A multi-center, randomized, double-blind, parallel-group, placebo controlled
study of mepolizumab 100 mg SC as add-on treatment in participants with
COPD experiencing frequent exacerbations and characterized by eosinophil levels (Study 208657)

1.Participant must be at least 40 years of age at Screening Visit 1.
2. A peripheral blood eosinophil count of >=300 cells/µL from the hematology
sample collected at Screening Visit 0.
AND
A documented historical blood eosinophil count of >=150/µL in the 12 months
prior to Screening Visit 0 that meets the following: It must have been measured
between 12 months and 1 month prior to Visit 0, and it must not have been
measured within 14 days of a COPD exacerbation.
Participants with no documented historical blood eosinophil count of >=150
cells/µL must meet this threshold at the Screening Visit 1 assessment in order
to return for Randomization Visit 2.
3.Participants 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.
4.Participants must present with the following:
• A measured pre- and post-salbutamol FEV1/FVC ratio of <0.70 at Screening
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 at Screening Visit 1.
5. Participants must have a well-documented history (e.g., medical record
verification) in the 12 months prior to Screening Visit 1 of:
• Two or more moderate COPD exacerbations that were treated with systemic
corticosteroids (intramuscular (IM), intravenous, or oral) with or without
antibiotics.
OR
• At least one severe COPD exacerbation requiring hospitalization
Note: At least one exacerbation must have occurred while the participant was
taking inhaled triple therapy, ICS plus LABA plus LAMA unless documented
intolerance or safety risk with either of the two long-acting bronchodilators.
If intolerance is documented, ICS plus LABA or ICS plus LAMA would be allowable
after discussion with the Medical Monitor.
Note: COPD exacerbations related to COVID-19 infection must not be counted as
COPD exacerbations for inclusion in the study.
6. Participants must have a well-documented requirement for optimized standard
of care background therapy that includes ICS plus 2 additional COPD medications
(i.e., ICS-based triple therapy) for the 12 months prior to Screening Visit 1
and meets the following criteria:
• Immediately prior to Screening 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 unless documentation of safety or
intolerance issues related to LABA or LAMA.
• For participants who are not continually maintained on ICS plus LABA plus
LAMA for the entire 12 months prior to Visit 1 use of the 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.inhaled LABA or inhaled LAMA and
c.Phosphodiesterase-4-inhibitors, methylxanthines, or scheduled daily use of
short acting beta2-agonist (SABA) and/or short acting muscarinic
antagonist (SAMA).
Note: Where intolerance or safety risk is documented for either LAMA or LABA,
ICS-based inhaled dual maintenance therapy, either ICS plus LABA or ICS plus
LAMA, is allowed in the 12 months prior to Visit 1 and during the clinical
trial but must be discussed with the Medical Monitor.
Note: Participants must be willing to receive optimized maintenance COPD
therapy for the duration of the study.
7. 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)]. Former smokers are
defined as those who have stopped smoking for at least 6 months prior to
Screening Visit 1.
Note: Pipe and/or cigar use cannot be used to calculate pack-year history.
8. Contraceptive use for women should be consistent with local regulations
regarding the methods of contraception for those
participating in clinical studies.
Female Participants:
A female participant is eligible to participate if she is not pregnant or
breastfeeding, and at least one of the following conditions applies:
o Is not a woman of childbearing potential (WOCBP)
o Is a WOCBP and using a contraceptive method that is highly effective, with a
failure rate of <1%, as described in Appendix 5, during the intervention period
and for at least 16 weeks after the last dose of study intervention. The
principal investigator (PI) should evaluate the effectiveness of the
contraceptive method in relation to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy urine test within 24
hours before the first dose of study intervention. If a urine test cannot be
confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is
required. In such cases, the participant must be excluded from participation if
the serum pregnancy result is positive. Additional requirements for pregnancy
testing during and after study intervention are located in Appendix 3
• The Investigator is responsible for review of medical history, menstrual
history, and recent sexual activity to decrease the risk of inclusion of a
woman with an early undetected pregnancy
9. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in
this protocol.

1. Participants with a past history or concurrent diagnosis of asthma are
excluded regardless of whether they have active or inactive disease.
2. The Investigator must judge that COPD is the primarydiagnosis accounting for
the clinical manifestations of the lung disease. Participantswith α1-
antitrypsin deficiency as the underlying cause of COPD are excluded.
