| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD). |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
|
| 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 the study is to evaluate the effect of FF/VI Inhalation Powder 100/25 mcg administered once daily (QD) compared with placebo on aPWV in subjects with COPD and aPWV ≥ 12.0 m/s at baseline. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to confirm the efficacy of FF/VI Inhalation
Powder 100/25 mcg QD compared with placebo in improving lung function in subjects with COPD and aPWV ≥ 12.0 m/s at baseline, and to further evaluate the safety in those subjects. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrollment in the study must meet all of the following criteria:
1.Type of subject: outpatient
2.Informed consent: Subjects must give their signed and dated written informed consent to participate.
3.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 amenorrheic for greater than 1 year with an appropriate clinical profile, e.g., age appropriate, history of vasomotor symptoms. However in questionable cases, a blood sample with FSH > 40MIU/ml and estradiol <40pg/ml (<140 pmol/L) is confirmatory.
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):
•Complete abstinence from intercourse from screening until the Follow-Up Phone Contact; or
•Male partner is sterile (vasectomy with documentation of azoospermia) prior to female subject entry into the study, and this male partner is the sole partner for that subject; or
•Implants of levonorgestrel inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or
•Injectable progestogen administered for at least 1 month prior to study medication administration and administered until the Follow-Up Phone Contact; or
•Oral contraceptive (combined or progestogen only) administered for at least one monthly cycle prior to study medication administration; or
•Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal agent (foam/gel/film/cream/ suppository); or
•An intrauterine device (IUD), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; or
•Estrogenic vaginal ring; or
•Percutaneous contraceptive patches
4.Age: ≥40 years of age at Screening (Visit 1)
5.COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society(ATS) /European Respiratory Society (ERS) [Celli, 2004]:
COPD is a preventable and treatable disease 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.Tobacco use: Subjects with a current or prior history of ≥10 pack-years of cigarette smoking at Screening (Visit 1). Former 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.
Number of pack years = (number of cigarettes per day/20) x number of years smoked
7.Severity of Disease:
•Subjects with a measured post-albuterol/salbutamol FEV1 ≤70% of predicted normal values calculated using NHANES III reference equations [Hankinson, 1999; Hankinson, 2010] at Screening (Visit 1).
•Subject with a measured post-albuterol/salbutamol FEV1/FVC ratio of ≤0.70 at Screening (Visit 1)[Pelligrino, 2005]
Post-bronchodilator spirometry will be performed approximately 10-15 minutes after the subject has self-administered 4 inhalations (i.e., total 400mcg) of albuterol/salbutamol via an MDI with a valved-holding chamber.
8.Baseline aPWV: subjects with a measured aPWV≥12.0 m/s at Screening (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: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD)
3.Alpha1-antitrypsin deficiency: Subjects with Alpha1-antitrypsin deficiency as the underlying cause of COPD
4.Other respiratory disorders: Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases.
5.A cardiovascular event (e.g., Acute Coronary Syndrome, Stroke, Coronary Artery Bypass Surgery, Percutaneous Coronary Intervention) in the 6 months prior to Visit 1.
6.Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1) or having had lung transplantation.
7.Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of ‘acute worsening of COPD that is managed by subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician in the 6 weeks prior to Visit 1’ or ‘subjects who are hospitalized due to poorly controlled COPD within 12 weeks of Visit 1’.
8.Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Visit 1.
9.Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, gastrointestinal, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled. 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.
10.Current severe heart failure: Subject with New York Heart Association Class IV heart failure. Subject will be excluded if they have a known ejection fraction of <30% [American Heart Association, 1994].
11.Hypertension: Subjects with clinically significant hypertension that is uncontrolled.
12.Abnormal and clinically significant 12-lead ECG: For this study, an abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following:
•Sinus bradycardia <45bpm
•Sinus tachycardia ≥110bpm
•Multifocal atrial tachycardia (wandering atrial pacemaker with rate >100bpm)
•PR interval >240msec
•Evidence of Mobitz II second degree or third degree atrioventricular (AV) block
•Pathological Q waves (defined as wide [>0.04 seconds] and deep [>0.4mV (4mm with 10mm/mV setting)] or >25% of the height of the corresponding R wave, providing the R wave was >0.5mV [5mm with 10mm/mV setting], appearing in at least two contiguous leads.
•Evidence of ventricular ectopic couplets, bigeminy, trigeminy or multifocal premature ventricular complexes.
*Note: Ventricular couplets, bigeminy, and trigeminy may be allowed for inclusion based upon investigator discretion.
•For subjects without complete right bundle branch block: QTc(F) ≥450msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave).
•For subjects with complete right bundle branch block: QTc(F) ≥480msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave).
•ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities)
•Clinically significant conduction abnormalities (e.g., Wolff-Parkinson-White syndrome or bifascicular block defined as complete left bundle branch block or complete right bundle branch block with concomitant left fascicular block)
•Clinically significant arrhythmias (e.g., atrial fibrillation with rapid ventricular response, ventricular tachycardia)
The investigator will determine the medical significance of ECG abnormalities that are not exclusionary a priori and determine if the subject is precluded from entering the study.
13.Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis.
Please refer to Exclusion Criteria-page 23 in Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is change from baseline in aortic pulse wave velocity
(aPWV) at the end of the 24-week study treatment period. Aortic Pulse Wave
Velocity (aPWV) |
|
| 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 | Yes |
| 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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