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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02836496
• Collaborator: (none)
• Enrollment: 108
• Locations: 43
• Arms: 2
• Actual Duration (Months): 29
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Hypereosinophilic Syndrome	Drug: Mepolizumab 300 mg; Drug: Placebo matching mepolizumab; Drug: Active OCS capsules (5 mg prednisolone or prednisone); Drug: Placebo matching OCS capsules	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 108 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: 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
• Actual Study Start Date: Mar 7, 2017
• Actual Primary Completion Date: Aug 8, 2019
• Actual Study Completion Date: Aug 8, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Experienced an HES Flare or Who Withdrew From the Study During the 32-Week Study Treatment Period [Up to Week 32]

   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.

Secondary Outcome Measures

1. Percentage of Participants Who Experienced a HES Flare or Who Withdrew From the Study During Week 20 Through Week 32 [Week 20 to 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.

2. Time to First HES Flare [Weeks 4, 8, 12, 16, 20, 24, 28 and 32]

   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.

3. Number of HES Flares Per Participant Per Year [Up to Week 32]

   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.

4. 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 [Baseline (Week 0) and at Week 32]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	San Diego	California	United States	92037-0641
2	GSK Investigational Site	New Haven	Connecticut	United States	06520
3	GSK Investigational Site	Rochester	Minnesota	United States	55905
4	GSK Investigational Site	Cincinnati	Ohio	United States	45229
5	GSK Investigational Site	Mayfield Heights	Ohio	United States	44124
6	GSK Investigational Site	Charleston	South Carolina	United States	29425
7	GSK Investigational Site	Salt Lake City	Utah	United States	84132
8	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1028AAP
9	GSK Investigational Site	La Plata	Buenos Aires	Argentina
10	GSK Investigational Site	Mar del Plata	Buenos Aires	Argentina	7600
11	GSK Investigational Site	Buenos Aires		Argentina	C1425BEN
12	GSK Investigational Site	Bruxelles		Belgium	1070
13	GSK Investigational Site	Leuven		Belgium	3000
14	GSK Investigational Site	Porto Alegre	Rio Grande Do Sul	Brazil	90610000
15	GSK Investigational Site	Blumenau	Santa Catarina	Brazil	89030-101
16	GSK Investigational Site	Santo André - SP	São Paulo	Brazil	09080-110
17	GSK Investigational Site	Sorocaba	São Paulo	Brazil	18040-425
18	GSK Investigational Site	Lille Cedex		France	59037
19	GSK Investigational Site	Nantes Cedex 1		France	44093
20	GSK Investigational Site	Suresnes		France	92150
21	GSK Investigational Site	Toulouse Cedex 9		France	31059
22	GSK Investigational Site	Kirchheim -Teck	Baden-Wuerttemberg	Germany	73230
23	GSK Investigational Site	Mannheim	Baden-Wuerttemberg	Germany	68167
24	GSK Investigational Site	Muenchen	Bayern	Germany	80802
25	GSK Investigational Site	Fulda	Hessen	Germany	36043
26	GSK Investigational Site	Hannover	Niedersachsen	Germany	30625
27	GSK Investigational Site	Napoli	Campania	Italy	80131
28	GSK Investigational Site	Firenze	Toscana	Italy	50134
29	GSK Investigational Site	Guadalajara	Jalisco	Mexico	44100
30	GSK Investigational Site	Monterrey	Nuevo León	Mexico	64710
31	GSK Investigational Site	Villahermosa	Tabasco	Mexico	86035
32	GSK Investigational Site	Krakow		Poland	31-066
33	GSK Investigational Site	Lodz		Poland	90-153
34	GSK Investigational Site	Bucharest		Romania	010306
35	GSK Investigational Site	Cluj-Napoca		Romania	400124
36	GSK Investigational Site	Targu Mures		Romania	540327
37	GSK Investigational Site	Moscow		Russian Federation	125167
38	GSK Investigational Site	Saint-Petersburg		Russian Federation	197341
39	GSK Investigational Site	St Petersburg		Russian Federation	193024
40	GSK Investigational Site	Barcelona		Spain	08035
41	GSK Investigational Site	Barcelona		Spain	08036
42	GSK Investigational Site	Valencia		Spain	46026
43	GSK Investigational Site	Leicester		United Kingdom	LE3 9QP