Also,excluded are participants with active tuberculosis, lung cancer,
bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary hypertension,
interstitial lung diseases
or other active pulmonary diseases.
3. Participants with pneumonia, COPD exacerbation, or lower respiratory tract
infection within the 4 weeks prior to Screening Visit 1.
4. Participants with lung volume reduction surgery within the 12 months prior
to Screening Visit 1.
5. Participation in the acute phase of a pulmonary rehabilitation program
within 4 weeks prior to Screening Visit 1. Participants who are in the
maintenance phase of a pulmonary rehabilitation program are not excluded.
6. Participants receiving treatment with oxygen more than 2 L/min at rest over
24 hrs. For participants receiving oxygen treatment, participants should
demonstrate an oxyhemoglobin saturation greater than or equal to 89% while
breathing supplemental oxygen.
7. Participants with a QT interval, from the ECG conducted at Screening Visit
1, corrected with Fridericia's formula (QTcF) >450 msec (or QTcF >480 msec in
participants with bundle branch block).
QTcF is the QT interval corrected for heart rate according to Fridericia*s
formula that is selected for this study. It is either machine-read or manually
over-read. when not automatically machine read. This specific formula must be
used to determine eligibility and discontinuation for an individual participant.
Participants are excluded if an abnormal ECG finding from the 12-lead ECG
conducted at Screening Visit 1 is considered to be clinically significant and
would impact the participant's participation during the study, based on the
evaluation of the Investigator.
Note: Where a single ECG demonstrates a prolonged QTcF interval, obtain two
more ECGs readings at a minimum of 2 min apart over a brief recording period
(e.g., 5-10 min), The average of the triplicate QTcF measurements should be
used to determine eligibility.
8. Participants with any of the following would be excluded:
• Myocardial infarction or unstable angina in the 6 months prior to Screening
Visit 1
• Unstable or life threatening cardiac arrhythmia requiring intervention in the
3 months prior to Screening Visit 1
• New York Heart Association (NYHA) Class IV Heart failure
9. Participants with (historical or) current evidence of clinically
significant, neurological, psychiatric, renal, hepatic, immunological,
endocrine (including uncontrolled diabetes or thyroid disease) or hematological
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 could affect the efficacy or safety analysis if
the disease/condition exacerbated during the study.
10. Participants 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. Participants with a known, pre-existing parasitic infestation within 6
months prior to Screening Visit 1.
12. A current malignancy or previous history of cancer in remission for less
than 12 months prior to Screening Visit 1 (Participants that had localized
carcinoma of the skin or cervix which was resected for cure will not be
excluded).
Note: for South Korea: Korean participants with a diagnosis of malignancy
within 5 years of Visit 1 are excluded.
13. A known immunodeficiency (e.g. human immunodeficiency virus - HIV), other
than that xplained by the use of corticosteroids taken for COPD.
14. Cirrhosis or current unstable liver disease per investigator assessment
defined by the presence of ascites, encephalopathy, coagulopathy,
hypoalbuminaemia, esophageal or gastric varices, or persistent jaundice. Stable
noncirrhotic chronic liver disease (including Gilbert's syndrome, asymptomatic
gallstones, and chronic stable hepatitis B or C) is acceptable if the
participant otherwise meets entry criteria
15. Participants who have received interventional product in previous
mepolizumab studies are excluded.
16. Subjects who have received any monoclonal antibody within 5 half lives of
Screening Visit 1
17. Participants 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).
18. Participants who have received short term use of oral corticosteroids
within 30 days of Visit 1
19. Participants with a known allergy or sensitivity to any of the study
interventions, or components thereof, or drug or other allergy
20. Participants at risk of non-compliance, or unable to comply with the study
procedures.
21. Participants 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. , e.g uncontrolled psychiatric
disease or intellectual deficiency.
22. A known or suspected history of alcohol or drug abuse within 2 years prior
to Screening Visit 1.
23. 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.
24. COVID-19: a- Participants that have a current active COVID-19 infection,
either laboratory confirmed or according to the investigator's medical
judgement.
Note: Participants who have confirmed or suspected COVID-19 infection may be
re-screened 4 weeks or more after the resolution of the COVID-19 infection and
only after approval from the Medical Monitor.
b- Participants known to be in contact with active COVID-19 positive
individuals within the past 14 days.
Note: Participants may be re-screened 14 days or more following the contact,
during which the participant should remain symptoms free, and only after
approval from the Medical Monitor.