Efficacy and Safety Study of Mepolizumab in Subjects With Severe Hypereosinophilic Syndrome (HES)
Condition: Hypereosinophilic Syndrome
MeSH terms: Hypereosinophilic Syndrome; Syndrome
Intervention: Mepolizumab 300 mg; Placebo matching mepolizumab; Active OCS capsules (5 mg prednisolone or prednisone); Placebo matching OCS capsules
Intervention description: Mepolizumab is available as lyophilized powder for injection reconstituted with Sterile Water for Injection, just prior to use.; Placebo is available as 0.9% sodium chloride solution; All subjects will be provided with 2 bottles of blinded OCS capsules, one containing 5mg OCS capsules (active OCS treatment) and a second one containing matching placebo capsules (placebo OCS treatment). These will be dispensed to each subject at each scheduled clinic visit and as needed. Subjects with an increase in blood eosinophils above the pre-specified threshold will be instructed to start blinded OCS treatment from one of the bottles provided (active treatment) unless the subject's HES therapy has already been increased due to a symptom flare within the past 2 weeks.; All subjects will be provided with 2 bottles of blinded OCS capsules, one containing 5mg OCS capsules (active OCS treatment) and a second one containing matching placebo capsules (placebo OCS treatment). These will be dispensed to each subject at each scheduled clinic visit and as needed.A subject who does not reach the pre-specified blood eosinophil threshold with a similar blood draw date will be selected to initiate a placebo OCS treatment in a blinded manner, unless the subject's HES therapy has already been increased due to a symptom flare within the past 2 weeks.
Intervention MeSH terms: Prednisone; Prednisolone
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 108.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Safety; Mepolizumab; Hypereosinophilic syndrome; HES flare; Efficacy

Summary:

      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).
    

Eligibility criteria:

        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.