Efficacy and Safety Study of Mepolizumab in Subjects With Severe Hypereosinophilic Syndrome (HES)
Efficacy and Safety Study of Mepolizumab in Subjects With Severe Hypereosinophilic Syndrome (HES)
Mepolizumab is a humanized monoclonal antibody. In conditions where eosinophilia is
 considered to play an important part in the pathology, including eosinophilic asthma, HES,
 and eosinophilic granulomatosis with polyangiitis, a consistent reduction in blood eosinophil
 counts is observed in association with mepolizumab administration, with concomitant clinical
 improvement. This is a 32-week treatment period, randomized, double-blind,
 placebo-controlled, parallel group, multicentre study of mepolizumab in adolescent and adult
 subjects with severe HES receiving standard of care (SoC) therapy. This study will
 demonstrate the efficacy of mepolizumab compared with placebo based on maintenance of control
 of HES symptoms during the treatment period. The study will comprise of a screening period of
 up to approximately 4 weeks followed by a 32-Week study treatment period (subjects will be
 randomized 1:1 to placebo or mepolizumab) and up to 8-week additional follow-up period (12
 weeks after the last dose of study treatment).
Inclusion Criteria:

 -  Capable of giving signed informed consent/assent which includes compliance with the
 requirements and restrictions listed in the consent form and in this protocol

 -  Twelve years of age or older, at the time of signing the informed consent/assent

 -  Subjects who have been diagnosed with HES for at least 6 months at randomization

 -  A history of two or more HES flares within the past 12 months prior to screening.
 Historical HES flares are defined as documented HES-related worsening of clinical
 symptoms or blood eosinophil counts requiring an escalation in therapy. At least one
 HES flare within the past 12 months must not be related to a decrease in HES therapy
 during the 4 weeks prior to the flare.

 -  Subjects must have blood eosinophil count >=1000 cells/µL present in the sample
 collected during screening (within 4 weeks prior to randomization).

 -  Subjects must be on a stable dose of HES therapy for the 4 weeks prior to
 randomization. HES therapy includes but is not limited to oral corticosteroid,
 immunosuppressive, and cytotoxic therapy.

 -  Male or female. A female subject is eligible to participate if she is not pregnant,
 not lactating, and either non-reproductive potential or reproductive potential and
 agree to use a highly effective method to avoid pregnancy from 30 days prior to the
 first dose of study medication and until 4 months after the last dose of study
 treatment.

 Exclusion Criteria:

 -  Life-threatening HES or life-threatening HES co-morbidities: Imminently
 life-threatening HES disease severity such that the likelihood of death is high unless
 the course of the disease is interrupted within 12 weeks prior to randomization.

 -  Subjects who have known, pre-existing, clinically significant endocrine, autoimmune,
 metabolic, neurological, renal, gastrointestinal, hepatic, hematological, respiratory
 or any other system abnormalities that are not associated with HES and are
 uncontrolled with standard treatment.

 -  Eosinophilia of unknown clinical significance

 -  Twelve-lead electrocardiogram (ECG) finding: QT interval corrected for heart rate
 (QTc) > 450 msec or QTc > 480 msec in subjects with bundle branch block or an abnormal
 ECG finding from the 12-lead ECG conducted at Visit 1 if considered to be clinically
 significant and would impact the subject's participation during the study based on the
 evaluation of the Investigator.

 -  Subjects with documented history of any clinically significant cardiac damage prior to
 screening that, in the opinion of the investigator, would impact the subject's
 participation during the study.

 -  Liver abnormality/disease - Alanine transaminase (ALT) >2.5x upper limit of normal
 (ULN) or ALT>5xULN if documented HES with liver manifestations, or bilirubin >1.5xULN
 (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
 bilirubin <35 percent), or current active liver or biliary disease (with the exception
 of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver
 disease per investigator assessment). Stable chronic liver disease should generally be
 defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia,
 oesophageal or gastric varices, or persistent jaundice, or cirrhosis.

 NOTE: Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen
 (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months prior
 to first dose of study treatment) are acceptable if subject otherwise meets entry criteria.

 -  Clinical diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)

 -  Subjects with a history of or current lymphoma, or subjects with current malignancy or
 previous history of cancer in remission for less than 12 months prior to
 randomization. Subjects that had localized carcinoma (i.e., basal or squamous cell) of
 the skin which was resected for cure will not be excluded.

 -  FIP1 like 1-platelet derived growth factor receptor (FIP1L1-PDGFR) Status: Subjects
 who test positive for the FIP1L1-PDGFR fusion tyrosine kinase gene translocation.

 -  Subjects with chronic or ongoing active infections requiring systemic treatment, as
 well as subjects who have experienced clinically significant infections due to
 viruses, bacteria, and fungi within 4 weeks prior to randomization or subjects with a
 pre-existing helminthes infestation within 6 months prior to randomization

 -  Subjects with a known human immunodeficiency virus (e.g., HIV), other than that
 explained by the use of OCS or other therapy taken for HES.

 -  Other laboratory abnormalities: Evidence of clinically significant abnormality in the
 hematological, biochemical or urinalysis screen from the sample collected at
 screening, that could put the subject's safety at risk by participating in the study,
 as judged by the investigator

 -  Subjects who have previously received mepolizumab in the 4 months prior to
 randomization

 -  Subjects receiving intravenous or subcutaneous corticosteroids in the 4-week period
 prior to randomization or any other monoclonal antibodies within 30 days or 5
 half-lives, whichever is longer, of randomization

 -  Subjects who have received treatment with an investigational agent (biologic or
 non-biologic) within the past 30 days or 5 drug half-lives whichever is longer, prior
 to randomization or subjects who are currently participating in any other
 interventional clinical study

 -  Subjects who are not responsive to oral corticosteroid based on clinical response or
 blood eosinophil counts

 -  Subjects with any history of hypersensitivity to any monoclonal antibody (including
 mepolizumab) or any steroid or steroid-containing product

 -  Subjects with a known or suspected history of alcohol or substance abuse at screening
 which in the opinion of the investigator could interfere with the subject's proper
 completion of the protocol requirement.