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Anti-inflammatory Pulmonal Therapy of Cystic Fibrosis (CF) Patients With Amitriptyline and Placebo (APA-IIb)

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ClinicalTrials.gov Identifier: NCT01309178
Recruitment Status : Unknown
Verified March 2009 by University Children's Hospital Tuebingen.
Recruitment status was:  Recruiting
First Posted : March 7, 2011
Last Update Posted : March 7, 2011
Universität Duisburg-Essen
University of Ulm
Information provided by:
University Children's Hospital Tuebingen

Brief Summary:

Cystic fibrosis patients suffer from a chronic destruction of the lung, frequent and finally chronic pneumonia and a reduced life expectancy. Unfortunately, no curative treatment for cystic fibrosis is available, neither are treatments established that prevent the disease. Our data identify ceramide as a potential novel target to treat cystic fibrosis.

Two smaller trials support the notion that inhibition of the acid sphingomyelinase by amitriptyline improves the lung function of CF-patients even at a dose that is low enough to avoid adverse effects.

In the present proposal the investigators, therefore, aim to test in a larger cystic fibrosis patient population whether an inhibition of ceramide release in the lung caused by the lack of functional CFTR improves the lung function of cystic fibrosis patients. Inhibition of ceramide-release in the lung will be achieved by treatment with amitriptyline, which is used as an anti-depressant drug for almost 50 years. Although it is not absolutely specific, it seems to be relatively specific for the degradation of acid sphingomyelinase (typically 60-80% of cellular acid sphingomyelinase are degraded), which releases ceramide from sphingomyelin.

If the data confirm the beneficial effect of amitriptyline already observed in our preliminary studies, the present clinical study may establish a novel treatment to improve clinical symptoms of cystic fibrosis and, moreover, to prevent or at least delay the onset of cystic fibrosis.


  • Amitriptyline reduces ceramide concentrations in respiratory epithelial cells (measured in nasal epithelial cells obtained by brushing nasal mucosa).
  • Amitriptyline treatment reduces cell death in bronchi and deposition of DNA on the respiratory epithelium, which permits elimination of P. aeruginosa from the lung (measured as P. aeruginosa counts in tracheal fluid).
  • Amitriptyline treatment results in normalization of the function of leukocytes (number determined in serum and tracheal fluid)
  • Amitriptyline reduces systemic and local inflammation (measured as cytokines in plasma and tracheal fluid).

Based on these effects amitriptyline increases the lung function of cystic fibrosis patients (measured by FEV1).

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Pneumonia Drug: Amitriptyline Drug: Mannite Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Anti-inflammatory Pulmonal Therapy of CF Patients With Amitriptyline and Placebo - a Randomised, Double-blind, Placebo-controlled, Multicenter, Cohort - Study
Study Start Date : May 2009
Estimated Primary Completion Date : May 2011
Estimated Study Completion Date : May 2011

Arm Intervention/treatment
Active Comparator: Amitriptyline
After the experience with the treatment of 18 CF-patients phase IIa study), the medication will be therefore 25 mg daily in two doses (2 x 12,5 mg). Because of a higher rate of side effects (tiredness, dry mucous membrane) the higher dose of 50 mg (2 x 25 mg) is not chosen first, but will be adapted after 2 weeks of treatment.
Drug: Amitriptyline
2 x 12,5 mg capsules for oral use in the first two weeks, the higher dose of 50 mg (2 x 25 mg) will be adapted after 2 weeks of treatment.
Other Name: Amitriptylinhydrochlorid

Placebo Comparator: Mannite
The placebo will be given 25 mg daily in two doses (2 x 12,5 mg). After 2 weeks of treatment the higher dose of 50 mg (2 x 25 mg) will be given
Drug: Mannite
Mannit capsules daily in two doses (2 x 12,5 mg). After 2 weeks of treatment the higher dose of 50 mg (2 x 25 mg) will be given
Other Name: Mannite Ph. Eur.

