| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| subjects with Chronic Obstructive Pulmonary Disease (COPD) |
|
| 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 | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 Tiotropium 18 mcg QD on arterial stiffness measured as aortic pulse wave velocity (aPWV) in subjects with COPD and aPWV ≥ 11.0 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 Tiotropium 18 mcg QD in improving lung
function in subjects with COPD and aPWV≥11.0 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 |
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
amenorrhoeic 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).
• Subjects 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.
8. Exacerbation History: Subjects who have been hospitalised or have been treated
with oral corticosteroids or antibiotics for their COPD within the last 3 years prior to
Screening (V1).
9. Baseline aPWV: subjects with a measured aPWV ≥ 11.0 m/s at Screening (Visit 1). |
|
| E.4 | Principal exclusion criteria |
1Pregnancy:Women who are pregnant or lactating or are planning on becoming pregnant during the study.
2Asthma:Subjects with a current diagnosis of asthma. Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD.
3Other respiratory disorders:The investigator must judge that COPD is the primary diagnosis accounting for the clinical manifestations of the lung disease. View protocol for further information.
4A cardiovascular event:(e.g., Acute Coronary Syndrome, Stroke, Coronary Artery Bypass Surgery, Percutaneous Coronary Intervention) in the 6 months prior to Visit 1.
5Lung resection:Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1) or having had lung transplantation.
6Poorly 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’
7Lower respiratory tract infection:Subjects with lower respiratory tract
infection that required the use of antibiotics within 6 weeks prior to Visit 1.
8Other diseases/abnormalities:Subjects with historical or current evidence of clinically significant cardiovascular, gastrointestinal, neurological, psychiatric, renal, hepatic, immunological, endocrine view protocol for further nformation.
9Current severe heart failure (New York Heart Association class IV). Subject will be excluded if they have a known ejection fraction of <30%.
10Hypertension: In the judgment of the investigator the subject does not have uncontrolled hypertension meaning that they are unlikely to require medication adjustments during the study period.
11Abnormal and clinically significant 12-lead ECG:Investigators will be
provided with ECG reviews conducted by a local cardiologist to
assist in evaluation of subject eligibility. 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: view protocol for further information.
The investigator will determine the medical significance of ECG abnormalities that are not exclusionary a priori at randomisation and determine if the subject is precluded from entering the study.
12Cancer:Subjects with carcinoma that has not been in complete remission for at least 5 years, view protocol for further information.
13Drug/food allergy:Subjects with a history of hypersensitivity to any of the study medications and or milk allergies view protocol.
14Drug/alcohol abuse:Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years.
15Subjects who are medically unable to withhold their albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit. For those subjects on a stable dose of Ipratropium bromide prior to V1, subjects who are medically unable to withhold their Ipratropium bromide for the 4-hour period required prior to spirometry testing at V1 and V2 (Ipratropium will not be allowed after V2).
16Additional medication:view Table 1.
17Initiation, discontinuation and/or changing dose of medications reported to affect a PWV: Subjects who have started, discontinued and/or are receiving the following medications, view protocol for further information.
18Oxygen therapy:Supplemental oxygen, with the following exceptions:
•Use at high altitude (> 5000 feet) provided subject does not require a flow rate of > 2
L/minute, view protocol for further information.
19Pulmonary rehabilitation:Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program, view protocol for further information.
20A body mass index (BMI) of ≥35kg/m2
21Lipid Panel:Subjects with LDL>3.3mmol/L, total cholesterol >5.2mmol/L, and triglycerides >2.24mmol/L (based on Visit 1 fasting lipid panel). View protocol for further information.
22Non-compliance:Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
23Questionable validity of consent:Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.
24Prior use of study medication/other investigational drugs:Subjects who have previously been randomised to treatment in the HZC113108/110 study. View protocol for further information
25Affiliation with investigator site:Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study.
|
|
| 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 12-week study treatment period. View protocol page 40 for further information. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A pulse wave velocity will be measured pre-dose aPWV at Screening (Visit 1), pre-dose Visit 3, Visit 4, and Visit 5. |
|
| E.5.2 | Secondary end point(s) |
• Change from baseline in morning clinic visit trough FEV1 (pre-bronchodilator and pre-dose) at the end of the 12-week study treatment period.
• Change from baseline in morning clinic visit trough IC (pre-bronchodilator and predose)
at the end of the 12-week study treatment period. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
At Visit 2 FEV1, FVC and IC (Trough Inspiratory Capacity) to be measured at -30 and -5 min pre-dose to provide ‘baseline’. At Visits 3,4, 5, FEV1, FVC (Forced Vital Capacity) and IC to be measured at 24 hours after the previous morning’s dosing.
|
|
| 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 | 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Argentina |
| Russian Federation |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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