COPD

Primary Objective  To evaluate the efficacy and safety of mepolizumab 100 mg and 300 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. Secondary Objective  To evaluate other efficacy assessments of mepolizumab 100 mg and 300 mg subcutaneous (SC) compared to placebo on changes in quality of life, health care utilization, and symptoms.

Mepolizumab

Mepolizumab

injection

100 mg

Primary
 Frequency of moderate/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
resulting in death.
Efficacy endpoints will be measured from Visit 2 through Visit 15.
Secondary
 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

1. COPD diagnosis: Subjects with a clinically documented history of COPD for at
least 1 year in accordance with the following definition by the American Thoracic
Society/European Respiratory Society [Celli, 2004]
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 equations [Hankinson 1999, Hankinson,
2010] at 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 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 antagnist).
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 (FCBP; see
Appendix 1 for definition) 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
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. Note: Pipe and/or
cigar use cannot be used to calculate pack-year history.
Current smokers are defined as those with a history of cigarette smoking of ≥10
pack-years [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)].
Former smokers are defined as those who meet the definition of a current
smoker but have stopped smoking for at least 6 months prior to Visit 1.
Never smokers are those that do not meet the definition of a current or former
smoker.

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. Specific ECG findings that preclude subject enrolment are found in
Appendix 2. 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 (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.
10. Eosinophilic disease: Subjects with other conditions that could lead to elevated
eosinophils such as Hypereosinophilic syndromes including Eosinophilic
Granulomatosis with Polyangiitis (EGPA, also known as Churg-Strauss Syndrome),
or Eosinophilic Esophagitis.
11. Parasitic infection: Subjects with a pre-existing helminthes infestation within 6
months prior to Visit 1 are also excluded.
12. 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).
Note for South Korea: Korean subjects with a diagnosis of malignancy within 5
years of Visit 1 are excluded
13. Immunodeficiency: A known immunodeficiency (e.g human immunodeficiency
virus – HIV), other than that explained by the use of corticosteroids taken for COPD.
14. Liver disease: Unstable liver disease (as defined by the presence of ascites,
encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, or
persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception
of Gilbert’s syndrome or asymptomatic gallstones). Chronic stable hepatitis B and C
are acceptable if subject otherwise meets entry criteria (e.g., presence of hepatitis B
surface antigen or positive hepatitis C test result within 3 months of screening)
15. Monoclonal antibodies: Subjects who have received any monoclonal antibody
within 5 half-lives of Visit 1
16. 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).
17. Hypersensitivity: Subjects with a known allergy or intolerance to another
monoclonal antibody or biologic including history of anaphylaxis to another biologic
18. 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.
19. 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.
20. 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.
21. Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse
within 2 years prior to Visit 1.
22. Previous participation: Subjects who have previously participated in any study of
mepolizumab.
23. 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.