| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease |
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| E.1.1.1 | Medical condition in easily understood language |
| A lung disease caused by smoking, which leads to long-term breathing problems, cough and sputum (phlegm) production. |
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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 | 17.0 |
| 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 |
To determine the efficacy, as defined by FEV1 2-hours post-dose on Day 169, of FP/FF 500/10 fixed dose combination compared with FP inhalation suspension 500µg BID, in order to assess the contribution of the LABA component (FF) to the efficacy of the combination.
To determine the efficacy, as defined by pre-dose FEV1 on Day 169, of FP/FF 500/10 and FP/FF 250/10 fixed dose combinations compared with FF inhalation solution 10µg BID, in order to assess the contribution of the ICS component (FP) to the efficacy of the combination. |
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| E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of FP/FF 500/10 and FP/FF 250/10 compared with placebo by evaluating quality of life (via SGRQ) and symptoms (via BDI/TDI), AECOPD and rescue medication use over 24 weeks.
- To evaluate the long-term safety of treatment with the combination FP/FF inhalation suspension at doses of FP/FF 500/10 and FP/FF 250/10μg BID for up to 52 weeks. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study 1: Serial 12-Hour Spirometry (included in current protocol, dated 05 June 2014)
In a subset of patients, serial spirometry will be measured over 12 hours and the following endpoints derived:
Objectives:
- Measure trough FEV1 at 12 hpd on Day 1 and Day 169.
- Measure FEV1 AUC0-12 on Day 1 and Day 169.
Sub-study 2: Ophthalmic examination substudy (included in current protocol dated 05 June 2014)
Objectives:
- Derive the maximum absolute value and maximum increase from baseline for each eye up to Visit 9 (Day 169) and up to Visit 14 (Day 365) for LOCS III grades, IOP and visual acuity and summarized by treatment group.
- Summarize the number (%) of patients with an increase from baseline in IOP >7 mmHg in either eye and the number of patients with an increase sustained for more than 1 visit. - Derive exposure-adjusted event rates for the above events to adjust for varying duration of exposure across treatment groups.
*If a sufficient number of events have occurred then the data will be analyzed* |
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| E.3 | Principal inclusion criteria |
1. Males and females at least 40 years of age. Females may be of either childbearing or non-childbearing potential. All females of childbearing potential must be using an acceptable, highly effect method of contraception and must also have a negative urine pregnancy test at screening.
2. A clinical diagnosis for at least 6 months prior to screening of COPD according to Global initiative for Obstructive Lung Disease guidelines (GOLD, 2014).
3. History of at least 10 pack-years of tobacco smoking.
4. Spirometry at Visit 1 and Visit 2 following 4 puffs (360 μg) albuterol pMDI via spacer showing:
a) post-bronchodilator FEV1 ≤70% of predicted normal (Global Lung Function Initiative reference range; Quanjer et al, 2012) and,
b) post-bronchodilator FEV1/FVC ratio <0.7
5. Capable of self-administering nebulized study medication, assessed at device training at Visit 1 and as witnessed on self-administered dosing at Visit 1 and Visit 2.
6. Able to understand and complete the study requirements (including literacy, to enable e-diary and questionnaire completion), provide written informed consent, and agree to abide by the study protocol and its restrictions. |
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| E.4 | Principal exclusion criteria |
1.Current diagnosis of asthma
2.Alpha-1 anti-trypsin deficiency
3.Other chronic or active respiratory disorder
4.Symptoms of, or treatment for an AECOPD requiring antibiotics and/or oral/systemic corticosteroids or in-patient hospitalization during the 28 days preceding screening
5.Lower respiratory tract infection requiring treatment with antibiotics during the 28 days preceding screening
6.History or presence of pulmonary hypertension, respiratory failure, cor pulmonale or right ventricular failure
7.History of pulmonary lobectomy, lung volume reduction surgery, or lung transplantation
8.Use of supplemental oxygen therapy for more than 12 hours per day (includes night-time use)
9.Patients participating in or planning to participate in the active phase of a supervised pulmonary rehabilitation program during the trial
10.Clinically significant, abnormal chest X-ray at screening indicating an active/significant disease process other than COPD. If a prior chest X-ray or thoracic high resolution CT scan within 6 months prior to screening is available this will be acceptable
11.History of long QT syndrome or screening ECG with QTcF greater than 460 milliseconds
12.History within past 5 years of paroxysmal atrial fibrillation.Patients with continuous atrial fibrillation controlled with a rate control strategy (i.e., cardioselective β-blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be included if the ventricular rate is below 100 bpm
13.Any other clinically significant abnormality on the 12-lead ECG at screening which in the judgment of the investigator would put the patient at potential risk if enrolled into the trial (these patients should not be re-screened)
14.Current evidence of, or history within the 6 months prior to screening of unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, or myocardial infarction
15.History of malignancy of any organ system treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases. The only exceptions are previous in situ carcinoma of the cervix, localized basal cell carcinoma of the skin or localized squamous carcinoma of the skin if the patient has been treated and is considered cured
16.Evidence of oropharyngeal candidiasis at screening
17.Known history of hypothalamic-pituitary-adrenal axis dysfunction
18.Uncontrolled glaucoma and/or raised IOP within 9 months of screening. Patients with chronic glaucoma will only be considered “controlled” and eligible for the trial if they have been on stable treatment (unchanged agent and dose) for the prior 9 months and they have had IOP measurement within this period documented as normal (≤21 mm Hg; documented evidence will be required for eligibility)
19.Patients known to be HIV positive. Specific testing for HIV will not be conducted for this trial
20.Use of any investigational drug within 28 days, or 5 half lives, prior to screening whichever is longer
21.Use of medications with the potential to interact with fluticasone propionate, formoterol fumarate (as indicated in the current Investigators’ Brochure), albuterol or ipratropium bromide (as indicated in respective product labels), or medications with the potential to affect or confound COPD disease status
22.Patients with a history of reactions/hypersensitivity to any of the following inhaled drugs or drugs of a similar class: short- or long-acting β2 agonists (e.g. albuterol, formoterol), corticosteroids (e.g. fluticasone propionate), anticholinergics (e.g. ipratropium bromide), sympathomimetic amines. Patients with previous reaction to inhaled agents due to lactose sensitivity alone will be permissible for this study
23.Patients who are unable to stop any of the following medications as of Visit 1, and refrain from their use throughout the study until the final dose of study drug
24.Pregnant or nursing females or females intending to become pregnant during the course of the study
25.Patients with a clinically significant abnormal laboratory test(s) at screening deemed exclusionary by the Investigator
26.Patients with a history of illegal drug or alcohol abuse within the past 5 years
27.Other acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
24 week placebo-controlled period
Co-primary efficacy endpoints:
- Change from baseline in pre-dose FEV1 at Day 169.
- Change from baseline in 2-hour post-dose FEV1 at Day 169.
28-week extension period
Primary endpoints – Safety
- AEs/SAEs
- Change from baseline in pre-dose vital signs (pulse rate, systolic and diastolic blood pressure) at Days 197, 281 and 365.
- Change from baseline in pre-dose 12-lead ECG parameters at Days 197, 281 and 365.
- Change from baseline in clinical chemistry and hematology parameters at Day 365.
- Change from baseline in visual acuity, IOP and LOCS III lens grades to Day 365 (subset of patients). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 week placebo-controlled period
- Both endpoints for will be assessed at Day 169.
28-week extension period
- All but two endpoints will be assessed at Day 365 and some at Days 197 and 281. |
|
| E.5.2 | Secondary end point(s) |
24 week placebo-controlled period
Secondary Efficacy endpoints:
• Rescue medication usage
- Change from baseline in no. of puffs of albuterol during a 24-hour period (averaged over each successive 4 week treatment interval and over the entire 24-week period).