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Apr 29, 2016
• Statistical Analysis Plan - Jun 18, 2019

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02836496
• Other Study ID Numbers: 200622
• First Posted: Jul 19, 2016
• Last Update Posted: Feb 21, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: Safety; Mepolizumab; Hypereosinophilic syndrome; HES flare; Efficacy
• Additional relevant MeSH terms: Hypereosinophilic Syndrome; Syndrome; Prednisone; Prednisolone

Study Results

Participant Flow

Recruitment Details	This 32-week, randomized, double-blind, placebo-controlled study assessed the efficacy and safety of mepolizumab 300 milligrams (mg) subcutaneous (SC) every 4 weeks compared with placebo in adolescent and adult participants with severe hypereosinophilic syndrome (HES) receiving standard of care (SoC) therapy.
Pre-assignment Detail	A total of 108 participants were enrolled in the study and randomized. The study was conducted in 13 countries.

Arm/Group Title	Placebo	Mepolizumab 300 mg SC
Arm/Group Description	Participants were randomized to receive matching placebo SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.	Participants were randomized to receive 300 mg mepolizumab SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.
Period Title: Overall Study
STARTED	54	54
COMPLETED	52	52
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Placebo	Mepolizumab 300 mg SC	Total
Arm/Group Description	Participants were randomized to receive matching placebo SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.	Participants were randomized to receive 300 mg mepolizumab SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.	Total of all reporting groups
Overall Participants	54	54	108
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	45.4 (18.25)	46.6 (12.99)	46.0 (15.78)
Sex: Female, Male (Count of Participants)
Female	27 50%	30 55.6%	57 52.8%
Male	27 50%	24 44.4%	51 47.2%
Race/Ethnicity, Customized (Number) [Number]
American Indian or Alaska Native	2 3.7%	1 1.9%	3 2.8%
Asian-Central/South Asian Heritage	0 0%	1 1.9%	1 0.9%
Asian-East Asian Heritage	1 1.9%	0 0%	1 0.9%
Asian-South East Asian Heritage	1 1.9%	0 0%	1 0.9%
Black or African American	2 3.7%	0 0%	2 1.9%
White-Arabic/North African Heritage	1 1.9%	0 0%	1 0.9%
White-White/Caucasian/European Heritage	47 87%	52 96.3%	99 91.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Experienced an HES Flare or Who Withdrew From the Study During the 32-Week Study Treatment Period
Description	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.
Time Frame	Up to Week 32

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	Mepolizumab 300 mg SC
Arm/Group Description	Participants were randomized to receive matching placebo SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.	Participants were randomized to receive 300 mg mepolizumab SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.
Measure Participants	54	54
Number [Percentage of participants]	56 103.7%	28 51.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 300 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	Cochran-Mantel-Haenszel test stratified by Baseline oral corticosteroid (OCS) (0-<=20 mg per day and >20mg perday prednisone or equivalent) and region
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 300 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression analysis adjusted for Baseline OCS dose and region.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; 0.12 to 0.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment comparison between placebo and mepolizumab 300 mg using odds ratio and 95% confidence interval (CI) has been presented. Odds ratio <1 indicated lower odds of HES flare with Mepolizumab compared with placebo.

2. Secondary Outcome

Title	Percentage of Participants Who Experienced a HES Flare or Who Withdrew From the Study During Week 20 Through Week 32
Description	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.
Time Frame	Week 20 to Week 32

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	Mepolizumab 300 mg SC
Arm/Group Description	Participants were randomized to receive matching placebo SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.	Participants were randomized to receive 300 mg mepolizumab SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.
Measure Participants	54	54
Number [Percentage of participants]	35 64.8%	17 31.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 300 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test stratified by Baseline OCS (0-<=20 mg per day and >20mg perday prednisone or equivalent) and region

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 300 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression analysis adjusted for Baseline OCS dose and region
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; 0.13 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment comparison between placebo and mepolizumab 300 mg using odds ratio and 95% CI has been presented. Odds ratio <1 indicated lower odds of HES flare with Mepolizumab compared with placebo.

