E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011763 |
E.1.2 | Term | Cystic fibrosis lung |
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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 |
To investigate the safety and tolerability of heparin 25 mg, inhalation powder, hard capsules in patients with CF. |
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E.2.2 | Secondary objectives of the trial |
Pharmacodynamic investigation of: Expectorated mucus (rheological). Effects on sputum inflammatory markers (neutrophil elastase, IL-6, -8, total cell count, % neutrophils, % macrophages; effect on pH in exhaled breath condensate may be measured; on inflammatory blood markers (neutrophil elastase, neutrophil elastase / alpha-1 antitrypsin complex, IL-6, -8, neutrophil count, C reactive protein); coagulation (aPTT, platelets). Evaluate efficacy by VAS based on change in symptoms: cough resolution; expectorated sputum clearability, thickness, volume, colour, viscoelasticity; breathlessness; general well being. Microbiology of sputum for effects on bacterial growth, density, antibiotic sensitivity (ID, culture, density, sensitivity of P aeruginosa, B cepacia, H influenzae and S aureus). Volume and weight of 24-h expectorated sputum sample. Pulmonary function ;FEV1, FVC, forced mid-expiratory flow (FEF25-75), arterial oxygen saturation (SaO2). Response to the CF Questionnaire. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female ≥ 16 years; 2. Non-smoker; 3. Written informed consent obtained prior to any trial specific procedures; 4. Confirmed diagnosis of CF lung disease (i.e., respiratory clinical symptoms and positive sweat test or disease inducing mutations) by CF expert / Investigator; 5. Patient considered, in the Investigator’s opinion, to be clinically stable and has at Screening and Baseline an FEV1 40 - 90% of predicted value for age, sex and height; 6. FEV1 value at Baseline is within +/-15% of FEV1 value 4 weeks earlier at Screening; 7. Regular mucus production due to CF; 8. Ease of sputum expectoration (i.e., clearability) VAS score of ≤ 80 mm; 9. Neutrophil elastase and / or IL-8 levels above detectable levels and/or upper limit of normal range for specified laboratory; 10. Adequate contraceptive measures (the subject [and his/her partner] should use adequate contraceptive measures, consisting of two forms of contraception, at least one of which must be a barrier method); 11. Able to comply with all the requirements of the protocol; 12. Able to use inhaler satisfactorily. |
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E.4 | Principal exclusion criteria |
1. Known sensitivity to any preparation of inhaled or parenteral heparin or the excipient leucine; 2. Any contra indication to Monoparin® considered clinically relevant; 3. Increased bleeding risk defined as any of : a. Any history of or current evidence of clinically significant haemoptysis (i.e., bright red blood or substantial blood clot in sputum) or any other clinically important signs, symptoms or features of haemoptysis which in the opinion of the patient’s Consultant Physician/Investigator responsible for the care of the patient and management of his/her CF are considered clinically significant and/ or liable to lead to an increased risk of developing haemoptysis; b. Haemorrhage of any major organ 6 months prior to Baseline (Day 1); c. Patients with active gastrointestinal ulcer / bleeding during 6 months prior to Baseline (Day 1); d. History of heparin-induced thrombocytopaenia; e. Patients with bleeding diathesis defined by: i) aPTT > 25% above normal (26-36 seconds) and / or; ii) Platelet count < 150 x 1,000,000 cells/mL and / or; iii) Prothrombin time (PT) > 25% above the upper limit of normal (ULN) (i.e., 18.8 s); f. Evidence of portal hypertension (e.g., hypersplenism or known Grade III/IV oesophageal varices; 4. Clinically significant liver disease (e.g., known severe liver disease or cirrhosis, raised serum transaminases [ALT, AST] more than 2 x ULN), which in the opinion of the Investigator would impose a significant clinical risk; 5. Clinically significant serious disease or organ system disease not currently controlled / stable on present therapy; 6. Patients with a history a clinically or radiologically diagnosed aspergilloma; 7. Pregnancy at Screening; or lactation; 8. Planned hospitalisations which could