| 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), also 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 | 17.1 |
| 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 |
The primary objective is to evaluate the efficacy and safety of the addition of UMEC 125 mcg to FF/VI 100/25 mcg once-daily and the addition of UMEC 62.5 mcg to FF/VI 100/25 mcg once-daily, compared with placebo plus FF/VI 100/25 once-daily over 12
weeks in subjects with COPD. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective is to evaluate the addition of UMEC 125 mcg to FF/VI 100/25mcg once-daily and the addition of UMEC 62.5 mcg to FF/VI 100/25 mcg once-daily, compared with placebo
plus FF/VI 100/25 once-daily on COPD-related health status
assessments over 12 weeks in subjects with COPD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion 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, 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 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].
6. Smoking History: Current or former cigarette smokers with a history of cigarette smoking of at least 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)]. Former 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-albuterol/salbutamol FEV1/FVC ratio of <0.70 and a pre and post-albuterol/salbutamol FEV1 of equal or less than 70% of predicted normal values at Visit 1 (Screening) calculated using Nutrition Health and Examination Survey (NHANES) III reference equations [Hankinson, 1999; Hankinson, 2010].
8. Dyspnea: A score of ≥2 on the mMRC Dyspnea Scale at Visit 1.
9. QTc Criteria:
QTc(F) <450msec or
QTc(F) <480msec for patients with QRS duration >120msec
The QTc is the QT interval corrected for heart rate according to either Bazett’s formula
(QTcB), Fridericia’s formula (QTcF), or another method, machine or manual overread.
For subject eligibility and withdrawal, QTcF will be used.
For purposes of data analysis, QTcF will be used as primary.
The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period. |
|
| E.4 | Principal exclusion criteria |
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 alpha-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 conditions in addition to COPD should be excluded. Examples
may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease.
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: Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, sympathomimetic, corticosteroid (intranasal, inhaled or systemic) lactose/milk protein or magnesium stearate, or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction, that, in the opinion of the study physician
contraindicates study participation or use of an inhaled LAMA, LABA or ICS.
6. Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.
7. Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Visit 1.
8. Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Visit 1.
9. 12-Lead ECG: An abnormal and clinical 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 study protocol. The study investigator will determine the medical significance of any ECG abnormalities not listed in Appendix 4 of the study protocol.
10. Clinically significant and abnormal laboratory finding at Screening (Visit1). After discussion with the Medical Monitor, the investigator may have the option to verify the abnormal lab result prior to Visit2.
11.Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
12. Excluded Medications: Use of the medications listed in the Table 1 of the study protocol (page 24) are not permitted within the defined time intervals prior to Visit 1and throughout the study
13. Prior enrolment in one of the replicate studies: subjects who have previously been assigned a subject number (enrolled) in study 200110 that is a replicate study of 200109.
14. 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., equal or less than 12 hours per
day) is not exclusionary.
15. Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy
16. Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1,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.
17. Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
18. 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.
19. Inability to read: In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete a questionnaire. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Trough Forced Expiratory Volume in one second (FEV1) on Day 85.
Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 84 (i.e., at Week 12). Baseline trough FEV1 is the mean of the two assessments made at -30 and -5 minutes pre-dose on Treatment Day 1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Weighted mean (WM) 0-6 hour FEV1 obtained post-dose on Day 84 (Week 12) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 |
| Open Label use of FF/VI throughout for 16 weeks |
|
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 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 | 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 |
| Canada |
| Chile |
| Romania |
| 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
|
| Phone call follow-up approximately 7 days after LSLV |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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