E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Maintenance treatment of patients with moderate to severe stable chronic obstructive pulmonary disorder. |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009033 |
|
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 |
1. To assess the long term bronchodilator efficacy and benefit in terms of exacerbation control and disease-related health status and other secondary outcomes of LAS 34273 200 μg administered once daily by inhalation (via Novolizer®) for 52 weeks compared to placebo in patients with moderate to severe, stable chronic obstructive pulmonary disease (COPD). 2. To evaluate the long term safety and tolerability of LAS 34273 200 μg administered once daily for 52 weeks by inhalation (via Novolizer®) compared to placebo in the same target population.
|
|
E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
For inclusion and randomization in the trial, patients must meet each of the following criteria:
1. Males and non-pregnant, non-lactating females aged ≥ 40. Women of childbearing potential are allowed to enter the trial ONLY if they use TWO medically approved (i.e., mechanical or pharmacological) contraceptive measures. A female is considered to be of childbearing potential unless she has had an hysterectomy, is at least one year post-menopausal or has undergone tubal ligation. All women of childbearing potential must have a negative pregnancy test at Visit 1. 2. Patients with a clinical diagnosis of COPD, according to the GOLD guidelines: (http://www.goldcopd.com) and stable airway obstruction. 3. Patients whose FEV1 at Visit 1 measured between 30-45 min post inhalation of 400 μg of salbutamol is <80% of the predicted normal value (i.e., 100xobserved post-salbutamol FEV1/predicted FEV1 <80%) Predicted normal values to be used for calculation purposes are to be based on European Community for Steel and Coal predicted values (Quanjer et al. 1993) 4. Under the same above conditions, pre-dose FEV1 at Visit 2 needs to be within the range of 80-120% of the FEV1 measured at Visit 1 prior to salbutamol inhalation [i.e. within the interval: 0.8xpre-salbutamol FEV1 (Visit 1) – 1.2xpre-salbutamol FEV1 (Visit 1)]. FEV1 value in the formulae will be the mean FEV1 of the greatest FEV1 values obtained at the two timepoints measured at Visits 1 and 2. 5. Post-salbutamol FEV1/FVC ≤70% at Visit 1 (i.e,. 100xpost-salbutamol FEV1/FVC ≤70%) and FEV1/FVC ≤70% at Visit 2 (Day 1). 6. Current, or ex-cigarette smokers with a smoking history of at least 10 packs-year. Pack-years are calculated by dividing the number of cigarettes smoked per day by 20 (the number of cigarettes in a pack) and multiplying this figure by the number of years a person has smoked. For example, a person who smokes 40 cigarettes a day and has smoked for 10 years would have a 20 pack-year smoking history (40 cigarettes per day ÷ 20 cigarettes per pack = 2; 2 x 10 years of smoking = 20 pack-year history). Patients smoking other tobacco types will not be allowed, unless they meet the cigarette criterion as well. 7. Patients who are eligible and able to participate in the trial and who consent to do so in writing after the purpose and nature of the investigation have been explained to them. |
|
E.4 | Principal exclusion criteria |
Patients randomised into the trial must not present any of the following conditions: 1. History or current diagnosis of asthma, allergic rhinitis or atopy. 2. Eosinophil count > 600 cells/mm3. 3. A respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the six weeks prior to Visit 1. Patients who develop a respiratory tract infection or exacerbation during the run-in period will be discontinued from the trial prior to randomisation. 4. Patients who have been hospitalised for an acute COPD exacerbation in the 3 months prior to Visit 1. 5. Use of long-term oxygen therapy (≥ 15 hours/day). 6. Clinically significant respiratory conditions defined as: • Known active tuberculosis. • History of interstitial lung or pulmonary thromboembolic disease. • Pulmonary resection during the past 12 months. • History of life-threatening COPD. • History of bronchiectasis secondary to respiratory diseases others than COPD (e.g., cystic fibrosis, Kartagener’s syndrome, etc). • Patients who in the investigator’s opinion may need pulmonary rehabilitation or a thoracotomy during the trial. 7. Clinically significant cardiovascular conditions defined as: • Myocardial infarction during the last 6 months. • Unstable arrhythmia which has required changes in the pharmacological therapy or other intervention during the last 12 months, or newly diagnosed arrhythmia within the previous 3 months. • Hospitalisation within the previous 12 months for heart failure functional classes III (marked limitation of activity and only comfortable at rest) and IV (need of complete rest, confinement to bed or chair, discomfort at any physical activity and presence of symptoms at rest) as per the New York Heart Association. 8. Patients in whom the use of anticholinergic drugs is contraindicated: those with a known symptomatic prostatic hypertrophy, bladder neck obstruction or narrow-angle glaucoma. 9. Patients with any other serious or uncontrolled physical or mental dysfunction at the discretion of the investigator which could place the patient at higher risk derived from his/her participation into the study, could confound the results of the trial or is likely to prevent the patient from complying with the requirements of the trial or completing the trial period. 10. QTc [calculated according to Bazett’s formulae (QTc=QT/RR1/2), as indicated in the paper tracing generated by the equipment used to record the ECGs] above 470 milliseconds in any of the ECGs performed at Visit 1 or pre-dosing at Visit 2 (Day 1). 11. Patients with a life expectancy of less than 1 year because of disease severity. 12. Patients who do not demonstrate to perform reproducible spirometry attempts at Visit 1 and predosing at Visit 2 (Day 1) as stated in section 11.2.1. 13. History of untoward reactions to inhaled anticholinergics, sympathomimetic amines or inhaled medication or any component thereof (including report of paradoxical bronchospasm). 14. Patients unable to properly use a dry powder or pMDI inhaler device or to perform spirometry and peak flow measurements. 15. Clinically relevant abnormalities in the results of laboratory, ECG parameters, other than QTc, or physical examination at the screening evaluation (Visit 1) if the abnormality defines a disease state listed as an exclusion criterion, except for those related to COPD. 16. Patients who intend to use any concomitant medication not permitted by this protocol or who have not undergone the required washout period for a particular prohibited medication (see section 10.5.1). 17. Patients with a history of drug and/or alcohol abuse that may prevent compliance with trial activities. 18. Patients who have participated in other studies involving LAS 34273. 19. Treatment with any Investigational Medicinal Product (IMP) within 1 month prior to Visit 1 or the equivalent time to 6 half-lives of the IMP, whichever is longer. 20. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers will be excluded). 21. Patients who are unlikely to be co-operative, take their medication, complete their Electronic and Paper Diaries or attend the clinic at the required times. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint: Trough forced expiratory volume in one second (FEV1). Trough FEV1 is defined as the mean FEV1 value of the two greatest FEV1 readings measured at 23 and 24 hours after the administration of the investigational medicinal product (IMP). The primary timepoint will be trough FEV1 values at the end of the first 28 weeks of treatment.
Secondary efficacy Endpoint: - Exacerbations: • Time to first exacerbation, rates of exacerbations, severity, associated treatment and need for hospitalisation will be assessed. • Resource utilisation, particularly associated with exacerbations will also be documented and average costs subsequently applied. - Health status / Quality of Life: • Saint George’s Respiratory Questionnaire (SGRQ): total and three dimension scores (symptoms, activity, impact) • EuroQol questionnaire (EQ-5D): weighted health state index and associated visual analogue scale (VAS)
Safety Endpoints: • Adverse events (AEs) • Serious adverse events (SAEs) • Physical examination (including blood pressure) • Laboratory assessments (standard haematology, biochemistry and urinalysis) • 12-lead ECG tracing • 3-lead 24-h Holter monitoring (in a subgroup of patients, approximately 20% of the total sample, performed at selected centres) • Number of withdrawals due to AEs • Reasons for withdrawal.
|
|
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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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
|
|
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 | |
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 |