- Change from baseline in percentage of rescue free 24-hour periods (during each successive 4 week treatment interval and over the entire 24-week treatment period).
• Other spirometry
- Change from baseline in pre-dose FEV1 on Days 15, 29, 57, 85 and 127.
- Change from baseline in pre-dose FVC on Days 15, 29, 57, 85, 127 and 169.
- Change from baseline in 2-hour post-dose FEV1 on Days 1 and 85.
- Change from baseline in 2-hour post-dose FVC on Days 1, 85 and 169.
- Onset of action (as measured by time to increase from pre-dose to post-dose FEV1 on Day 1 of ≥ 100 mL or ≥12% on Day 1).
- Peak FEV1 up to 2 hours post-dose on Day 1.
- FEV1 AUC0-12 on Days 1 and 169 (subset of patients).
- Trough FEV1 at 12 hours post-dose on Days 1 and 169 (subset of patients).
• AECOPD
- Proportion of patients with investigator-reported AECOPD (mild, moderate or severe, and moderate-or-severe) up to Day 169.
- Time from Day 1 to first investigator-reported AECOPD (mild, moderate or severe, and moderate-or-severe).
- Duration of investigator-reported AECOPD (mild, moderate or severe, and moderate-or-severe).
- Proportion of patients with patient-reported AECOPD via EXACT-PRO up to Day 169.
- Time from Day 1 to first patient-reported AECOPD via EXACT-PRO.
- Duration of patient-reported AECOPD via EXACT-PRO.
• Change from baseline in SGRQ total score and individual domain scores on Day 85 and Day 169.
• TDI focal score on Days 15, 29, 57, 85, 127 and 169.
Safety endpoints:
• Adverse events (AEs)/serious AEs (SAEs).
• Change from baseline in pre-dose vital signs (pulse rate, systolic and diastolic blood pressure) at Days 15, 29, 57, 85, 127 and 169.
• Change from baseline in post-dose vital signs (pulse rate, systolic and diastolic blood pressure) at Days 1, 85 and 169.
• Change from baseline in pre- and post-dose 12-lead ECG parameters at Days 1, 85, 169.
• Change from baseline in clinical chemistry and hematology parameters at Day 169.
• Change from baseline in visual acuity, IOP and LOCS III lens grades to Day 169 (subset of patients).
28-week extension period:
Secondary endpoints – efficacy
• Rescue medication usage
- Change from baseline in no. of puffs of albuterol during a 24-hour period (averaged over each successive 4 week treatment interval and over the entire 52-week treatment period).
- Change from baseline in percentage of rescue free 24-hour periods (during each successive 4 week treatment interval and over the entire 52-week treatment period).
• Change from baseline in pre-dose FEV1 and FVC at Days 197, 281 and 365.
• AECOPD
- Proportion of patients up to Day 365 with investigator-reported AECOPD (mild, moderate or severe, and moderate-or-severe).
- Time from Day 1 to first investigator-reported AECOPD (mild, moderate or severe, and moderate-or-severe).
- Duration of investigator-reported AECOPD (mild, moderate or severe, and moderate-or-severe).
- Proportion of patients up to Day 365 with patient-reported AECOPD via EXACT-PRO.
- Time from Day 1 to first patient-reported AECOPD via EXACT-PRO.
- Duration of patient-reported AECOPD via EXACT-PRO.
• Change from baseline SGRQ total score and individual domain scores at Days 281 and 365. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to section 5.2 of the current Protocol, dated 05 June 2014 |
|
| 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 | 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) | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Formoterol Fumarate Inhalation Solution (PR3) & Fluticasone Propionate Inhalation Suspension (PR4) |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| 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 | No |
| 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 |
| Argentina |
| Belgium |
| Canada |
| Chile |
| Colombia |
| Germany |
| Guatemala |
| Israel |
| Mexico |
| Netherlands |
| Peru |
| Poland |
| Russian Federation |
| Turkey |
| United States |
|
| 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
|
| Last visit of the last subject |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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