Primary Outcome Measures :
  1. Improvement of the lung function parameter FEV1 (absolute and relative to baseline) under verum and placebo [ Time Frame: in 4 weeks ]
    The primary aim is the change of the lung function parameter Forced Expiratory Volume in 1 second (FEV1) relative to baseline under verum and placebo

Secondary Outcome Measures :
  1. Increase in lung function measurements [ Time Frame: in 2 and 4 weeks ]
    Increase (absolute and relative to baseline) in lung function (FVC, FEV1, MEF 25, LCI, CO-Diffusion) in 2 and 4 weeks

  2. Ceramide concentration in epithelial cells [ Time Frame: in 4 weeks ]
    Decrease of Ceramide concentration in epithelial cells detected in sputum

  3. Inflammation status [ Time Frame: in 4 weeks ]
    Reduction of IL-8 (facultatively IL-1ß, IL-6, IL-8, TNFα) as well as an increase of anti-inflammatory IL-10 in tracheal mucus

  4. Bacteriological and cell status [ Time Frame: in 4 weeks ]
    Reduction of the DNA-content and granulocyte concentration and decrease of chronic bacterial colonization (P. aerug., S. aureus, etc.) in tracheal mucus.

  5. Side effects [ Time Frame: in 4 weeks ]
    Number of upper and lower respiratory tract infections pulmonary exacerbations)

Information from the National Library of Medicine

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Ages Eligible for Study:   14 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Cystic Fibrosis is verified
  • Patient is older than 14 years
  • Patients weight is more than 35 kg
  • FEV1 is higher than 30% and lower than 90%
  • The patient is pulmonal colonized with bacteria
  • No acute pulmonal illness is present
  • CRP is not elevated two fold (2 mg/dl) of normal
  • Lung function testing is possible
  • A full course of therapy is possible without any restrictions

Exclusion Criteria:

  • FEV1 in baseline differs more than 10% from screening visit
  • CRP in baseline differs more than 50% from screening visit
  • Glaucoma, seizures, heart insufficiency or major depression are present
  • Intravenous antibiotic treatment was necessary in the last 4 weeks before visit 2
  • High dose steroid therapy
  • On-off-therapy of tobramycin in the last 2 weeks
  • Involvement of the patient in another study
  • Pregnancy and
  • Nursing mothers

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01309178

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Contact: Joachim Riethmueller, Dr. +49 7071 2981442 joachim.riethmueller@med.uni-tuebingen.de

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Lutz Naehrlich Recruiting
Giessen, Germany, 35385
Contact: Lutz Naehrlich, Dr.    +49 641 99 43430    Lutz.Naehrlich@paediat.med.uni-giessen.de   
Principal Investigator: Lutz Naehrlich, Dr.         
Jochen Mainz Recruiting
Jena, Germany, 07740
Contact: Jochen Mainz, Dr.    +49 3641 938425    jochen.mainz@med.uni-jena.de   
Principal Investigator: Jochen Mainz, Dr.         
Joachim Riethmueller Recruiting
Tuebingen, Germany, 72076
Contact: Joachim Riethmueller, Dr    +49 7071 2981442    joachim.riethmueller@med.uni-tuebingen.de   
Principal Investigator: Joachim Riethmueller, Dr.         
Sponsors and Collaborators
University Children's Hospital Tuebingen
Universität Duisburg-Essen
University of Ulm
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Study Director: Joachim Riethmueller, Dr University Children´s Hospital Tubeingen, Germany
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Responsible Party: University Hospital Tuebingen, University Children´s Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT01309178    
Other Study ID Numbers: APA-IIb
2008-002673-13 ( EudraCT Number )
First Posted: March 7, 2011    Key Record Dates
Last Update Posted: March 7, 2011
Last Verified: March 2009
Additional relevant MeSH terms:
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Cystic Fibrosis
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Pancreatic Diseases
Digestive System Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Antidepressive Agents, Tricyclic
Antidepressive Agents
Psychotropic Drugs
Analgesics, Non-Narcotic
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
Diuretics, Osmotic
Natriuretic Agents