| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 of this study is to demonstrate that UMEC/VI, when used in symptomatic moderate to very severe COPD subjects, is non-inferior to the combination of indacaterol plus tiotropium, as measured by trough FEV1 on treatment day 85 (Visit 8). |
|
| E.2.2 | Secondary objectives of the trial |
|
| 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 Standard Operating Procedure (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.
6. Smoking History: Current or former cigarette smokers with a history of cigarette smoking of ≥10 pack-years. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
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 ≤70% predicted normal value at Visit 1, calculated using Quanjer reference equations [Quanjer, 2012].
8. Dyspnoea: A score of ≥ 2 on the Modified Medical Research Council Dyspnoea Scale (mMRC) at Visit 1.
9. QTc Criteria:
QTc <450 msec or
QTc <480 msec for patients with bundle branch block
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 ECGs obtained over a brief recording period.
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
|
|
| 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 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. Allergy 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, 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 or beta-2-agonist.
6. Hospitalisation: Hospitalisation for COPD or pneumonia within 12 weeks prior to Visit 1.
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. Specific ECG findings that preclude subject eligibility will be listed in Appendix 1. The study investigator will determine the medical significance of any ECG abnormalities not listed.
9. Screening labs: Significantly abnormal finding from clinical chemistry or haematology tests at Visit 1 as determined by the study investigator.
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 according to the following defined time intervals prior to Visit 1: Please view protocol for further information.
12 Oxygen: Use of LTOT.This is defined as oxygen therapy prescribed for greater than 12 hours per 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. 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: 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) |
Trough FEV1 on Treatment Day 85 (Visit 8).
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 + 1 day). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Visit 3 (Day2), Visit 7 (Wk12), Visit 8 (Wk12+1 or Day 85) |
|
| E.5.2 | Secondary end point(s) |
• Weighted mean (WM) FEV1 over 0-6 hours post dose at Week 12 (Visit 7). WM FEV1 is calculated from the pre-dose FEV1 (taken -30minutes and -5 minutes) and post dose FEV1 measurements at 1 hour, 3 hours and 6 hours post dose.
Other efficacy endpoints will include:
• Mean number of puffs per day of rescue medication over the study duration (from Day 1 to Week 12) and percentage of rescue free days.
• TDI focal score at 4 weeks, 8 weeks and 12 weeks.
• The Baseline Dyspnoea Index (BDI) and Transition Dyspnoea Index (TDI) will be used to measure the severity of breathlessness.
• SGRQ-C score at Week 4, 8 and 12 (Visits 5, 6, and 7 respectively).
• Trough FEV1 at Week 4 and Week 8 (Visit 5 and Visit 6).
• Weighted Mean FEV1 over 0-6 hours post dose at Day 1
• Inhaler preference (ELLIPTA DPI versus HANDIHALER versus BREEZHALER) at Week 12 (Visit 7).
Safety
• Incidence and severity of adverse events.
• Vital signs (pulse rate and systolic and diastolic pressure), taken at screening and end of treatment (plus any Early Withdrawal visits).
• COPD exacerbations.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Weighted Mean FEV1 - Visit 2 (Day 1) and Visit 7 (Week 12)
• Rescue albuterol/salbutamol use (number of puffs/day) and percentage of rescue free days - Baseline use will be during the 5-7 day run-in period, Rescue use will be evaluated over weeks 1-12 of the study.
• BDI/TDI – BDI at Visit 2 (Day1) and TDI at Visit 5 (Wk 4), Visit 6 (Wk 8)and Visit 7 (Wk 2)
• SGRQ-C – Visit 2 (Day 1), Visit 5 (Wk 4), Visit 6 (Wk 8) and Visit 7 (Wk 12).
• Trough FEV1 - Visit 5 (Week 4), and Visit 6 (Week 8)
• Inhaler preference – Visit 7 (Wk 12)
• Adverse event and COPD exacerbations: from Visit 1 to f-up contact
• Vital signs – Visit 1 and Visit 8 (Day 85)
|
|
| 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) | 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 | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| indacaterol plus tiotropium |
|
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 59 |
| 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 |
| Estonia |
| France |
| Germany |
| Hungary |
| Italy |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
|
| 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 | 11 |
Print
