| 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 |
COPD is a chronic lung disease that causes shortness of breath and coughing.
A bronchodilator helps to open your airways and makes it easier to get air in and out of the lungs. |
|
| 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 | 19.0 |
| 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 |
Primary Objective for EU:
To assess the non-inferior bronchodilation of AB 400 μg BID as compared to TIO 18 μg QD in COPD patients.
Primary Objectives for USA:
To assess the bronchodilatory effect of AB/FF 400/12 μg compared to each individual component when administered twice daily via inhalation to COPD patients. |
|
| E.2.2 | Secondary objectives of the trial |
| To further characterize the effect of AB/FF 400/12 μg on bronchodilation and health related quality of life compared to individual components when administered twice daily via inhalation to COPD patients. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: SERIAL SPIROMETRY SUBSTUDY
Date and version: please be referred to section A.4.
Patients participating in the sub-study will be requested to sign an additional informed consent form. Patients will be required to stay overnight at the study site at Visits 2 and Visit 7 to perform 24h-spirometry assessments.
Additional Pulmonary Function Tests (PFTs) at Visit 2 and 7 only for 35% of patients who will participate in the 24-hour serial spirometry sub-study: +4h, +6h, +9h, +12h (pre-evening dose), +12.5h, +13h, +14h, +22, +23.5h and +24h after the morning dose. |
|
| E.3 | Principal inclusion criteria |
1. Adult male or non-pregnant, non-lactating female patients aged ≥ 40.
Explanatory note: A female is considered to be of childbearing potential unless is at least one year post-menopausal or permanently sterilised (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy). Women of childbearing potential are allowed to enter the trial if they show to have a negative pregnancy test at the Screening Visit and are using, during the last two months before the Screening Visit and during the whole duration of the trial, at least one medically approved and highly effective method of birth control defined as those, alone or in combination, which result in a low failure rate (i.e less than 1% per year) when used consistently and correctly. Male participants are not requested to use contraception methods during their participation on the trial.
2. Patients with diagnosis of moderate to very severe stable COPD: post-bronchodilator FEV1 < 80% of the predicted normal and post-bronchodilator FEV1/FVC < 70% at Screening Visit.
Explanatory note: Moderate to very severe COPD (Stage II or Stage IV, according to the GOLD guidelines classification 2015). Post-bronchodilation means FEV1 and FVC between 10 to 15 minutes after inhalation of 4 puffs of albuterol/salbutamol from acceptable and repeatable pulmonary function testing according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria. Predicted normal values to be used are based on the Global Lung Function Initiative predicted values (Quanjer et al. 2012).
3. Symptomatic patients with a CAT score ≥10 at Screening and Randomization visit (Visits 1 and 2).
4. Current or former-smokers, with a smoking history of ≥ 10 pack-years.
Explanatory notes:
a. Former smoker condition defined as having quit smoking ≥ 6 months before Visit 1 (Screening).
b. Pack-years is calculated by dividing the number of cigarettes smoked per day by 20 (the number of cigarettes in a pack) and multiplying this figure by the number of years a person has smoked. For example, a person who smokes 40 cigarettes a day and has smoked for 10 years would have a 20 pack-year smoking history (40 cigarettes per day, 20 cigarettes per pack = 2; 2 x 10 years of smoking = 20 packyear history). In case of intermittent smoking/non-smoking periods, pack-years is calculated by summing all periods pack-years.
c. Patients smoking other tobacco types will not be allowed, unless they meet the cigarette criterion as well.
5. Patients able to perform acceptable and repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria at Visit 1.
6. Patients eligible and able to participate in the study and who had signed an Informed Consent Form prior to initiation of any study-related procedures. |
|
| E.4 | Principal exclusion criteria |
1. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or site staff), or patients employed by or relatives of the employees of the site or
sponsor.
3. Patients with predominant asthma.
Explanatory note: If the investigator in his or her medical judgement determines the prior asthma diagnosis is unrelated to subject current condition (e.g. misdiagnosis, premature diagnosis, or resolution of early onset disease), then the patient is eligible for the study.
4. Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation (including the mild COPD exacerbation) within 6 weeks prior to screening or during the run-in period.
5. Patients hospitalized for a COPD exacerbation (an emergency room visit for longer than 24 hours is considered a hospitalization) within 3 months prior to Screening Visit.