3. Secondary Outcome

Title	Time to First HES Flare
Description	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.
Time Frame	Weeks 4, 8, 12, 16, 20, 24, 28 and 32

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	Mepolizumab 300 mg SC
Arm/Group Description	Participants were randomized to receive matching placebo SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.	Participants were randomized to receive 300 mg mepolizumab SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.
Measure Participants	54	54
Flares by Week 4	7.4	5.6
Flares by Week 8	14.9	7.4
Flares by Week 12	26.2	9.3
Flares by Week 16	33.8	13.0
Flares by Week 20	41.3	13.0
Flares by Week 24	48.9	14.8
Flares by Week 28	50.8	20.5
Flares by Week 32	52.7	26.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 300 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	Cox proportional hazards regression analysis adjusted for Baseline OCS dose and region.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 95%; 0.18 to 0.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment comparison between placebo and mepolizumab 300 mg using hazards ratio and its corresponding 95% CI has been presented. Hazard ratio <1 indicated a lower risk of HES flare with Mepolizumab compared with Placebo.

4. Secondary Outcome

Title	Number of HES Flares Per Participant Per Year
Description	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.
Time Frame	Up to Week 32

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	Mepolizumab 300 mg SC
Arm/Group Description	Participants were randomized to receive matching placebo SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.	Participants were randomized to receive 300 mg mepolizumab SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.
Measure Participants	54	54
Mean (95% Confidence Interval) [Flares per participant per year]	1.46	0.50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 300 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Wilcoxon Rank Sum Test
	Comments	Wilcoxon test stratified by Baseline OCS (0-<=20 mg/day, >20 mg/day prednisone or equivalent) and region.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 95%; 0.19 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment comparison between placebo and mepolizumab 300 mg using rate ratio and 95% CI has been presented. Rate ratio <1 indicates a lower flare rate with Mepolizumab compared with Placebo.

5. Secondary Outcome

Title	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
Description	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).
Time Frame	Baseline (Week 0) and at Week 32

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Placebo	Mepolizumab 300 mg SC
Arm/Group Description	Participants were randomized to receive matching placebo SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.	Participants were randomized to receive 300 mg mepolizumab SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.
Measure Participants	54	54
>=4 point increase (>=3.5)	7 13%	5 9.3%
3 point increase (>=2.5 to <3.5)	4 7.4%	0 0%
2 point increase (>=1.5 to <2.5)	4 7.4%	5 9.3%
1 point increase (>=0.5 to <1.5)	9 16.7%	6 11.1%
No change (>-0.5 to <0.5)	14 25.9%	9 16.7%
1 point reduction (>-1.5 to <=-0.5)	5 9.3%	11 20.4%
2 point reduction (>-2.5 to <=-1.5)	3 5.6%	7 13%
3 point reduction (>-3.5 to <=-2.5)	5 9.3%	2 3.7%
>=4 point reduction (<=-3.5)	3 5.6%	9 16.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 300 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	Wilcoxon Rank Sum Test
	Comments	P-value was calculated using Wilcoxon Rank Sum Test

