E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe Chronic Obstructive Pulmonary Disease (COPD) |
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E.1.1.1 | Medical condition in easily understood language |
disease affecting the lungs and leading to respiratory capacity decrease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009033 |
E.1.2 | Term | Chronic obstructive pulmonary disease |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective is to compare the efficacy and the safety of masitinib at 3 mg/kg/day or 4.5 mg/kg/day versus placebo in the treatment of patients with severe COPD. Primary endpoint: • Absolute change from baseline in the 6-minutes walking distance test at Week 24
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E.2.2 | Secondary objectives of the trial |
• Absolute change from baseline in the 6-minutes walking distance test at Week 4, 8, 12, 16 and 20 • Absolute change from baseline in the post-bronchodilator FEV1 (Forced Expiratory Volume in one second) at Week 4, 8, 12, 16, 20 and 24 • Absolute change from baseline over 24 weeks in the weekly dose of rescue medication (salbutamol) • Absolute change from baseline in the TDI Focal Score over 24 weeks of treatment • Absolute change from baseline in the SGRQ at Week 4, 8, 12, 16, 20 and 24 • Absolute change from baseline (W0) until Week 4, 8, 12, 16, 20 and 24 in symptoms of cough and sputum • Exacerbation rate during the W0-W24 period • Rate of Severe exacerbations during the W0-W24 period • Absolute change from baseline in CRP at Week 24 • Absolute change from baseline in further spirometry parameters (IC, FVC) at Week 4, 8, 12, 16, 20 and 24 • Absolute change from baseline in plethysmography parameters at Week 4, 8, 12, 16, 20 and 24. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient with history of chronic obstructive pulmonary disease for at least 12 months prior to screening visit (ATS/ERS 2005) and chronic productive cough for 3 months in each of the 2 years prior to screening visit (if other causes of productive cough have been excluded), and present during the 4 weeks preceding screening. 2. Patient with at least one exacerbation during the preceding year. 3. Patient with FEV1/FVC ratio (post-bronchodilator) 70%. 4. Patient with FEV1 (post-bronchodilator) between ≥ 30 % and 50 % of predicted value 5. Patient pre-treated with adequate and stable symptomatic treatment for at least 3 months prior to screening visit. 6. Former smoker (defined as: smoking cessation at least one year ago) or current smoker both with a smoking history of at least 10 pack years 7. Patient with normal organ function defined as: • absolute neutrophils count (ANC) ≥ 2.0 x 109/L, • haemoglobin ≥ 10 g/dL • platelets (PTL) ≥ 100 x 109/L • AST/ALT ≤ 3x ULN • bilirubin ≤ 1.5x ULN • creatinin clearance > 60 mL/min • albumin > 1 x LLN • Proteinuria < 30 mg/dL (1+) on the dipstick. If proteinuria is ≥ 1+ on the dipstick, 24 hours proteinuria must be < 1.5g/24 hours. 8. Male or female patient, aged 40 to 75 years inclusive, weight > 50 kg and BMI between 18 and 35 kg/m² 9. Female patient of childbearing potential (entering the study after a menstrual period and who have a negative pregnancy test), who agrees to use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. Acceptable forms of contraception include: • A documented placement of an intrauterine device (IUD) or intrauterine system (IUS) and the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) • Documented tubal ligation (female sterilization). In addition, a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used • Double barrier method: Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository • Any other contraceptive method with a documented failure rate of <1% per year • Abstinence 10. Male patients must use medically acceptable methods of contraception if your female partner is pregnant, from the time of the first administration of the study drug until three months following administration of the last dose of study drug. Acceptable methods include: • Condom; • If you have undergone surgical sterilization (vasectomy with documentation of azoospermia) a condom should also be used. Male patients must use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. The acceptable methods of contraception are as follows: • Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; • Surgical sterilization (vasectomy with documentation of azoospermia) and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository); • Your female partner uses oral contraceptives (combination oestrogen/progesterone pills), injectable progesterone or subdermal implants and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository); • Medically prescribed topically-applied transdermal contraceptive patch and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository); • Your female partner has undergone documented tubal ligation (female sterilization). In addition, a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used; • Your female partner has undergone documented placement of an intrauterine device (IUD) or intrauterine system (IUS) and the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository); • Abstinence. 11. Female patient of childbearing potential must have a negative pregnancy test at screening and baseline 12. Patient able and willing to comply with study procedures as per protocol. 13. Patient able to understand the patient card and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, during the first 2 months. 14. Patient able to understand, sign, and date the written voluntary informed consent form at screening visit prior to any protocol-specific procedures.
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E.4 | Principal exclusion criteria |
1. Pregnant, or nursing female patient 2. Patient experiencing COPD exacerbation indicated by a treatment with systemic glucocorticosteroids and/or antibiotics not stopped at least 4 weeks prior to the screening visit. 3. Patient with lower respiratory tract infection not resolved 4 weeks prior to the screening visit. 4. Patient with asthma and/or other relevant lung disease (e.g. history of bronchiectasis, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [e.g. fibrosis, silicosis, sarcoidosis], and active tuberculosis). 5. Patient currently participating in a pulmonary rehabilitation program or completion of a pulmonary rehabilitation program within 3 months preceding the screening visit. 6. Patients with known alpha-1-antitrypsin deficiency. 7. Patient with clinically significant cardiopulmonary abnormalities (diagnosed clinically or by X-ray / CT-scan / ECG) that are not related to COPD and that require further evaluation. 8. Patient who had major surgery within 2 weeks prior to screening visit 9. Patient presenting with cardiac disorders defined by at least one of the following conditions: • Patient with recent cardiac history (within 6 months) of: - Acute coronary syndrome - Acute heart failure (class III or IV of the NYHA classification) - Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death) • Patient with cardiac failure class III or IV of the NYHA classification • Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block) • Syncope without known aetiology within 3 months • Uncontrolled severe hypertension, according to the judgment of the investigator, or symptomatic hypertension 10. Patient with: • Life expectancy < 6 months • < 5 years free of malignancy, except treated basal cell skin cancer or cervical carcinoma in situ • Any severe and/or uncontrolled medical condition • Patient with an active infection (Human immunodeficiency virus infection and/or hepatitis B or C infection, tuberculosis...) 11. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent 12. Treatment with any investigational agent within 4 weeks prior baseline |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Absolute change from randomisation in the 6-minutes walking distance test at Week 24 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Absolute change from baseline in the 6-minutes walking distance test at Week 4, 8, 12, 16 and 20 • Absolute change from baseline in the post-bronchodilator FEV1 (Forced Expiratory Volume in one second) at Week 4, 8, 12, 16, 20 and 24 • Absolute change from baseline over 24 weeks in the weekly dose of rescue medication (salbutamol) • Absolute change from baseline in the TDI Focal Score over 24 weeks of treatment • Absolute change from baseline in the SGRQ at Week 4, 8, 12, 16, 20 and 24 • Absolute change from baseline (W0) until Week 4, 8, 12, 16, 20 and 24 in symptoms of cough and sputum • Exacerbation rate during the W0-W24 period • Rate of Severe exacerbations during the W0-W24 period • Absolute change from baseline in CRP at Week 24 • Absolute change from baseline in further spirometry parameters (IC, FVC) at Week 4, 8, 12, 16, 20 and 24 • Absolute change from baseline in plethysmography parameters at Week 4, 8, 12, 16, 20 and 24. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | 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) | 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.8.2.4 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |