| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease (COPD) which may also be called emphysema or chronic bronchitis |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Compare the efficacy and safety of UMEC/VI Inhalation Powder (62.5/25mcg oncedaily) with fluticasone propionate/salmeterol (250/50mcg twice-daily) over 12 weeks in subjects with COPD who have a history of infrequent COPD exacerbations |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Type of subject: Outpatient
2. Informed Consent: A signed and dated written informed consent prior to study
participation
3. Age: Subjects 40 years of age or older at Visit 1
4. Gender: Male or female subjects.
A female is eligible to enter and participate in the study if she is of:
Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, ncluding 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 one of the following acceptable contraceptive methods used 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):
• Abstinence
• Oral Contraceptive, either combined or progestogen alone
• Injectable progestogen
• Implants of levonorgestrel
• Estrogenic vaginal ring
• Percutaneous contraceptive patches
• Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP
effectiveness criteria as stated in the product label
• 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. 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.
• Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent
(foam/gel/film/cream/suppository)
5. Diagnosis: An established clinical history of COPD in accordance with the definition
by the American Thoracic Society/European Respiratory Society [Celli, 2004] as follows:
Chronic obstructive pulmonary disease is a preventable and treatable disease state
characterized 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.
6. Smoking history: Current or former cigarette smokers with a history of cigarette
smoking of ≥10 pack-years [number of pack years = (number of cigarettes per
day/20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10
cigarettes per day for 20 years)]. Previous smokers are defined as those who have
stopped smoking for at least 6 months prior to Visit 1. Pipe and/or cigar use cannot
be used to calculate pack year history.
7. Severity of disease: A pre and post-salbutamol FEV1/FVC ratio of <0.70 and a postsalbutamol FEV1 of ≥30% and ≤70% of predicted normal values calculated using
NHANES III reference equations at Visit 1 [Hankinson, 1999; Hankinson, 2010].
8. Dyspnea: A score of ≥2 on the Modified Medical Research Council Dyspnea Scale
(mMRC) at Visit 1. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Pregnancy: Women who are pregnant or lactating or are planning on becoming
pregnant during the study
2. Asthma: A current diagnosis of asthma
3. Other Respiratory Disorders: Known α-1 antitrypsin deficiency, active lung
infections (such as tuberculosis), and lung cancer are absolute exclusionary
conditions. A subject, who, in the opinion of the investigator, has any other
significant respiratory condition in addition to COPD should be excluded. Examples
may include clinically significant bronchiectasis, pulmonary hypertension,
sarcoidosis, or interstitial lung disease. Inactive tuberculosis in more than one lobe is exclusionary. Allergic rhinitis is not exclusionary.
4. Other Diseases/Abnormalities: Subjects with historical or current evidence of
clinically significant cardiovascular, neurological, psychiatric, renal, hepatic,
immunological, endocrine (including uncontrolled diabetes or thyroid disease) or
hematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for <5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
5. Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, corticosteroid,
lactose/milk protein or magnesium stearate or a medical condition such as narrowangle
glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician contraindicates study participation or use of an inhaled anticholinergic.
6. Hospitalization: Hospitalization for pneumonia within 12 weeks prior to Visit 1
7. History of COPD Exacerbation: A documented history of at least one COPD
exacerbation in the 12 months prior to Visit 1 that required either oral corticosteroids, antibiotics, and/or hospitalization. Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, sputum volume, or sputum purulence.
8. Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1)
9. 12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1. Investigators will be provided with ECG reviews conducted by
a centralized independent cardiologist to assist in evaluation of subject eligibility.
Specific ECG findings that preclude subject eligibility are listed in Appendix 4 of the protocol.
(Section 11.4). The study investigator will determine the medical significance of any
ECG abnormalities not listed in Appendix 4.
10. Medication Prior to Spirometry: Unable to withhold salbutamol for the 4 hour
period required prior to spirometry testing at each study visit
11. Medications Prior to Screening: Use of the following medications according to the
following defined time intervals prior to Visit 1: (refer to protocol p.25).
12. 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.
13. Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., salbutamol) via nebulized therapy.
14. 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.
15. Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse
within 2 years prior to Visit 1.
16. Affiliation with Investigator Site: A subject will not be eligible for this study if
he/she is an immediate family member of the participating investigator, subinvestigator, study coordinator, or employee of the participating investigator.
17. Inability to read: A subject will not be eligible for the study if in the opinion of the
investigator the subject cannot read. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 24-hour weighted-mean FEV1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Trough and Weighted Mean FEV1
Rescue salbutamol use (percentage of rescue-free days and puffs/day)
Proportion of subjects achieving an increase in FEV1 of 12% and 200mL above baseline
Proportion of subjects achieving an increase of 100mL above baseline in trough FEV1
Peak and serial FEV1
Serial, trough and weighted mean FVC
TDI focal score
inspiratory capacity
Incidence of adverse events (AEs)
COPD exacerbations
Vital signs
EQ-5D health outcome assessment
COPD Assessment Test (CAT)
St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Trough FEV1 on Day 85, defined as the mean of the FEV1 values obtained 23 and 24 hours after morning dosing on Day 84.
Weighted Mean FEV1 over 0-6 hours post-dose on Day 1 Trough FEV1 at Day 28, Day 56, and Day 84 Rescue salbutamol use (percentage of rescue-free days and puffs/day) Proportion of subjects achieving an increase in FEV1 of 12% and 200mL above baseline at any time during 0-6 hours post-dose on Treatment Day 1
Proportion of subjects achieving an increase of 100mL above baseline in trough FEV1 Peak FEV1 Serial FEV1 over 0 to 6 hours post-dose on Day 1 Serial FEV1 over 0 to 24 hours post-dose on Day 84
Serial FVC at Day 1 (0-6 hours post-dose) and Day 84 (0-24 hours post-dose)
Trough FVC at Day 28, Day 56, Day 84 and Day. For further deatils refer to the protocol. |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | No |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Chile |
| Greece |
| Peru |
| Romania |
| Ukraine |
| 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
|
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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