interfere with trial compliance; 9. Previous thoracic or scheduled major surgery during trial period; 10. Previous or current regular use of proscribed medication defined as: a. Chronic / regular non-steroidal anti-inflammatory drug (NSAID) use (i.e., more than 3 times per week); b. Any regular anti coagulant therapy (e.g., warfarin, aspirin) in the 2 weeks prior to Screening; c. Any previous use of inhaled heparin; d. Use of parenteral heparin 1 month prior to Screening; e. Use of other investigational drugs 1 month prior to Screening; f. Chronic / regular corticosteroid (1 month prior to Screening) use except for: i) inhaled corticosteroids ≤ 1 mg/day of beclometasone dipropionate (BDP) or equivalent (e.g., 500 ug/day Seretide); Note: It is acceptable for the dose to be reduced 1 month prior to and during Screening as long as this lower dose subsequently remains stable. ii) systemic doses of ≤ 5 mg/day of oral prednisolone or equivalent; iii) limited dermatological use (a maximum of 3 times per week); g. Any regular inhaled tobramycin (Tobi®) or other antibiotic use for oral, inhaled or parenteral treatment to be stable for at least 1 month prior to Screening and during the course of the trial (e.g., erythromycin, clarithromycin; azithromycin; colistin). (Note: If dosing changes between Screening and Baseline (Day 1), the patient can not be entered in the trial); h. Modification of medication to treat respiratory disease between Screening and Baseline (Day 1) i.e. administration of additional medication for a respiratory infection such as antibiotics (e.g., any inhaled antibiotic such as Tobi® and colistin or any oral or parenteral antibiotic); i. Patients prescribed mucolytics, or hypertonic saline, but who have been taking them for less than 3 months prior to Screening are excluded. NB Patients who at Screening have been taking a mucolytic (e.g., Pulmozyme®, erdosteine), or hypertonic saline, continuously at a stable dose for ≥ 3 months, as prescribed by their Physician, are eligible and may remain on this/these concomitant medication(s) throughout the study providing the medication(s) and dose(s) remains consistent from Screening onward. Patients at Screening who are not taking mucolytics or hypertonic saline at all are also eligible; 11. Unable for any other reason to satisfactorily comply with the protocol (e.g., attendance for trial visits, treatment or assessments). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pharmacodynamic Endpoints The PD variables are: Expectorated mucus measurement parameters (i.e., rheological viscoelasticity / physicochemical measurement parameters) (in accordance with advised tests) (expectorated sputum samples must be collected after standard physiotherapy regime); Induced sputum markers (neutrophil elastase, interleukins [IL-6, IL-8]) and cell counts (i.e. total cell counts, % neutrophils, % macrophages); EBC levels of pH may be measured at selected sites); Blood markers, neutrophil elastase, neutrophil elastase / AAT complex, neutrophil count, IL-6, IL-8 and CRP levels; aPTT and platelets. Evaluation of Efficacy Endpoints The efficacy variables are: VAS parameters, i.e., cough resolution; expectorated sputum clearability, thickness, volume, colour, viscoelasticity (stickiness); breathlessness; general well being (including feeling, energy, physical activity, appetite and sleep); Microbiology assays of expectorated sputum (i.e., analysis of bacterial growth, density, antibiotic sensitivity of the following organisms are included: Pseudomonas aeruginosa [mucoid and other types], Burkholderia cepacia, Haemophilus influenzae, Staphylococcus aureus. Volume and weight of 24-h cumulative expectorated sputum sample. Pulmonary function parameters FEV1, FVC and FEF25-75, and SaO2 by finger oximetry at rest, post physiotherapy and before induced sputum; Response to the CFQ: responses to the questionnaire are to be measured by a six point Likert scale which are then transformed into values of between 0 and 100. Transformed scores of less than 50 represent negative scores, suggesting that the individuals may be experiencing difficulties within that particular domain.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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.8.3 |
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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |