| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic obstructive pulmonary disease (COPD) |
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| E.1.1.1 | Medical condition in easily understood language |
COPD is a progressive disease characterised by increasing obstruction to airflow and the development of respiratory symptoms including chronic cough, sputum production, dyspnoea and wheezing.
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| 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 | 20.0 |
| 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 |
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| 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 single inhaler triple therapy (FF/UMEC/VI) compared to multiple inhaler triple combination therapy with budesonide/formoterol plus tiotropium after 12 weeks of treatment on lung function.
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effects of single inhaler triple therapy (FF/UMEC/VI) compared to multiple inhaler triple combination therapy with budesonide/formoterol plus tiotropium after 12 weeks of treatment on Health Status.
To evaluate the effects of single inhaler triple therapy (FF/UMEC/VI) compared to multiple inhaler triple combination therapy with budesonide/formoterol plus tiotropium after 12 weeks of treatment on COPD exacerbations.
Assess how inspiratory airflow limitation affects ability to use the ELLIPTA
To evaluate the safety profile of single inhaler triple therapy (FF/UMEC/VI) compared to multiple inhaler triple combination therapy with budesonide/formoterol plus tiotropium over 84 days of treatment
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed consent: capable of giving signed informed consent prior to study start which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Type of participant: Outpatient.
3. Age: Participants 40 years of age or older at Screening (Visit 1).
4. Gender: Male or female participants.
Female participants:
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
Not a woman of childbearing potential (WOCBP)
OR
A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 of the protocol during the treatment period and until the safety follow-up contact after the last dose of study treatment.
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:
Participants 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.
Participants must also have a measured post albuterol/salbutamol FEV1/forced vital capacity (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). Participant verbal reports are not acceptable.
9. Existing COPD maintenance treatment: participant must have been receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening.
Note: Participants taking only as-needed COPD medications are not eligible.
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| E.4 | Principal exclusion criteria |
1. Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
2. Asthma: Participants with a current diagnosis of asthma. (Participants with a prior history of asthma are eligible if they have a current diagnosis of COPD).
3. α1-antitrypsin deficiency: Participants with α1-antitrypsin deficiency as the underlying cause of COPD.
4. Other respiratory disorders: Participants with active tuberculosis, lung cancer, and clinically significant: bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung disease or other active pulmonary diseases.
5. Lung resection: Participants who have undergone lung volume reduction surgery within the 12 months prior to Screening.
6. Risk Factors for Pneumonia: immune suppression (e.g. advanced human immunodeficiency virus [HIV] with high viral load and low CD4 count, lupus on immunosuppressants) that in the opinion of the investigator would increase risk of pneumonia or other risk factors for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson’s Disease, Myasthenia Gravis).
Participants at potentially high risk for pneumonia (e.g. very low body mass index [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).
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 chest X-ray (e.g. significant cardiomegaly, pleural effusion or scarring).
All participants will have a chest X-ray at Screening Visit 1 (or historical radiograph or computerized tomography [CT] scan obtained within 3 months prior to screening).
Note: Participants who have experienced pneumonia and/or moderate or severe COPD exacerbations within 3 months of screening must provide a post pneumonia/exacerbation chest X-ray 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: Participants 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 participant at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
11. Unstable liver disease: ALT >2x Upper Limit of Normal (ULN); and bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 %)
Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
NOTES:
Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis.
Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment) are acceptable if participant otherwise meets entry criteria.
12. Unstable or life threatening cardiac disease: Participants 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
- New York Heart Association (NYHA) Class IV Heart failure
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Weighted mean change from baseline in FEV1 over 0-24 hours at Week 12
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| For the timepoints of evaluation of endpoints please refer to section E.5.1 |
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| E.5.2 | Secondary end point(s) |
Secondary end points
- Change from baseline in trough FEV1 on Day 2, Day 28, Day 84 and Day 85
- Weighted mean change from baseline in FEV1 over 0-24 hours on Day 1
Other end points
- Proportion of responders based on the St George’s Respiratory Questionnaire (SGRQ) Total Score at Week 4 and Week 12
- Change from baseline in SGRQ Total Score at Week 4 and Week 12
- Proportion of responders based on the COPD Assessment Test (CAT) Total Score at Week 4 and Week 12
- Change from baseline in CAT Total Score at Week 4 and Week 12
- Moderate or severe exacerbation event
- Peak Inspiratory Flow Rate (PIFR) at Screening (Week -4)
Safety end points
- Incidence of adverse events
- Vital signs
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the timepoints of evaluation of endpoints please refer to section E.5.2
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| 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 | 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 |
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| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Czech Republic |
| Germany |
| Portugal |
| United States |
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| 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
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| 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 | 7 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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