| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| COPD Subjects with an Asthmatic Component |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease (COPD and asthma) |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009028 |
| E.1.2 | Term | Chronic obstructive asthma (with obstructive pulmonary disease) |
| E.1.2 | System Organ Class | 100000004855 |
|
| 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 evaluate the dose-response of once-daily
UMEC in combination with FF (100/15.6, 100/62.5, 100/125,
and 100/250 mcg) compared to FF 100 mcg monotherapy
over a 4-week treatment period in COPD subjects with an
asthmatic component. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the treatment effect of FF/UMEC compared to the combination of FF and VI over a 4-week treatment period in COPD subjects with an asthmatic
component.
Exploratory Objective(s)
- To evaluate the treatment effect of VI in COPD subjects with an asthmatic
component treated with FF/UMEC
- To evaluate the effect on lung function of discontinuing UMEC in COPD subjects with an asthmatic component
- To explore the relationship of patient reported outcomes (PROs) with patient
characteristics such as level of reversibility and obstruction, diagnosis and other measures of disease severity
- To explore the responsiveness of PRO measures to response on other outcomes and determine potential responder definitions
- To determine differential responses and their phenotypic characteristics by
exploratory and subgroup analyses
Other Objective(s)
- To evaluate the safety of FF/UMEC therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age: 18 years of age or older at Visit 0
2.Diagnosis: At the point of screening subjects, have sufficient medical
history (e.g., signs and symptoms) to diagnose the subject as having
COPD in accordance with the definition by the American Thoracic
Society/European Respiratory Society (Celli, 2004), AND evidence of an
asthmatic component as demonstrated by spirometry, reversibility and
current therapy at Visit 1 as follows:
A.Spirometry:
1.A best post-bronchodilator morning (AM) FEV1 ≥50% and ≤80% of
the predicted normal value at Visit 1 will be based upon the ERS Global
Lung Function Initiative.
AND
2. Pre- and post-bronchodilator FEV1/FVC ratio <0.7 at Visit 1.
B. Reversibility of Disease: defined as: ≥12% and ≥200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1. If a subject fails to demonstrate an increase in FEV1 ≥12% and ≥200 mL at Visit 1, then the subject will not be allowed to repeat spirometry at a subsequent visit to determine eligibility.
C. Current Therapy: Subjects are eligible if they have received ICS-containing therapy for at least 12 weeks prior to Visit 1 and if their treatment during the 4 weeks immediately prior to Visit 1 consisted of either of the two regimens (1 or 2) below.
1. A stable ICS dose taken alone (e.g., FP ≥200-1000 mcg daily or equivalent dose)
OR
2. A stable dose of ICS (e.g., FP ≤500 mcg daily or equivalent dose) with adjunctive therapy (i.e., LABA, LAMA, leukotriene receptor antagonists [LTRA], theophylline, etc.). Subjects taking Symbicort as needed must switch to Symbicort maintenance dosing with as-needed use of a short acting
beta2 agonist (SABA) for symptom relief at least 4 weeks prior to Visit 1. Examples of acceptable doses of commonly prescribed ICS and ICS/LABA combination medication will be provided. Dosing regimen (once or twice daily to equal the total daily dose) should be restricted to the current local product labels.
3. Short-Acting β2 Agonists (SABAs): All subjects must be able to replace their current SABA inhaler with albuterol/salbutamol aerosol inhaler at Visit 1 as needed for the duration of the study. Subjects may instead use their own nebulized albuterol/salbutamol as needed, if this method is preferred. Subjects must be judged capable of withholding albuterol/salbutamol for at least 4 hours prior to study visits.
4. Type of Subject: Outpatient subjects who are smokers or non-smokers
5. Gender: Male or Eligible Female, defined as having documentation of nonchildbearing potential or childbearing potential as follows:
Non-child bearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile): Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile (e.g., age appropriate, >45 years, in the absence of hormone replacement therapy).
OR
Child bearing potential: Has a negative pregnancy test at screening and agrees to use an acceptable contraceptive method consistently and correctly (i.e., in accordance with the approved product label and the instructions of the physician for the duration of the study – screening to follow-up contact).
The following is the GSK list of acceptable, highly effective methods for avoiding pregnancy with failure rates of less than 1% per year:
• Abstinence from penile-vaginal intercourse when this is the female’s preferred and usual lifestyle [Hatcher, 2007a]
• Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a]
• Injectable progestogen [Hatcher, 2007a]
• Implants of etonogestrel or levonorgestrel [Hatcher, 2007a]
• Estrogenic vaginal ring [Hatcher, 2007a]
• Percutaneous contraceptive patches [Hatcher, 2007a]
• Intrauterine device (IUD) or intrauterine system (IUS) with a failure
rate <1% per year as stated in the product label [Hatcher, 2007a]
• Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject [Hatcher, 2007a]. For this definition, “documented” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records.
• Male condom combined with a female diaphragm either with or without a vaginal spermicide (foam, gel, film, cream, or suppository) [Hatcher, 2007b] Female subjects should not be enrolled if they are pregnant or lactating or if they plan to become pregnant during the time of study participation. Serum and urine pregnancy testing is required of all females of child bearing potential as defined in the Time and Events table (Table 12).
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| E.4 | Principal exclusion criteria |
1. History of Life-threatening Respiratory Event: Defined for this protocol as an episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures within the last 5 years.
2. Respiratory Infection: Any infection of the upper or lower respiratory tract, sinus, or middle ear that is not resolved within 4 weeks of Visit 1 and led to a change in COPD/asthma management or, in the opinion of the investigator, is expected to affect the subject’s COPD/asthma status or the subject’s ability to participate in the study.
3. Severe Exacerbation: A subject must not have had an exacerbation
prior to Visit 1 meeting either of the following criteria:
- Deterioration of COPD or asthma requiring either the use of oral
corticosteroids for at least 3 days or parenteral corticosteroids in the
previous 3 months.
- An in-patient hospitalization or emergency department visit due to
COPD or asthma that required any oral or parenteral corticosteroids in the previous 6 months
For consistency, courses of corticosteroids separated by 1 week or more
should be treated as separate exacerbations.
4. Risk Factors for Pneumonia: Immune suppression (e.g., Human Immunodeficiency Virus [HIV], Lupus) or other risk factors for pneumonia (e.g.,neurological disorders affecting control of the upper airway, such as Parkinson’s Disease, Myasthenia Gravis). Please view protocol for further information.
5. Pneumonia: Hospitalization for pneumonia within 3 months prior to Visit 1.
6. Concurrent Respiratory Disease: A subject must not have current evidence of the following: pneumonia, pneumothorax, atelectasis (segmental or larger), pulmonary fibrotic disease, bronchopulmonary dysplasia, or other respiratory abnormalities other than chronic obstructive pulmonary disease (including chronic bronchitis and emphysema) or asthma. Please view protocol for further information.
7. Other Concurrent Diseases/Abnormalities: A subject must not have any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation. Please view protocol for further information.
8. Viral Hepatitis and HIV: A positive Hepatitis B surface antigen or positive Hepatitis C antibody pre-study or at Visit 1. Subjects with HIV-positive history are not eligible.
9. Hepatic Impairment: Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
10. Allergies:
- Drug Allergy: Any immediate or delayed hypersensitivity reaction to a β2 agonist, sympathomimetic drug, corticosteroid please view protocol for further information.
11. Concomitant Medication: Administration of prescription or over-the-counter medication that would significantly affect the course of COPD or asthma, or interact with study drug, please view protocol for further information.
12. Lung Resection: Subjects with lung volume reduction surgery within 12 months prior to Visit 1.
13. Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., ≤12 hours per day) is not exclusionary.
14. Nebulized Therapy: Regular use (prescribed for use every day) of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy. As-needed nebulized albuterol/salbutamol use is not exclusionary.
15. Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
16. Unstable or life-threatening cardiac disease: please view protocol for further information.
17. Abnormal and clinically significant 12-Lead ECG finding: Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject’s medical history and exclude subjects who would be at undue risk by participating in the trial, and the subject would be considered a run-in failure. Please view protocol for further information.
18. Diseases Preventing Use of Anticholinergic: Subjects with medical conditions such as narrow-angle glaucoma, prostatic hyperplasia, or bladder neck obstruction should only be included if, in the opinion of the investigator, the benefit outweighs the risk.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in clinic trough (pre-dose) FEV1 at the end of Treatment Phase A |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Visit 3 (baseline) and Visit 6 (Week 4, Day 29) |
|
| E.5.2 | Secondary end point(s) |
Mean change from baseline in rescue medication use at the end of Treatment Phase A
Mean change from baseline in EXACT-RS score at the end of Treatment Phase A
Change from baseline in daily morning (AM) PEF (pre-dose and pre-rescue bronchodilator) measured at home and averaged over the last 21 days of Treatment Phase A
Change from trough in FEV1 at 3 hours post-study treatment at Visit 5
Change in clinic FEV1 following 2 puffs of albuterol/salbutamol given 3 hours post-study treatment dose at Visit 5
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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 | 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) | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| (Fluticasone Furoate/Vilanterol), Fluticasone Furoate |
|
| E.8.2.4 | Number of treatment arms in the trial | 12 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Germany |
| Poland |
| Romania |
| Russian Federation |
| Ukraine |
| United States |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 17 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 17 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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