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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified March 2009 by University Children’s Hospital Tuebingen.
Recruitment status was  Recruiting
Sponsor:
Collaborators:
Universität Duisburg-Essen
University of Ulm
Information provided by:
University Children’s Hospital Tuebingen
ClinicalTrials.gov Identifier:
NCT01309178
First received: March 4, 2011
Last updated: NA
Last verified: March 2009
History: No changes posted
  Purpose

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.

Hypothesis

  • 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 Intervention Phase
Cystic Fibrosis
Pneumonia
Drug: Amitriptyline
Drug: Mannite
Phase 2

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

Resource links provided by NLM:


Further study details as provided by University Children’s Hospital Tuebingen:

Primary Outcome Measures:
  • Improvement of the lung function parameter FEV1 (absolute and relative to baseline) under verum and placebo [ Time Frame: in 4 weeks ] [ Designated as safety issue: No ]
    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:
  • Increase in lung function measurements [ Time Frame: in 2 and 4 weeks ] [ Designated as safety issue: No ]
    Increase (absolute and relative to baseline) in lung function (FVC, FEV1, MEF 25, LCI, CO-Diffusion) in 2 and 4 weeks

  • Ceramide concentration in epithelial cells [ Time Frame: in 4 weeks ] [ Designated as safety issue: No ]
    Decrease of Ceramide concentration in epithelial cells detected in sputum

  • Inflammation status [ Time Frame: in 4 weeks ] [ Designated as safety issue: No ]
    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

  • Bacteriological and cell status [ Time Frame: in 4 weeks ] [ Designated as safety issue: No ]
    Reduction of the DNA-content and granulocyte concentration and decrease of chronic bacterial colonization (P. aerug., S. aureus, etc.) in tracheal mucus.

  • Side effects [ Time Frame: in 4 weeks ] [ Designated as safety issue: Yes ]
    Number of upper and lower respiratory tract infections pulmonary exacerbations)


Estimated Enrollment: 30
Study Start Date: May 2009
Estimated Study Completion Date: May 2011
Estimated Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   14 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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: NCT01309178

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

Locations
Germany
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
Investigators
Study Director: Joachim Riethmueller, Dr University Children´s Hospital Tubeingen, Germany
  More Information

No publications provided

Responsible Party: University Hospital Tuebingen, University Children´s Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT01309178     History of Changes
Other Study ID Numbers: APA-IIb, 2008-002673-13
Study First Received: March 4, 2011
Last Updated: March 4, 2011
Health Authority: Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Cystic Fibrosis
Fibrosis
Digestive System Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Lung Diseases
Pancreatic Diseases
Pathologic Processes
Respiratory Tract Diseases
Amitriptyline
Amitriptyline, perphenazine drug combination
Anti-Inflammatory Agents
Adrenergic Agents
Adrenergic Uptake Inhibitors
Analgesics
Analgesics, Non-Narcotic
Antidepressive Agents
Antidepressive Agents, Tricyclic
Antipsychotic Agents
Central Nervous System Agents
Central Nervous System Depressants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014