| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD) which may also be called emphysema or chronic bronchitis |
|
| 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 |
| The primary objective is to compare the efficacy of UMEC/VI Inhalation Powder (62.5/25 mcg) once-daily with tiotropium (18 mcg) once-daily over 12 weeks for the treatment of subjects with COPD who have received tiotropium and continue to have symptoms while on tiotropium. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to compare effects of UMEC/VI Inhalation Powder (62.5/25 mcg once-daily) with tiotropium (18 mcg once-daily) on Health Related Outcomes and symptoms over 12 weeks in subjects with COPD.
Safety and tolerability of UMEC/VI will also be assessed. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the run-in phase must be able to read and understand the study documentation relating to informed consent and patient questionnaires and meet all 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, 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. Bronchodilator Treatment: Subjects must have been on tiotropium either via the HandiHaler device or Respimat for at least 3 months prior to screening.
6. COPD Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society [Celli, 2004].
7. 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.
Note: Pipe and/or cigar use cannot be used to calculate pack-year history
8. Severity of Disease: A pre and post-albuterol/salbutamol FEV₁/FVC ratio of <0.70 and a pre and post-albuterol/salbutamol FEV₁ of ≤70% and ≥50% predicted normal values calculated using NHANES III reference equations at Visit 1 [Hankinson, 1999; Hankinson, 2010].
9. Dyspnoea: A score of ≥2 on the Modified Medical Research Council Dyspnoea 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 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. Exacerbations: Has had more than 1 COPD exacerbation in the past 12 months. Subjects with an exacerbation within 6 weeks prior to Visit 1 are excluded from study.
COPD exacerbation is defined as worsening symptoms of COPD requiring the use of any additional treatment -other than the prescribed bronchodilator- such as the use of antibiotics, systemic corticosteroids, and/or emergency treatment or hospitalisation.
6. Contraindications: A history of allergy or hypersensitivity to any
anticholinergic/muscarinic receptor antagonist, beta2-agonist, 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 anticholinergic.
7. Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
8. 12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1, including the presence of a paced rhythm on a 12-lead ECG which causes the underlying rhythm and ECG to be obscured. 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 3.
The study investigator will determine the medical significance of any ECG abnormalities not listed in Appendix 3.
9. Inhaled Steroids: Currently taking an inhaled corticosteroid as part of their maintenance treatment for COPD. (Maintenance is defined as daily use for ≥1month)
10. Medication Prior to Spirometry: Unable to withhold albuterol/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 (see Protocol, Section 4.3) according to the following defined time intervals prior to Visit 1.
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., albuterol/salbutamol) via nebulized therapy.
14. Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 12 weeks prior to Visit 1 or are in the maintenance phase of a pulmonary rehabilitation program are 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: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.
17. 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) |
| The primary efficacy endpoint is trough FEV₁ on Day 85. Trough FEV₁ on Day 85 is defined as the mean of the FEV₁ values obtained at 23 and 24 hours after dosing on Day 84 (i.e. at Week 12) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary efficacy endpoint is trough FEV₁ on Day 85. Trough FEV₁ on Day 85 is defined as the mean of the FEV₁ values obtained at 23 and 24 hours after dosing on Day 84 (i.e. at Week 12) |
|
| E.5.2 | Secondary end point(s) |
• FEV₁ at 3 hrs post-dose on Day 84
Other endpoints will include:
• Trough FEV₁ at other time points
• Trough FVC at Day 85 and other time points
• Measure of lung volume (IC, FRC and RV) at 3 hrs post-dose
• FEV₁ at 15 mins and 3 hours post-dose at other time points
• FVC at 15 mins and 3 hours post-dose
• Measure of trough lung volume (IC, FRC and RV)
• Mean TDI focal score at Day 28, Day 56 and Day 84
• Rescue albuterol/salbutamol use (percentage of rescue-free
days and puffs/day)
Safety
• Incidence of adverse events
• Vital signs (pulse rate and systolic and diastolic pressure)
• COPD exacerbations
Health-Related Quality of Life/Health Outcomes
• EQ-5D
• Quality of Life Assessment with St. George's Respiratory
Questionnaire (SGRQ-C) total
• COPD Assessment Test (CAT)
• The Patient Reported Global Severity Impression and Global
Impression of Change
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• FEV₁ at 3 hrs post-dose on Day 84
• Trough FEV₁ at other time points
• Trough FVC at Day 85 and other time points
• Measure of lung volume (IC, FRC and RV) at 3 hrs post-dose
• FEV₁ at 15 mins and 3 hours post-dose at other time points
• FVC at 15 mins and 3 hours post-dose
• Measure of trough lung volume (IC, FRC and RV)
• Mean TDI focal score at Day 28, Day 56 and
Day 84
• Rescue albuterol/salbutamol use (percentage of rescue-free
days and puffs/day) recorded each morning
|
|
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 101 |
| 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 |
| Czech Republic |
| Estonia |
| Germany |
| Greece |
| Korea, Republic of |
| Netherlands |
| Norway |
| Russian Federation |
| South Africa |
| Spain |
| Sweden |
| Taiwan |
| Ukraine |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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