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

NCT01309178 | Unknown Phase 2 DMC

• 2 other identifiers: APA-IIb2008-002673-13
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 3

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. 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).

Conditions

Cystic Fibrosis; Pneumonia

Outcome Measures

Primary Outcomes (1)

• Improvement of the lung function parameter FEV1 (absolute and relative to baseline) under verum and placebo

  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

  in 4 weeks

Secondary Outcomes (5)

• Increase in lung function measurements

  in 2 and 4 weeks

• Ceramide concentration in epithelial cells

  in 4 weeks

• Inflammation status

  in 4 weeks

• Bacteriological and cell status

  in 4 weeks

• Side effects

  in 4 weeks

Study Arms (2)

Amitriptyline

ACTIVE COMPARATOR

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

Mannite

PLACEBO COMPARATOR

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

Interventions

Amitriptyline DRUG

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.

Also known as: Amitriptylinhydrochlorid

Amitriptyline

Mannite DRUG

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

Also known as: Mannite Ph. Eur.

Mannite

Eligibility Criteria

• Age: 14 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Children's Hospital Tuebingen: lead
• Universität Duisburg-Essen: collaborator
• University of Ulm: collaborator

Study Sites (3)

Lutz Naehrlich

Giessen, 35385, Germany

RECRUITING

Jochen Mainz

Jena, 07740, Germany

RECRUITING

Joachim Riethmueller

Tübingen, 72076, Germany

RECRUITING

MeSH Terms

Conditions

Cystic Fibrosis; Pneumonia

Interventions

Amitriptyline; Mannitol

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Respiratory Tract Infections; Infections

Intervention Hierarchy (Ancestors)

Dibenzocycloheptenes; Benzocycloheptenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Sugar Alcohols; Alcohols; Carbohydrates

Study Officials

• Joachim Riethmueller, Dr

  University Children´s Hospital Tubeingen, Germany

  STUDY DIRECTOR

Central Study Contacts

Joachim Riethmueller, Dr.

CONTACT

+49 7071 2981442; joachim.riethmueller@med.uni-tuebingen.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: March 4, 2011
• First Posted: March 7, 2011
• Study Start: May 1, 2009
• Primary Completion: May 1, 2011
• Study Completion: May 1, 2011
• Last Updated: March 7, 2011

Record last verified: 2009-03

Locations

DE (3)