| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease |
|
| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
| 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 |
| To evaluate the effects of FF/UMEC/VI on lung function and health related quality of life compared with budesonide/formoterol after 24 weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the effect on annual rate of exacerbations of FF/UMEC/VI compared to budesonide/formoterol
- To evaluate the safety profile of FF/UMEC/VI compared to budesonide/formoterol over 24 weeks and 52 weeks of treatment |
|
| 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:
Genetic Research
Objectives:
The objectives of the genetic research are to investigate the relationship between genetic variants and:
- Response to medicine, including Fluticasone Furoate (FF)/Umeclidinium (UMEC)/Vilanterol (VI), Budesonide Formoterol or any concomitant medicines;
- COPD susceptibility, severity, and progression and related conditions |
|
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Informed Consent: A signed and dated written informed consent prior to study participation.
2. Type of subject: Outpatient.
3. Age: Subjects 40 years of age or older at Screening (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 safety 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)
- 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. COPD Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society [Celli, 2004].
6. Smoking History: Current or former cigarette smokers with a history of cigarette smoking of ≥10 pack-years at Screening (Visit 1) [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.
7. Severity of COPD symptoms: A score of ≥10 on the COPD Assessment Test (CAT) at Screening (Visit 1).
8. Severity of Disease:
Subjects must demonstrate at Screening:
- a post-bronchodilator FEV1 <50% predicted normal
OR
- a post-bronchodilator FEV1 <80% predicted normal and a documented history of ≥2 moderate exacerbations or one severe (hospitalized) exacerbation in the previous 12 months Subjects must also have a measured post albuterol/salbutamol FEV1/FVC ratio of <0.70 at screening.
Note: Percent predicted will be calculated using the European Respiratory Society Global Lung Function Initiative reference equations [Quanjer, 2012].
Note: A documented history of a COPD exacerbation (e.g., medical record verification) is a medical record of worsening COPD symptoms that required systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or hospitalization (for a severe exacerbation).
Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnoea, sputum volume, or sputum purulence (colour). Subject verbal reports are not acceptable.
9. Existing COPD maintenance treatment: Subject must be receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening.
Note: Subjects receiving only PRN COPD medications are not eligible.
10. Liver function tests:
- alanine aminotransferase (ALT) <2x upper limit of normal (ULN);
- alkaline phosphatase ≤1.5xULN
- bilirubin ≤1.5xULN (isolated bilirubin >1.5 x ULN is acceptable if
bilirubin is fractionated and direct bilirubin <35%).
|
|
| 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. α1-antitrypsin deficiency: Subjects with α1-antitrypsin deficiency as the underlying cause of COPD.
4. Other respiratory disorders: Subjects with active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases.
5. Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening.
6. Risk Factors for Pneumonia: immune suppression (e.g. HIV, Lupus) or other risk factors for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson's Disease, Myasthenia Gravis).
Patients at potentially high risk (e.g. very low BMI, severely malnourished, or very low FEV1) will only be included at the discretion of the investigator.
7. Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least 14 days prior to Screening and at least 30 days following the last dose of oral/systemic corticosteroids (if applicable). In addition, any subject that experiences pneumonia and/or moderate or severe COPD exacerbation during the run-in period will be excluded.
8. Respiratory tract infection that has not resolved at least 7 days prior to Screening.
9. Abnormal Chest x-ray: Chest x-ray (posteroanterior and lateral) reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD, or another condition that would hinder the ability to detect an infiltrate on CXR (e.g. significant cardiomegaly, pleural effusion or scarring). All subjects will have a chest x-ray at Screening Visit 1) (or historical radiograph or CT scan obtained within 3 months prior to screening) that will be over-read by a central vendor.
Note: Subjects who have experienced pneumonia and/or moderate or severe COPD exacerbation within 3 months of screening must provide a post pneumonia/exacerbation chest x-ray to be over-read by the central vendor or have a chest x-ray conducted at Screening.
For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to Screening (Visit 1) is not available, approval to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office for Radiation Protection (BfS).
10. Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid disease) or haematological 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.
For subjects taking part in the physical activity monitor subset: Orthopaedic, neurological or other complaints that significantly impair normal biomechanical movement patterns and limit the ability to walk/cycle, as judged by the Investigator.
11. Unstable liver disease as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice, cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Note: Chronic stable hepatitis B and C are acceptable if the subject otherwise meets entry criteria.
12. Unstable or life threatening cardiac disease: subjects with any of the following at Screening (Visit 1) would be excluded:
- Myocardial infarction or unstable angina in the last 6 months
- Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months
- NYHA Class IV Heart failure
13. Abnormal and clinically significant 12-Lead ECG finding:
Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The PI will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial.
For the remaining exclusion criteria please refer to protocol page 33 and 34. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Change from baseline in trough FEV1 at Week 24
- Change from baseline in SGRQ total score at Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Change from baseline in trough FEV1 at 24 weeks: Visit 2 (Day 1) and Visit 6 (Week 24)
- Change from baseline in SGRQ total score at 24 weeks: Visit 2 (Day 1) and Visit 6 (Week 24) |
|
| E.5.2 | Secondary end point(s) |
- Annual rate of on-treatment moderate and/or severe COPD exacerbations
- Assessment of respiratory symptoms using EXACT Respiratory Symptoms PRO and its subscales (breathlessness, cough and sputum and chest symptoms)
- Transitional Dyspnea Index (TDI) focal score at Week 24
- Daily Activity Question |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Annual rate of on-treatment moderate and/or severe COPD exacerbations: Visit 2 (Day 1) to Visit 6 (Week 24) or Visit 8 (Week 52)-for the subset of subjects continuing for an additional 28 weeks or at Early Withdrawal.
- Assessment of respiratory symptoms using EXACT Respiratory Symptoms PRO and its subscales (breathlessness, cough and sputum and chest symptoms) : Daily from Visit 1 (Week 2) to Visit 6 (Week 24) or Visit 8 (Week 52)- for the subset of subjects continuing for an additional 28 weeks or at Early Withdrawal.
- Transitional Dyspnea Index (TDI) focal score at 24 weeks: Visit 6 (24 weeks)
- Daily Activity Question: Daily from Visit 1 (Week 2) to Visit 6 (Week 24) or Visit 8 (Week 52)- for the subset of subjects continuing for an additional 28 weeks or at Early Withdrawal. |
|
| 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 | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 136 |
| 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 |
| China |
| Czech Republic |
| Estonia |
| Germany |
| Greece |
| Hungary |
| Italy |
| Korea, Republic of |
| Mexico |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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