E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amitriptyline reduces ceramide concentrations in bronchial epithelial cells and reduces cell death and reduces the deposition of DNA on the respiratory epithelium. This reduction promotes the elimination of P. aeruginosa bacteria from the lung. As a result, treatment normalizes inflammation in CF lungs. Amitriptyline thus reduces systemic and local inflammation. Because of these effects, amitriptyline increases lung function in CF patients.
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E.1.1.1 | Medical condition in easily understood language |
Amitriptyline reduces cell death in epithelial cells of the lung, reduces inflammation and increases lung function. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Difference in absolute FEV1 % predicted between verum and placebo at week 8 compared to baseline |
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E.2.2 | Secondary objectives of the trial |
1. Maintenance of the reached FEV1 in the verum group between week 8 and week 16. 2. Absolute and relative FEV1 as % predicted after 4, 8, 12 and 16 weeks compared to baseline, if not primary; 3. All other lung function parameters (FVC, MEFs and lung clearance index-LCI); 4. Concentration of Ceramide in sputum; 5. Concentration of pro-inflammatory cytokines, change of anti-inflammatory IL-10 in tracheal mucus; 6. Content of DNA and granulocyte concentration in sputum; 7. Bacterial colonisation in sputum; 8. Number of exacerbations of pulmonary symptoms; 9. Incidence of discontinuation of treatment because perceived side ef-fects. 10. Changes in body weight 11. Quality of life questionnaire adapted to CF
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Cystic Fibrosis is verified; 2. Patient is older than 12 years; 3. Patients weight is more than 35 kg; 4. FEV1 is higher than 25% and lower than 100% (two times in 3 months); 5. The patients lung is colonised with bacteria; 6. No acute pulmonal illness is present; 7. Lung function testing is possible; 8. A full course of therapy is possible without any restrictions; 9. Informed consent is given.
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E.4 | Principal exclusion criteria |
1. FEV1 in screening and baseline differs more than 10%; 2. Clinicial detoriation is present (exacerbation symptoms); 3. Change of CRP of more than 50% in screening period; 4. Glaucoma, seizures, heart insufficiency or major depression is pre-sent; 5. Intravenous antibiotic treatment was necessary for the last 2 weeks prior to the trial; 6. High dose steroid therapy; 7. On-therapy of tobramycine in the last 2 weeks; 8. Involvement of the patient in another study; 9. Pregnancy.
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E.5 End points |
E.5.1 | Primary end point(s) |
Difference in mean absolute differences in percent predicted FEV1 between verum and placebo at week 8 compared to baseline |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at week 8 compared to baseline |
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E.5.2 | Secondary end point(s) |
- Maintenance of the reached FEV1 amount in the verum group between week 8 and week 16 re-garding a difference up to 4,2% as being equivalent. - Absolute and relative FEV1 increase after 4, 8, 12 and 16 weeks compared to baseline, if not pri-mary. - All other lung function parameters (FVC, MEF25, MEF50, MEF75, MEF25-75, LCI) after 4, 8, 12 and 16 weeks compared to baseline. - Concentration of Ceramide in sputum after 8 and 16 weeks compared to baseline. - Concentration of pro-inflammatory cytokines (IL-6, IL-8, TNFα), change of anti-inflammatory IL-10 in tracheal mucus after 4, 8, 12 and 16 weeks compared to baseline. - Content of DNA and granulocyte concentration in sputum after 4, 8, 12 and 16 weeks compared to baseline. - Chronic bacterial colonisation (cumulative Cfu) in sputum after 4, 8, 12 and 16 weeks compared to baseline. - Number of exacerbations of pulmonary symptoms (pulmonary infections treated with antibiotics) after 8 and 16 weeks compared to baseline. - Incidence of discontinuation of treatment due to perceived side effects. - Question 18 of quality of life questionnaire adapted to CF after 8 and 16 weeks compared to baseline.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Each after 4, 8, 12 and 16 weeks compared to baseline. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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There is a follow up visit 28 days after therapy will be finished because of safety reasons |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |