| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD) |
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| MedDRA Classification |
| 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 primary objective is to determine if selected novel endpoints of peripheral airways resistance and reactance (measured by IOS), airway wall dimensions (measured by CT), and systemic inflammation (assessed by serum biomarkers) are sensitive to change following treatment with FSC 500/50, FP 500 and SAL 50, each compared with placebo, over a treatment period of 12 weeks in subjects with COPD. |
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| 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 |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Subjects who give their signed written informed consent to participate.
2. Male or female adults > or =40 years of age.
3. A female is eligible to enter and participate in this study if she is of:
a. non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal); or,
b. child-bearing potential, has a negative pregnancy test (urine) at screen, and one of the following applies:
• Abstinence from intercourse, or,
• Male partner was sterile prior to the female subject’s entry into the study, or,
• Use of implants of levonorgestrel; or,
• Injectable progesterone; or,
• Oral contraceptive (combined or progesterone only), contraceptive patch, vaginal ring; or,
• Any intrauterine device (IUD) with published data showing that the highest expected failure rate is less than 1% per year (e.g., PARAGARD), or,
• Double Barrier technique simultaneously using two of the following: spermicide, male condom, diaphragm, or female condom.
4. COPD Diagnosis: An established clinical history of COPD in accordance with the following definition by the American Thoracic Society/European Respiratory Society [American Thoracic Society / European Respiratory Society , 2004]:
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.
5. Tobacco Use: Must have current or prior history of at least 10 pack-years of cigarette smoking. All subjects randomised to the study will be stratified according to their smoking status (current or ex-smoker). Ex-smokers are defined as those who have stopped smoking for at least 6 months prior to visit 1. Ex-smokers are eligible to enter the study provided they have at least 10 pack years smoking history. Subjects making a conscious decision to stop smoking at anytime during the study and who refrain from smoking for >4 weeks will be discontinued from the study. Additionally, subjects who start smoking during the study and smoke for at least 7 consecutive days will be discontinued from the study.
6. Severity of Disease:
• Subjects with a measured post-albuterol (salbutamol) FEV1/FVC < or = 70% at Visit 1 (Screening).
• Subjects with a measured post-albuterol (salbutamol) FEV1 > or = 30% and < or = 70% of predicted normal and applicable correction factor according to ECCS. [Quanjer, 1993] at Visit 1 (Screening).
7. Evidence of bronchitis as a component of the COPD disease. Presence of a chronic productive (sputum-producing) cough for 3 months, in each of 2 successive years where other causes of chronic cough have been excluded.
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Women who are pregnant or lactating.
2. Subjects with a primary diagnosis of asthma. (Subjects with a prior history of asthma are eligible if COPD is currently their primary diagnosis)
3. Subjects with alpha-1 antitrypsin deficiency as the underlying cause of COPD.
4. Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung disease or other active pulmonary disease.
5. Subjects with lung volume reduction surgery within the previous 12 months.
6. Evidence of clinically significant abnormalities not believed to be due to the presence of COPD as noted on the screening visit CT scan.
7. Subjects with clinically significant cardiovascular (including clinically significant ECG abnormalities), neurological, psychiatric, renal, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that is uncontrolled.
8. Subjects with carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma would not be considered exclusion criteria if the subject was considered cured in less than 5 years since diagnosis.
9. Subjects who are medically unable to withhold their albuterol (salbutamol) or ipratropium for the 6 hour period required prior to spirometry and IOS testing at each study visit.
10. Any adverse reaction including immediate or delayed hypersensitivity to any beta-agonist, sympathomimetic drug, or intranasal, inhaled, or oral corticosteroid including any components of the formulations (e.g. lactose or milk protein).
11. Initiation of systemic beta-blocker medications at any time during the study. Systemic beta-blockers and beta-blocker eye drops are allowed for those subjects who have been on a stable regimen for at least 30 days prior to screening and judged capable to continue this regimen until discharged from the study.
12. The following medications are not permitted during the study and must not have been taken for the indicated times prior to Visit 1 (Screening):
- Inhaled anticholinergic and short-acting beta2-agonist combination product: No use within 6 hours of Visit 1 or at any time during the study
- Oral beta-agonists: No use within 48 hours of Visit 1 or at any time during the study
- Long acting beta-agonists: No use within 48 hours of Visit 1 or at any time during the study
- Theophylline preparations:No use within 48 hours of Visit 1 or at any time during the study
- Cromolyn and Nedocromil inhaler: No use within 48 hours of Visit 1 or at any time during the study
- Zafirlukast, montelukast, zileuton: No use within 48 hours of Visit 1 or at any time during the study
- Tiotropium: No use within 7 days of Visit 1 or at any time during the study
- Oral, inhaled or parenteral corticosteroid or Inhaled corticosteroid/long acting beta-agonist combination product: No use for > 14 consecutive days in the 6 months prior to Visit 1 AND no use within 30 days of Visit 1 or at any time during the study. See also exclusion #16.
- Any other investigational medication: 30 days or 5 half-lives, whichever is longer; not currently part of another IND study
13. Subjects receiving treatment with long-term oxygen therapy (LTOT), defined as oxygen therapy prescribed for 12 hours or more per day, or subjects who require supplemental oxygen more often than on an occasional (prn) basis with the following exceptions.
• Subjects who reside at altitudes > 5000 feet above sea level requiring oxygen round-the-clock not exceeding 2L/min will be eligible to participate in this study.
• Subjects who require nocturnal oxygen therapy with a flow rate not exceeding 2L/min will be eligible to participate in this study.
• Subjects who require oxygen with exertion for less than 2 hours per day at a flow rate no greater than 2L/min will be eligible to participate in this study.
14. Use of ritonavir at any time during the study.
15. Use of immunosuppressive medications at any time during the study. Immunotherapy for the treatment of allergies is allowed during the study provided that the subject has received a constant dose for 30 days prior to the Screening Visit and the dose is maintained during the study.
16. Subjects with COPD exacerbation requiring corticosteroid (inhaled or systemic) and/or antibiotics in the last two months prior to screening.
17. Subjects who require nocturnal positive pressure for sleep apnea.
18. Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Visit 1 (Screening) or who will enter the acute phase of a Pulmonary Rehabilitation Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation program are not excluded. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Pre-dose R5 – R15 (i.e. the difference in the resistance measured at 5Hz and 15Hz, which is an indicator of peripheral airway obstruction) as measured by IOS |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Information not present in EudraCT |
| E.6.5 | Efficacy | Information not present in EudraCT |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Evaluation of novel endpoints |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | No |
| 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 |
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| 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
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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 | 0 |
| 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 | 1 |
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