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

Primary Purpose

Cystic Fibrosis, Infection, Pseudomonas Aeruginosa

Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
amitriptyline
Sponsored by
University Hospital Tuebingen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cystic Fibrosis focused on measuring cystic fibrosis, ceramide, amitriptyline, Pseudomonas aeruginosa, lung function

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Tuebingen

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

1

2

3

0

Arm Description

Verum 1: Each individual capsule has a filling volume of 25 mg amitriptyline, given once an day in the evening over 28 days

Verum 1: Each individual capsule has a filling volume of 50 mg amitriptyline, given once an day in the evening over 28 days

Verum 3: Each individual capsule has a filling volume of 75 mg amitriptyline, given once an day in the evening over 28 days

Placebo: Each individual capsule has a filling volume of 25 mg placebo (corn starch), given once an day in the evening over 28 days

Outcomes

Primary Outcome Measures

Increase in lung function, especially the FEV1 increase

Secondary Outcome Measures

Increase of CO-Diffusion
Pulmonary Ceramide expression
Decrease of cytokine-concentrations
Decrease of leukocytes (sputum)
Decrease of Pseudomonas
Infection parameters in serum
Exacerbations

Full Information

First Posted
August 9, 2007
Last Updated
August 10, 2007
Sponsor
University Hospital Tuebingen
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1. Study Identification

Unique Protocol Identification Number
NCT00515229
Brief Title
Anti-Inflammatory Pulmonal Therapy of CF-Patients With Amitriptyline and Placebo
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 Type
Interventional

2. Study Status

Record Verification Date
August 2007
Overall Recruitment Status
Completed
Study Start Date
October 2006 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
July 2007 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
University Hospital Tuebingen

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis, Infection, Pseudomonas Aeruginosa
Keywords
cystic fibrosis, ceramide, amitriptyline, Pseudomonas aeruginosa, lung function

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Active Comparator
Arm Description
Verum 1: Each individual capsule has a filling volume of 25 mg amitriptyline, given once an day in the evening over 28 days
Arm Title
2
Arm Type
Active Comparator
Arm Description
Verum 1: Each individual capsule has a filling volume of 50 mg amitriptyline, given once an day in the evening over 28 days
Arm Title
3
Arm Type
Active Comparator
Arm Description
Verum 3: Each individual capsule has a filling volume of 75 mg amitriptyline, given once an day in the evening over 28 days
Arm Title
0
Arm Type
Placebo Comparator
Arm Description
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 Type
Drug
Intervention Name(s)
amitriptyline
Intervention Description
Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch
Primary Outcome Measure Information:
Title
Increase in lung function, especially the FEV1 increase
Time Frame
5 months
Secondary Outcome Measure Information:
Title
Increase of CO-Diffusion
Time Frame
5 months
Title
Pulmonary Ceramide expression
Time Frame
5 months
Title
Decrease of cytokine-concentrations
Time Frame
5 months
Title
Decrease of leukocytes (sputum)
Time Frame
5 months
Title
Decrease of Pseudomonas
Time Frame
5 months
Title
Infection parameters in serum
Time Frame
5 months
Title
Exacerbations
Time Frame
5 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joachim Reithmueller, Dr.
Organizational Affiliation
University of Tuebingen, Paediatric Department
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Tuebingen
City
Tuebingen
State/Province
Baden-Wuerttemberg
ZIP/Postal Code
72076
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
19635928
Citation
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.
Results Reference
derived

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

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