by NLM:

Genetics Home Reference related topics: cystic fibrosis

MedlinePlus related topics: Cystic Fibrosis

Drug Information available for: Amitriptyline Amitriptyline hydrochloride Triavil

Genetic and Rare Diseases Information Center resources: Cystic Fibrosis

U.S. FDA Resources

Further study details as provided by University Hospital Tuebingen:

Primary Outcome Measures:

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

Secondary Outcome Measures:

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


Enrollment:	18
Study Start Date:	October 2006
Study Completion Date:	July 2007

Arms	Assigned Interventions
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

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


Ages Eligible for Study:	18 Years to 50 Years (Adult)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00515229

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, Riethmüller J, Lüth A, Döring 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 History of Changes
Other Study ID Numbers:	APA-II
Study First Received:	August 9, 2007
Last Updated:	August 10, 2007
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University Hospital Tuebingen:


cystic fibrosis ceramide amitriptyline Pseudomonas aeruginosa lung function

Additional relevant MeSH terms:


Fibrosis Cystic Fibrosis Pseudomonas Infections Pathologic Processes Pancreatic Diseases Digestive System Diseases Lung Diseases Respiratory Tract Diseases Genetic Diseases, Inborn Infant, Newborn, Diseases Gram-Negative Bacterial Infections Bacterial Infections Anti-Inflammatory Agents Amitriptyline Amitriptyline, perphenazine drug combination	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 Antipsychotic Agents

ClinicalTrials.gov processed this record on September 28, 2016