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

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

Tracking Information
First Submitted Date  ICMJE August 9, 2007
First Posted Date  ICMJE August 13, 2007
Last Update Posted Date August 13, 2007
Study Start Date  ICMJE October 2006
Primary Completion Date Not Provided
Current Primary Outcome Measures  ICMJE
 (submitted: August 10, 2007)
Increase in lung function, especially the FEV1 increase [ Time Frame: 5 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2007)
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Anti-Inflammatory Pulmonal Therapy of CF-Patients With Amitriptyline and Placebo
Official Title  ICMJE 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 -
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Cystic Fibrosis
  • Infection
  • Pseudomonas Aeruginosa
Intervention  ICMJE Drug: amitriptyline

Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline.

Placebo: 25 mg corn starch

Study Arms  ICMJE
  • 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
    Intervention: Drug: amitriptyline
  • 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
    Intervention: Drug: amitriptyline
  • 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
    Intervention: Drug: amitriptyline
  • 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
    Intervention: Drug: amitriptyline
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 10, 2007)
18
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2007
Primary Completion Date Not Provided
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00515229
Other Study ID Numbers  ICMJE APA-II
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Not Provided
Study Sponsor  ICMJE University Hospital Tuebingen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Joachim Reithmueller, Dr. University of Tuebingen, Paediatric Department
PRS Account University Hospital Tuebingen
Verification Date August 2007

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP