Study to Evaluate Efficacy and Safety of Mepolizumab for Frequently Exacerbating Chronic Obstructive Pulmonary Disease (COPD) Patients
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: Mepolizumab; Placebo
Intervention description: Humanised IgG antibody (IgG1, kappa) with human heavy and light chain frameworks, provided as a lyophilised cake in sterile vial. Vial to be reconstituted with Sterile Water for Injection, just prior to use.; Sterile 0.9% sodium chloride solution
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 837.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: eosinophils; SB240563; exacerbations; Chronic Obstructive Pulmonary Disease; mepolizumab

Summary:

      This is a multi-center, randomized, placebo-controlled, double-blind, parallel group trial
      evaluating mepolizumab 100 mg against placebo given every 4 weeks through subcutaneous (SC)
      injection.

      In severe COPD patients, sputum eosinophils levels are elevated similar as those seen in
      severe asthmatics. It is hypothesized that the reduction of eosinophils with mepolizumab in
      COPD patients would translate into a reduction of COPD exacerbations. The study will
      determine the reduction in exacerbations in subjects who are above and below the baseline
      blood eosinophil count of at least 150 cells/microlitres. The study will evaluate the
      efficacy and safety of mepolizumab 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.

      Overall in this study, a total of 800 subjects will be randomised in 1:1 ratio to receive
      placebo or mepolizumab (100 milligram (mg)) administered SC. The total duration of this study
      will be approximately 62 weeks, consisting of a 1 to 2 week screening period, 52-week
      treatment period and 8-week follow-up period.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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.

          -  Severity of COPD: Subjects must present with the following: a measured pre and
             post-salbutamol Forced expiratory volume in one second/ Forced vital capacity
             (FEV1/FVC) ratio of <0.70 at Visit 1 to confirm the diagnosis of COPD; a measured
             post-salbutamol FEV1>20 percent and <=80 percent of predicted normal values calculated
             using National Health and Nutrition Examination Survey (NHANES) III reference
             equations at Visit 1.

          -  History of exacerbations: A well documented history (like 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 (IM, intravenous, or oral)
             and/or treatment with antibiotics, or at least one severe COPD exacerbation. Severe is
             defined as having required hospitalization. Note: At least one exacerbation must have
             occurred while the subject was taking Inhaled corticosteroid (ICS) plus long acting
             beta2-agonist (LABA) plus long acting muscarinic antagonist (LAMA). Note: Prior use of
             antibiotics alone does not qualify as a moderate exacerbation unless the use was
             specifically for the treatment of worsening symptoms of COPD.

          -  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 inhaled corticosteroid
             (at a dose >=500 micrograms (mcg)/day fluticasone propionate dose equivalent plus); or
             LABA and 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): inhaled corticosteroid at a dose >=500 mcg/day fluticasone propionate
        dose equivalent plus ; a LABA or a LAMA and use of at least one other class of COPD
        medication suggested by the 2013 Global Initiative for Chronic Obstructive Lung Disease
        (GOLD) guidelines for patients who are prone to exacerbation (i.e.,
        phosphodiesterase-4-inhibitors, methylxanthines, or a combination of short acting
        beta-2-agonist and short acting muscarinic antagonist). Note: Subjects must be willing to
        stay on their SoC COPD medication for the duration of the study.

          -  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.

          -  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.

          -  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; 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.

          -  French subjects: In France, a subject will be eligible for inclusion in this study
             only if either affiliated to or a beneficiary of a social security category.

        Exclusion Criteria:

          -  Subjects having 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;
             Other respiratory disorders: The investigator must judge that COPD is the primary
             diagnosis accounting for the clinical manifestations of the lung disease. Subjects
             with alpha-1-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.

          -  COPD stability: Subjects with pneumonia, exacerbation, lower respiratory infection
             within the 4 weeks prior to Visit 1.

          -  Lung resection: Subjects with lung volume reduction surgery within the 12 months prior
             to Visit 1.

          -  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.

          -  Oxygen: Subjects receiving treatment with oxygen more than 4.0 Litres/minute (L/min).
             While breathing supplemental oxygen, subjects should demonstrate an oxyhemoglobin
             saturation greater than or equal to 89 percent.

          -  12-lead Electrocardiography (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.

          -  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.

          -  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.

          -  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.

          -  Parasitic infection: Subjects with a pre-existing helminthes infestation within 6
             months prior to Visit 1 are also excluded.

          -  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.

          -  Immunodeficiency: A known immunodeficiency e.g. human immunodeficiency virus (HIV),
             other than that explained by the use of corticosteroids taken for COPD.

          -  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).

          -  Monoclonal antibodies: Subjects who have received any monoclonal antibody within 5
             half-lives of Visit 1.

          -  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).

          -  Hypersensitivity: Subjects with a known allergy or intolerance to another monoclonal
             antibody or biologic including history of anaphylaxis to another biologic

          -  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.

          -  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.

          -  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.

          -  Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse within 2
             years prior to Visit 1.

          -  Previous participation: Subjects who have previously participated in any study of
             mepolizumab.

          -  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.

        Randomization Criteria

        In order to be randomized to study drug the subject must meet the following randomization
        criteria at Visit 2:

          -  Blood eosinophils: While there is no threshold for enrolment, information on
             eosinophil level should be obtained prior to randomization.

          -  Electronic Diary Compliance: Compliance with completion of the eDiary defined as
             completion of all questions on 5 or more days out of the 7 days immediately preceding
             Visit 2.

          -  12-lead ECG: No evidence of an abnormal and significant ECG finding from the 12- lead
             ECG conducted at Visit 1 as indicated on the over-read provided by the centralized
             independent cardiologist. Subjects with a QT interval corrected with Fridericia's
             formulas (QTcF)>=450 msec are not eligible. For subjects with a QRS interval >=120
             msec, those with QTcF>=480 msec are not eligible. Specific ECG findings that preclude
             subject eligibility are listed in the protocol.

          -  Abnormal chest X-ray (or Computerized Tomography [CT scan]): No chest X-ray (or CT
             scan) that reveals evidence of clinically significant abnormalities other than those
             believed to be due to the presence of COPD. If a chest X-ray or CT scan is not
             available within 6 months prior to Visit 1, then a chest X-ray must be taken at Visit
             1 and the results reviewed prior to randomization. For sites in Germany: If a chest
             X-ray (or CT scan) within 6 months prior to Screening (Visit 1) is not available, the
             subject will not be eligible for the study.

          -  Laboratory abnormality: No evidence of clinically significant abnormality in the
             haematological, biochemical, or urinalysis screen at Visit 1, as judged by the
             investigator.

          -  Hepatitis B: Subjects who are HBsAg positive or HBcAb positive must not have a HBV DNA
             level >= 2000 IU/ml.

          -  Liver function test: Subjects must meet the following based on results from sample
             taken at Visit 1: Alanine aminotransferase (ALT) <2x ULN (upper limit of normal);
             Alkaline Phosphatase (Alk Phos) <=2x ULN; Bilirubin <=1.5x ULN (isolated
             bilirubin>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35
             percent)