Efficacy and Safety Study of Mepolizumab in Subjects With Severe Hypereosinophilic Syndrome (HES)

Study Overview
=================
Brief 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).

Official Title
-----------------
Study 200622: A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Mepolizumab in the Treatment of Adolescent and Adult Subjects With Severe Hypereosinophilic Syndrome

Conditions
-----------------
Hypereosinophilic Syndrome

Intervention / Treatment
-----------------
* Drug: Mepolizumab 300 mg
* Drug: Placebo matching mepolizumab
* Drug: Active OCS capsules (5 mg prednisolone or prednisone)
* Drug: Placebo matching OCS capsules


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mepolizumab<br>Enrolled subjects will receive either mepolizumab 300 mg or placebo subcutaneous (SC) every 4 weeks while continuing their HES therapy. | Drug: Mepolizumab 300 mg<br>* Mepolizumab is available as lyophilized powder for injection reconstituted with Sterile Water for Injection, just prior to use.<br>Drug: Active OCS capsules (5 mg prednisolone or prednisone)<br>* 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.<br>Drug: Placebo matching OCS capsules<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Enrolled subjects will receive either mepolizumab 300 mg or placebo SC every 4 weeks while continuing their HES therapy. | Drug: Placebo matching mepolizumab<br>* Placebo is available as 0.9% sodium chloride solution<br>Drug: Active OCS capsules (5 mg prednisolone or prednisone)<br>* 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.<br>Drug: Placebo matching OCS capsules<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced an HES Flare or Who Withdrew From the Study During the 32-Week Study Treatment Period | Percentage of participants who experienced >=1 HES flare during the 32-Week treatment period or who withdrew from the study has been presented. A HES flare is defined as a HES related clinical manifestation based on a physician-documented change in clinical signs or symptoms which resulted in need for an increase in the maintenance Oral Corticosteroid (OCS) dose by at least 10 mg per day for 5 days or an increase in or addition of any cytotoxic or immunosuppressive HES therapy. HES flare is also defined as receipt of two or more courses of blinded active OCS during the treatment period. Intent-to-treat (ITT) Population comprises of all randomized participants. This population was based on the treatment to which the participants were randomized. Any participant who received a treatment randomization number were considered to be randomized. | Up to Week 32 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced a HES Flare or Who Withdrew From the Study During Week 20 Through Week 32 | HES flare during Week 20 through Week 32 was defined as a HES flare starting or ongoing on or after the date of the Week 20 visit up to and including the date of the Week 32 visit. Percentage of participants who experienced >=1 HES flare during Week 20 through Week 32 or who withdrew from the study has been presented. | Week 20 to Week 32 | 
| Time to First HES Flare | The time to first HES flare was calculated as (onset date of first HES flare minus date of first dose of study treatment) plus 1. Probability of first flare (by week 4, 8, 12, 16, 20, 24, 28, and 32) and corresponding 95% CI have been presented, calculated using the Kaplan-Meier method. | Weeks 4, 8, 12, 16, 20, 24, 28 and 32 | 
| Number of HES Flares Per Participant Per Year | The rate of HES flares for each participant was calculated as the number of observed HES flares divided by the time (expressed in years) between randomization and either the week 32 visit date if available, or the study withdrawal date. Negative binomial generalized linear model including Baseline OCS dose, region, treatment and observed time (offset variable). Wilcoxon test stratified by Baseline OCS (0-<=20mg/day, >20mg/day prednisone or equivalent) and region. Adjusted mean and 95% CI rate/year has been presented. | Up to Week 32 | 
| Number of Participants With Change From Baseline in Fatigue Severity Based on Brief Fatigue Inventory (BFI) in Item 3 (Worst Level of Fatigue During Past 24 Hours) at Week 32 by Category | The change from Baseline in fatigue severity (worst level of fatigue during past 24 hours) at Week 32 was calculated using the mean of the 7 daily assessments of BFI item 3 up to and including the date of the Week 32 visit as the Week 32 assessment, and the mean of the 7 daily assessments of BFI item 3 up to but not including the date of first dose of study treatment as the Baseline assessment. Wilcoxon Rank Sum test stratified by Baseline fatigue severity (severe defined as BFI item 3>=7 and not severe defined as BFI item 3<7), Baseline OCS (0-<=20mg/day and >20mg/day prednisone or equivalent) and region. Participants with missing change from Baseline at Week 32 were included in the worst category (>=4 point increase). | Baseline (Week 0) and at Week 32 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Safety, Mepolizumab, Hypereosinophilic syndrome, HES flare, Efficacy