E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of severe Chronic Obstructive Pulmonary Disease (COPD) in patients presenting frequent exacerbations |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
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 efficacy and safety of mepolizumab 100 mg
subcutaneous (SC) given every 4 weeks compared to placebo on the frequency of moderate and severe exacerbations in COPD subjects at high risk of exacerbations despite the use of optimized standard of care
background therapy. |
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E.2.2 | Secondary objectives of the trial |
To evaluate other efficacy assessments of mepolizumab 100 mg subcutaneous (SC) compared to placebo on changes in health care utilization, COPD symptoms, quality of life, and lung function.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.COPD diagnosis: Subjects with a clinically documented history of COPD for at least 1 year in accordance with the definition by the American Thoracic Society/European Respiratory Society
2.Severity of COPD: Subjects must present with the following:
- A measured pre and post-salbutamol FEV1/FVC ratio of <0.70 at Visit 1 to confirm the diagnosis of COPD
- A measured post-salbutamol FEV1> 20% and ≤80% of predicted normal values calculated using NHANES III reference equationsat Visit 1
3.History of exacerbations: A well documented history (e.g., medical record verification) in the 12 months prior to Visit 1 of:
at least two moderate COPD exacerbations. Moderate is defined as the use of systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or treatment with antibiotics.
OR
at least one severe COPD exacerbation. Severe is defined as having required hospitalization
4.Concomitant COPD therapy: A well documented requirement for optimized standard of care (SoC) background therapy that includes ICS plus 2 additional COPD medications (i.e., triple therapy) for the 12 months prior to Visit 1 and meets the following criteria:
Immediately prior to Visit 1, minimum of 3 months of use of an a) inhaled corticosteroid at a dose ≥500 mcg/day fluticasone propionate dose equivalent plus b) LABA and c) LAMA.
For subjects who are not continually maintained on ICS plus LABA plus LAMA for the entire 12 months prior to Visit 1 use of following is allowed (but not in the 3 months immediately prior to Visit 1):
a.inhaled corticosteroid at a dose ≥500 mcg/day fluticasone propionate dose equivalent plus
b.a LABA or a LAMA and
c.use of at least one other class of COPD medication suggested by the 2013 GOLD guidelines for patients who are prone to exacerbation (i.e., phosphodiesterase-4-inhibitors, methylxanthines, or a combination of short acting beta2-agonist and short acting muscarinic antagonist).
5.Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.
6.Gender: Male or Eligible Female
To be eligible for entry into the study females of child bearing potential must commit to consistent and correct use of an acceptable method of birth control from the time of consent, for the duration of the trial, and for 4 months after last study drug administration. See Appendix 1 for a listing of acceptable methods of birth control.
7.Age: At least 40 years of age at Visit 1
8.Smoking status: Subject with confirmed COPD are eligible to participate independent of their smoking status and smoking history, i.e. current smokers, never smokers or ex-smokers can be enrolled into the study.
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E.4 | Principal exclusion criteria |
1.Asthma:
•Current and Former Smokers: Subjects with a current diagnosis of asthma (those with a prior history are eligible if they meet inclusion criteria for a current diagnosis of COPD)
•Never-Smokers: Subjects with any history of asthma
2.Other respiratory disorders: The investigator must judge that COPD is the primary diagnosis accounting for the clinical manifestations of the lung disease. Subjects with α1-antitrypsin deficiency as the underlying cause of COPD are excluded. Also, excluded are subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases. Subjects are also excluded if maintenance use of bi-level positive airway pressure is required for the treatment of respiratory disorder.
3.COPD stability: Subjects with pneumonia, exacerbation, lower respiratory infection within the 4 weeks prior to Visit 1.
4.Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Visit 1.
5.Pulmonary rehabilitation program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
6.Oxygen: Subjects receiving treatment with oxygen more than 4.0L/min. While breathing supplemental oxygen, subjects should demonstrate an oxyhemoglobin saturation greater than or equal to 89%.
7.12-lead ECG finding: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1 if considered to be clinically significant by the Investigator. 12-lead ECGs will be over-read by a centralized independent cardiologist to assist in consistent evaluation of subject eligibility. Results from the 12-lead ECG over-read must be received prior to assessing eligibility at Visit 2.
8.Unstable or life threatening cardiac disease: Subjects with any of the following 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
9.Other diseases/abnormalities: Subjects with (historical or) current evidence of clinically significant, neurological, psychiatric, renal, hepatic, immunological, endocrine or haematological abnormalities that are uncontrolled. Eosinophilic disease: Subjects with other conditions that could lead to elevated eosinophils
10.Parasitic infection: Subjects with a pre-existing helminthes infestation within 6 months prior to Visit 1 are also excluded.
11.Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to Visit 1 (Subjects that had localized carcinoma of the skin or cervix which was resected for cure will not be excluded).
12.Immunodeficiency: A known immunodeficiency other than that explained by the use of corticosteroids taken for COPD.
13.Liver disease: Unstable liver disease, cirrhosis, and known bilary abnormalities. Chronic stable hepatitis B and C are acceptable if subject otherwise meets entry criteria.
14.Monoclonal antibodies: Subjects who have received any monoclonal antibody within 5 half-lives of Visit 1
15.Investigational medications: Subjects who have received an investigational drug within 30 days of Visit 1, or within 5 drug half-lives of the investigational drug, whichever is longer (this also includes investigational formulations of a marketed product).
16.Hypersensitivity: Subjects with a known allergy or intolerance to another monoclonal antibody or biologic including history of anaphylaxis to another biologic
17.Inability to read: In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete study related materials.
18.Non-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.
19.Questionable 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.
20.Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
21.Previous participation: Subjects who have previously participated in any study of mepolizumab.
22.Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Frequency of moderate and severe exacerbations.
Moderate exacerbations are defined as COPD exacerbations that require either systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics.
Severe exacerbations are defined as COPD exacerbations requiring hospitalization or result in death.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Over the 52 week treatment period |
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E.5.2 | Secondary end point(s) |
•Time to first moderate/severe exacerbation
•Frequency of COPD exacerbations requiring emergency department (ED) visits and/or hospitalizations
•Change from baseline mean total St. George’s Respiratory Questionnaire-COPD (SGRQ-C) score
•Change from baseline COPD assessment test (CAT) score
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As specified in the endpoint. |
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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 | Yes |
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.8.2.4 | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 53 |
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 |
Australia |
Belgium |
Canada |
Czech Republic |
Estonia |
France |
Greece |
Italy |
Mexico |
Norway |
Peru |
Poland |
Russian Federation |
Spain |
Sweden |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |