| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
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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 |
1. To determine the efficacy (as defined by FEV1 (AUC0-12 hr)) of MF/F MDI 400/10 mcg BID compared with MF 400 mcg BID, in order to assess the added benefit of F to the combination
2. To determine the efficacy (as defined by pre-dose FEV1 in the morning) of MF/F 400/10 mcg BID and MF/F 200/10 mcg BID compared with F 10 mcg BID, in order to assess the benefit of the steroid component to the combination.
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| E.2.2 | Secondary objectives of the trial |
| To evaluate safety and to assess the efficacy of MF/F MDI 400/10 mcg BID and MF/F MDI 200/10 mcg BID compared with placebo by evaluating the change from baseline to Endpoint in quality-of-life assessments using the St George’s Respiratory Questionnaire (SGRQ), nocturnal COPD symptoms, a composite score reflecting partly stable COPD control, and the time-to-first COPD exacerbation. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- A diagnosis of moderate to severe COPD based on a pre-bronchodilator FEV1/FVC ratio of <=70%.
- At Screening, the subject’s post-bronchodilator FEV1 must be <=60% predicted normal and >=25% predicted normal.
- A subject must have symptoms of COPD (chronic cough and sputum production that are not attributable to another disease process) for at least 24 months.
- A subject must be an ex-smoker or current smoker with a smoking history of >=10 pack years. NOTE: Current smokers must provide verbal notification or written documentation that attests to their inability to stop smoking after participation (or declining to participate) in a smoking cessation program. Ex-smokers are defined as those who have stopped smoking at least 12 months prior to Visit 1.
- A subject must have been on only SABA/short-acting anticholinergics for relief, for at least 2 weeks prior to randomization (Visit 2).
- A subject must have a documented history of one or more COPD exacerbations requiring a course of oral corticosteroid and/or antibiotics within 2 to 14 months before screening.
- A subject must withdraw from parenteral steroids, oral steroids and antibiotics at least 4 weeks prior to Screening (Visit 1).
- If, based on the medical judgment of the investigator, there is no inherent harm in changing the subject’s current COPD therapy, the subject must be willing to discontinue his/her prescribed short-acting anticholinergics, ICS or ICS/LABA combination at the Screening Visit, and be transferred to treatment with SABA/short-acting anticholinergics for relief for 2 weeks prior to the Baseline/Randomization Visit.
- The subject must have two valid scans, as confirmed by the local dual energy X-ray absorptiometry (DXA) centre for
lumbar spine, left total femur (right femur will not be an acceptable substitute), and femoral neck prior to randomization. ’Valid scans’ are defined in the protocol.
- Clinical laboratory tests (complete differential blood counts [CBC], blood chemistries, C-reactive protein, and urinalysis) conducted at the Screening Visit must be clinically acceptable to the investigator/sponsor. An electrocardiogram (ECG)
performed at the Screening Visit must be clinically acceptable to the investigator. A chest X-ray performed at the Screening Visit or within 12 months prior to the Screening Visit must be clinically acceptable to the investigator.
- A female subject of childbearing potential must be using a medically acceptable, adequate form of birth control, as defined in the protocol, and must have a negative serum pregnancy test at Screening in order to be considered eligible for enrollment.
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| E.4 | Principal exclusion criteria |
1. A subject who demonstrates an increase in absolute volume of ≥400 mL at the Screening Visit or prior to the Baseline Visit within 30 minutes after administration of four inhalations of albuterol/salbutamol (total dose of 360 to 400 mcg), or nebulized 2.5 mg albuterol/salbutamol.
2. A current diagnosis of asthma.
3. Blood eosinophil count greater than 0.57 x 103/μL.
4. A subject who has undergone lobectomy, pneumonectomy or lung volume reduction surgery.
5. A diagnosis of lung cancer.
6. A subject who requires long-term administration of oxygen (>15 hours per day).
7. A subject who experiences an exacerbation of COPD requiring medical intervention within 4 weeks prior to randomization or treatment with 3 additional excluded medication (other than SABA/short acting anticholintergic to be used as rescue medication.)
8. Alpha-1-antitrypsin deficiency
9. A subject with cataract extractions on both eyes.
10. A subject with a history and/or presence of intraocular pressure in either eye ³22 mm Hg, glaucoma, and/or posterior subcapsular cataracts. A subject who has undergone incisional or intraocular surgery in which the natural lens is still present in the eye. A subject with a history of penetrating trauma to both eyes. A subject with one or more of the following LOCS III grades at screening:
• NO: ³3.0
• NC: ³3.0
• C: ³2.0
• P: ³0.5
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. To assess the contribution of F 10 mcg BID to the combination: The mean AUC (0-12 hr) of the change from Baseline to Week 13 Endpoint. The baseline FEV1 will be the average of the two predose FEV1 measurements (30 minutes prior to dosing and 0 hour, immediately prior to dosing) at the baseline Visit.
2. To assess the contribution of MF to the combination: The mean change from Baseline to the Week 13 Endpoint in AM predose FEV1
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 | No |
| 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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The subject is considered to have completed the study upon completion of the last protocol-specified contact (eg, visits or telephone contacts).
For those subjects, who do not complete the study, subject participation will be considered upon the completion of the last visit or contact (eg, phone contact with the investigator or qualified designee).
The overall study ends when the last remaining subject has completed or has been discontinued from the study.
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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 | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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