6. Clinically significant respiratory conditions other than COPD.
Explanatory note: Clinically significant respiratory conditions defined as:
a. Known active tuberculosis.
b. History of interstitial lung disease or massive pulmonary thromboembolic disease.
c. Pulmonary resection or lung volume reduction surgery.
d. History of lung transplantation.
e. Patients who in the Investigator’s opinion might need thoracotomy or other lung surgery during the study.
f. Bronchiectasis secondary to respiratory diseases other than COPD (e.g. cystic fibrosis, Kartagener’s syndrome, etc.)
g. Known α1-antitrypsin deficiency.
7. Patients who in the Investigator’s opinion may need to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to Screening.
8. Use of long-term oxygen therapy (≥ 15 hours/day).
9. Patients who do not maintain regular day/night, waking/sleeping cycles including night shift workers.
Explanatory note: the use of continuous positive airway pressure (CPAP) is not an exclusion criteria.
10. Clinically significant cardiovascular conditions.
Explanatory note: Clinically significant cardiovascular conditions, some examples are:
a. Myocardial infarction within the 6 months prior to screening.
b. Thoracic surgery within 6 months prior to screening.
c. Unstable angina or unstable arrhythmia which had required changes in the pharmacological therapy or other intervention within 6 months prior to screening, or newly diagnosed arrhythmia within the 3 months prior to screening which required the pharmacological therapy or other intervention.
d. Hospitalization within 6 months prior to screening for heart failure functional classes III (marked limitation of activity and only comfortable at rest) and IV (need of complete rest, confinement to bed or chair, discomfort at any physical activity and presence of symptoms at rest) as per the New York Heart Association.
e. Presence of an implantable cardioverter-defibrillato (ICD) within the last year prior to Screening visit.
11. Patients with uncontrolled Type I or Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled hypertension.
12. Patients with history of long QT syndrome or whose QTc (calculated according to Fridericia’s Formula QTc=QT/RR1/3) > 470 ms as indicated in the centralised reading report assessed at Screening.
13. Patients with clinically significant abnormalities in the laboratory tests, ECG parameters (other than QTc) or in the physical examination at Screening Visit that might comprise patient safety.
14. Patient with known non-controlled history of infection with human immunodeficiency virus and/or active hepatitis.
Explanatory note:
a. Active hepatitis is defined as clinical symptoms associated with chronic portal inflammation with regional necrosis and fibrosis, which may progress to nodular postnecrotic cirrhosis or patients with antibody to hepatitis B core antigen (HBcAg) and hepatitis B surface antigen (HBsAg) test with positive results or antihepatitis C virus (HCV) antibody and HCV recombinant immunoblot assay HCV positive tests or genetic material (ribonucleic acid) testing positive results.
b. Active infection with human immunodeficiency virus is defined as a confirmed viral load >200 copies/mL and or CD4 Count < 500 cells/mm3.
15. Patient with a history of hypersensitivity reaction to inhaled medication or any component thereof, including paradoxical bronchospasm.
16. Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention or symptomatic non-stable prostate hypertrophy.
Explanatory note: Patients with well-controlled, stable, benign prostatic hypertrophy are not excluded.
17. History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer.
Explanatory note: Patients are excluded whether or not there is evidence of local recurrence or metastases. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
For EU: Outcome measure and primary comparison
- Change from baseline in morning predose (trough) FEV1 at week 24 comparing AB 400 μg versus TIO 18 μg.
For USA: Outcome measure and comparison
- Change from baseline in 1-hour morning post-dose dose FEV1 of AB/FF 400/12 μg compared to AB 400 μg at week 24.
- Change from baseline in morning predose (trough) FEV1 of AB/FF 400/12 μg compared to FF 12 μg at week 24. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 24 weeks of treatment. |
|
| E.5.2 | Secondary end point(s) |
Outcome measure and primary comparison:
- Change from baseline in normalized AUC0-3/3h FEV1 of AB/FF 400/12 μg at week 24 compared to AB 400 μg and FF
12 μg.
- Number (%) of patients achieving a clinically meaningful improvement (a decrease of at least 4 units from baseline)
with AB/FF 400/12 μg in SGRQ total score at week 24 compared to AB 400 μg and FF 12 μg. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After 24 weeks on treatment. |
|
| 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 | Yes |
| 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 | No |
| 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 | 4 |
| 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 | 79 |
| 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 |
| Bulgaria |
| Czech Republic |
| Germany |
| Hungary |
| Israel |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Ukraine |
| United Kingdom |
| 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
|
| The “end of trial” is defined as the date when last subject randomized in the trial perform the last contact (either Visit 7 or Follow-up contact). |
|
| 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 | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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