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 adults 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). Pulmonary function ;FEV1, FVC, forced mid-expiratory flow (FEF25-75), arterial oxygen saturation (SaO2). Response to the CF Questionnaire; Exercise performance. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female ≥ 18 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. FEV1 40 - 80% of predicted value for age, sex and height; during 6 months prior to Screening; 6. FEV1 within 10% of best value during 6 months prior to 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.Evidence of clinically significant haemoptysis (i.e., bright red blood or substantial blood clot in sputum);or an increased risk of developing haemoptysis by virtue of previous clinical history of clinically significant 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 < 100 x 106 cells/mL and / or; iii) Prothrombin time (PT) > 25% above the upper limit of normal (ULN) (i.e., 18.8s); 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 of 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. Any vaccination within 1 month of Screening; 11. 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 mg/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) 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); ii) use of mucolytics (e.g., Pulmozyme®, erdosteine). Patients must be off Pulmozyme® for 1 month prior to Baseline (Day 1) and during the treatment period; iii) concomitant use of hypertonic saline treatment (Note: Patients treated with Pulmozyme® or hypertonic saline should have a 4 week Screening washout period, while patients not receiving these treatments are to have a minimum 2-week Screening period. Pulmozyme® and hypertonic saline cannot be used after Baseline [Day 1]). 12. 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 IL-10]) and cell counts (i.e., neutrophils, macrophages) (induced samples collected at all centres; pre-dose and 1 hour post treatment and at selected centres; 1 hour post treatment and at 4 hours post treatment for inflammatory markers); EBC levels of pH and superoxide (and / or 8-isoprostane); Blood markers, neutrophil elastase, neutrophil elastase / AAT complex, neutrophil count, IL-6, IL-8, IL-10 and CRP levels; aPTT and platelet count. 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; 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; Response to 10-metre shuttle exercise test (Singh et al 1994; Serisier et al 2006).
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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) | No |
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
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | |
E.8.9.1 | In the Member State concerned months | 12 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 12 |