Cystic FibrosisPhase 2NCT00515229
Anti-Inflammatory Pulmonal Therapy of CF-Patients With Amitriptyline and Placebo
A Phase 2 study testing amitriptyline in people with Cystic Fibrosis and Infection, run by University Hospital Tuebingen at 1 site in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 50 years
- Conditions the study is for
- Cystic Fibrosis, Infection, Pseudomonas Aeruginosa
- What is being tested?
- amitriptyline
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 18 participants
- Where
- 1 siteGermany
- Study dates
- Oct 2006to Jul 2007
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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 -
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.
Read the 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.
- Conditions
- Cystic Fibrosis, Infection, Pseudomonas Aeruginosa
- Being tested
- amitriptyline
- Keywords
- cystic fibrosis, ceramide, amitriptyline, Pseudomonas aeruginosa, lung function
- Medical subject headings
- Cystic Fibrosis, Infections, Pseudomonas Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
amitriptylineDrug
Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline.
Placebo: 25 mg corn starch
| Study group | Role | What they receive |
|---|---|---|
| 1 | Active comparator | Verum 1: Each individual capsule has a filling volume of 25 mg amitriptyline, given once an day in the evening over 28 days Receives: Drug: amitriptyline |
| 2 | Active comparator | Verum 1: Each individual capsule has a filling volume of 50 mg amitriptyline, given once an day in the evening over 28 days Receives: Drug: amitriptyline |
| 3 | Active comparator | Verum 3: Each individual capsule has a filling volume of 75 mg amitriptyline, given once an day in the evening over 28 days Receives: Drug: amitriptyline |
| 0 | Placebo comparator | Placebo: Each individual capsule has a filling volume of 25 mg placebo (corn starch), given once an day in the evening over 28 days Receives: Drug: amitriptyline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Increase in lung function, especially the FEV1 increase
Measured: 5 months
Secondary outcomes (7)
Increase of CO-Diffusion
Measured: 5 months
Pulmonary Ceramide expression
Measured: 5 months
Decrease of cytokine-concentrations
Measured: 5 months
Decrease of leukocytes (sputum)
Measured: 5 months
Decrease of Pseudomonas
Measured: 5 months
Infection parameters in serum
Measured: 5 months
Exacerbations
Measured: 5 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Aug 2007 (estimated)
- Study startOct 2006
- Study completionJul 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cystic FibrosisStudies of the same condition, open and under way.
- More trials run by University Hospital TuebingenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital Tuebingen
- Sponsor type
- University, hospital or other
- Investigators
- Joachim Reithmueller, Dr., Principal investigator, University of Tuebingen, Paediatric Department
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00515229
- Sponsor's protocol ID
- APA-II
- Status last verified
- Aug 2007
- First submitted
- 9 Aug 2007
- Last updated
- 13 Aug 2007
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 19635928
Study at a glance
From the registry record, last updated by the sponsor on 13 Aug 2007. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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 -
- ClinicalTrials.gov ID
- NCT00515229
- Acronym / sponsor ID
- APA-II
- Conditions
- Cystic Fibrosis, Infection, Pseudomonas Aeruginosa
- Keywords
- cystic fibrosis, ceramide, amitriptyline, Pseudomonas aeruginosa, lung function
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- University Hospital TuebingenUniversity, hospital or other
- Study start
- Oct 2006
- Study completion
- Jul 2007 (actual)
- First posted
- 13 Aug 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| 1 | Active comparator | Drug: amitriptylineVerum 1: Each individual capsule has a filling volume of 25 mg amitriptyline, given once an day in the evening over 28 days |
| 2 | Active comparator | Drug: amitriptylineVerum 1: Each individual capsule has a filling volume of 50 mg amitriptyline, given once an day in the evening over 28 days |
| 3 | Active comparator | Drug: amitriptylineVerum 3: Each individual capsule has a filling volume of 75 mg amitriptyline, given once an day in the evening over 28 days |
| 0 | Placebo comparator | Drug: amitriptylinePlacebo: Each individual capsule has a filling volume of 25 mg placebo (corn starch), given once an day in the evening over 28 days |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| amitriptylineEach individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline. Placebo: 25 mg corn starch | Drug | 0, 1, 2, 3 |
Primary outcome
Increase in lung function, especially the FEV1 increase
Time frame: 5 months
7 secondary outcomes
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Aug 2007.
- Derived from this study: PubMed 19635928Becker 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joachim Reithmueller, Dr. principal investigator
University of Tuebingen, Paediatric Department
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing amitriptyline in people with Cystic Fibrosis and Infection, run by University Hospital Tuebingen at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Aug 2007. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Increase in lung function, especially the FEV1 increase (time frame: 5 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00515229, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2007.