Efficacy and Safety Study of Mepolizumab Adjunctive Therapy in Participants With Severe Eosinophilic Asthma on Markers of Asthma Control
Condition: Asthma
MeSH terms: Asthma; Pulmonary Eosinophilia
Intervention: Mepolizumab; Placebo; SOC
Intervention description: Humanised Immunoglobulin G (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; Standard of Care (SOC) will differ by participants, however it will include high dose ICS with at least one other controller, e.g. LABA, with or without maintenance OCS
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 556.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Asthma control; Lung function; Health-related quality of life; Mepolizumab; Severe Eosinophilic asthma

Summary:

      This is a multi-centre, placebo-controlled, double-blind, parallel-group study to evaluate
      the efficacy and safety of mepolizumab adjunctive therapy in participants with severe
      eosinophilic asthma on markers of asthma control. The overall intent of the current study is
      to more fully explore the impact of mepolizumab on health-related quality of life (HR-QoL)
      and other measures of asthma control, including lung function.

      Participants who meet the predefined criteria will be randomised to receive either
      mepolizumab or placebo in addition to standard of care asthma treatment. Approximately 780
      participants with severe eosinophilic asthma will be screened to ensure the randomisation of
      544 participants (272 participants per treatment group) into the study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age: At least 12 years of age at the time of signing the informed consent/assent (For
             those countries where local regulations permit enrolment of adults only, participant
             recruitment will be restricted to those who are >=18 years of age)

          -  Inhaled Corticosteroid: A well-documented requirement for regular treatment with high
             dose inhaled corticosteroid (ICS) in the 12 months prior to Visit 1 with or without
             maintenance oral corticosteroids (OCS). For participants >=18 years old: ICS dose must
             be >=880 micrograms (mcg)/day fluticasone propionate (FP) (exactuator) or equivalent
             daily. For ICS/long-acting beta-2-agonist (LABA) combination preparations, the highest
             approved maintenance dose in the local country will meet this ICS criterion. For
             participants >=12 to <=17 years old: ICS dose must be >=440 mcg/day FP (ex-actuator)
             or equivalent daily. For ICS/LABA combination preparations, the mid-strength approved
             maintenance dose in the local country will meet this ICS criterion

          -  Controller Medication: Current treatment with an additional controller medication,
             besides ICS, for at least 3 months or a documented failure in the past 12 months of an
             additional controller medication for at least 3 successive months (e.g. LABA,
             leukotriene receptor antagonist [LTRA], or theophylline)

          -  Eosinophilic asthma: Prior documentation of eosinophilic asthma or high likelihood of
             eosinophilic asthma as per Randomisation Criteria 1 and 2

          -  FEV1: Persistent airflow obstruction as indicated by : For participants >=18 years of
             age at visit 1, a pre-bronchodilator FEV1 <80% predicted (National Health and
             Nutrition Examination Survey [NHANES III]) recorded at Visit 1. For participants 12-17
             years of age at Visit 1: A pre-bronchodilator FEV1 <90% predicted (NHANES III)
             recorded at Visit 1 OR FEV1:FVC ratio <0.8 recorded at Visit 1

          -  Exacerbation history: Previously confirmed history of two or more exacerbations
             requiring treatment with systemic Corticosteroid (CS) (intramuscular, intravenous, or
             oral), in the 12 months prior to visit 1, despite the use of high-dose inhaled
             corticosteroids (ICS). For participants receiving maintenance CS, the CS treatment for
             the exacerbations must have been a two-fold dose increase or greater.

          -  Gender: Male or Eligible Female. To be eligible for entry into the study, females of
             childbearing potential must commit to consistent and correct use of an acceptable
             method of birth control listed in the protocol for the duration of the trial and for 4
             months after the last study drug administration.

          -  Informed Consent/Assent: Able to give written informed consent/assent prior to
             participation in the core study, which will include the ability to comply with the
             requirements and restrictions listed in the consent/assent form and in this protocol.
             Participants must be able to read, comprehend, and write at a level sufficient to
             complete study related materials. Written informed consent must be obtained from ALL
             patients/legally authorized representative(s); for patients 12-17 years old, written
             informed assent must be obtained in addition to the legally authorized
             representative(s)' consent.

          -  French participants: In France, a participant will be eligible for inclusion in this
             study only if either affiliated to or a beneficiary of a social security category.

        Exclusion Criteria:

          -  Smoking history: Current smokers or former smokers with a smoking history of >=10 pack
             years (number of pack years = (number of cigarettes per day/20) x number of years
             smoked). A former smoker is defined as a participant who quit smoking at least 6
             months prior to Visit 1.

          -  Concurrent Respiratory Disease: Presence of a known pre-existing, clinically important
             lung condition other than asthma. This includes current infection, bronchiectasis,
             pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of emphysema or
             chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a
             history of lung cancer.

          -  Malignancy: A current malignancy or previous history of cancer in remission for less
             than 12 months prior to screening (Participants that had localized carcinoma of the
             skin which was resected for cure will not be excluded).

          -  Liver Disease: Known, pre-existing, 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).

          -  Cardiovascular: Participants who have severe or clinically significant cardiovascular
             disease uncontrolled with standard treatment. Including but not limited to: (a) known
             ejection fraction of <30% OR (b) severe heart failure meeting New York Heart
             Association Class IV classification OR (c) hospitalised in the 12 months prior to
             Visit 1 for severe heart failure meeting New York Heart Association Class III OR (d)
             angina diagnosed less than 3 months prior to Visit 1 or at Visit 1.

          -  Other Concurrent Medical Conditions: Participants who have known, pre-existing,
             clinically significant endocrine, autoimmune, metabolic, neurological, renal,
             gastrointestinal, hepatic, haematological or any other system abnormalities that are
             uncontrolled with standard treatment.

          -  Eosinophilic Diseases: Participants with other conditions that could lead to elevated
             eosinophils such as Hypereosinophilic Syndromes, including Churg-Strauss Syndrome
             (Eosinophilic Granulomatosis with Polyangiitis [EGPA]), or Eosinophilic Esophagitis.
             Participants with a known, pre-existing parasitic infestation within 6 months prior to
             Visit 1 are also to be excluded.

          -  Electrocardiogram (ECG) Assessment: QT interval corrected for heart rate by
             Fridericia's formula (QTc(F)) >=450 milliseconds (msec) or QTc(F) >=480 msec for
             participants with Bundle Branch Block at Visit 1.

          -  Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or
             substance abuse within 2 years prior to Visit 1.

          -  Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency virus [HIV]),
             other than that explained by the use of corticosteroids taken as therapy for asthma.

          -  Xolair: Participants who have received omalizumab (Xolair) within 130 days of Visit 1.

          -  Other Monoclonal Antibodies: Participants who have received any monoclonal antibody
             (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1.

          -  Investigational Medications: Participants who have received treatment with an
             investigational drug within the past 30 days or five terminal phase half-lives of the
             drug whichever is longer, prior to Visit 1 (this also includes investigational
             formulations of marketed products).

          -  Hypersensitivity: Participants with allergy/intolerance to a monoclonal antibody or
             biologic.

          -  Pregnancy: Participants who are pregnant or breastfeeding. Patients should not be
             enrolled if they plan to become pregnant during the time of study participation. A
             urine pregnancy test is required of all women of child bearing potential. This test
             will be performed at the time points specified in the Time and Events Schedule in
             protocol.

          -  Adherence: Participants who have known evidence of lack of adherence to controller
             medications and/or ability to follow physician's recommendations.

          -  Previous participation: Previously participated in any study with mepolizumab and
             received investigational product (including placebo)