Adverse Events

Time Frame	Non-serious adverse events (non-SAEs) from start of study treatment until 28 days after last dose (Up to 32 weeks) are reported. Serious adverse events (SAEs) were collected from the day of randomization (Week 0) up to end of study (Up to Week 40).
Adverse Event Reporting Description	Non-SAEs and SAEs were collected for Safety Population. The Safety Population comprises of all participants who were randomized and who received at least one dose of study treatment.
Arm/Group Title	Placebo		Mepolizumab 300 mg SC
Arm/Group Description	Participants were randomized to receive matching placebo SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.		Participants were randomized to receive 300 mg mepolizumab SC every 4 weeks during the 32-Week treatment period while continuing their HES therapy. The final dose was administered at Week 28 with the completion of study treatment period achieved in the next 4-weekly visit.
All Cause Mortality
	Placebo		Mepolizumab 300 mg SC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/54 (0%)		1/54 (1.9%)
Serious Adverse Events
	Placebo		Mepolizumab 300 mg SC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/54 (16.7%)		10/54 (18.5%)
Blood and lymphatic system disorders
Hypereosinophilic syndrome	1/54 (1.9%)		1/54 (1.9%)
Cardiac disorders
Arrhythmia	0/54 (0%)		1/54 (1.9%)
Restrictive cardiomyopathy	1/54 (1.9%)		0/54 (0%)
Gastrointestinal disorders
Abdominal pain	1/54 (1.9%)		0/54 (0%)
Abdominal pain upper	1/54 (1.9%)		0/54 (0%)
Faecaloma	0/54 (0%)		1/54 (1.9%)
Vomiting	0/54 (0%)		1/54 (1.9%)
Immune system disorders
Anaphylactic reaction	1/54 (1.9%)		0/54 (0%)
Infections and infestations
Bronchitis	0/54 (0%)		1/54 (1.9%)
Bursitis infective	0/54 (0%)		1/54 (1.9%)
Diverticulitis	0/54 (0%)		1/54 (1.9%)
Erysipelas	0/54 (0%)		1/54 (1.9%)
Gastroenteritis	0/54 (0%)		1/54 (1.9%)
Liver abscess	0/54 (0%)		1/54 (1.9%)
Pneumonia	0/54 (0%)		1/54 (1.9%)
Septic shock	0/54 (0%)		1/54 (1.9%)
Tooth infection	0/54 (0%)		1/54 (1.9%)
Injury, poisoning and procedural complications
Contusion	0/54 (0%)		1/54 (1.9%)
Foot fracture	0/54 (0%)		1/54 (1.9%)
Metabolism and nutrition disorders
Dehydration	0/54 (0%)		1/54 (1.9%)
Musculoskeletal and connective tissue disorders
Costochondritis	0/54 (0%)		1/54 (1.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant	1/54 (1.9%)		0/54 (0%)
T-cell lymphoma	1/54 (1.9%)		0/54 (0%)
Uterine leiomyoma	1/54 (1.9%)		0/54 (0%)
Reproductive system and breast disorders
Vaginal haemorrhage	0/54 (0%)		1/54 (1.9%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	0/54 (0%)		1/54 (1.9%)
Vascular disorders
Hypertension	0/54 (0%)		1/54 (1.9%)
Peripheral artery occlusion	1/54 (1.9%)		0/54 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Mepolizumab 300 mg SC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/54 (79.6%)		41/54 (75.9%)
Cardiac disorders
Palpitations	0/54 (0%)		2/54 (3.7%)
Ear and labyrinth disorders
Tinnitus	0/54 (0%)		2/54 (3.7%)
Gastrointestinal disorders
Diarrhoea	7/54 (13%)		5/54 (9.3%)
Vomiting	3/54 (5.6%)		3/54 (5.6%)
Nausea	2/54 (3.7%)		3/54 (5.6%)
Constipation	1/54 (1.9%)		3/54 (5.6%)
Abdominal pain	2/54 (3.7%)		1/54 (1.9%)
Abdominal pain upper	2/54 (3.7%)		1/54 (1.9%)
Stomatitis	1/54 (1.9%)		2/54 (3.7%)
Toothache	1/54 (1.9%)		2/54 (3.7%)
Gastrooesophageal reflux disease	2/54 (3.7%)		0/54 (0%)
General disorders
Fatigue	5/54 (9.3%)		3/54 (5.6%)
Pyrexia	2/54 (3.7%)		4/54 (7.4%)
Asthenia	5/54 (9.3%)		0/54 (0%)
Influenza like illness	2/54 (3.7%)		3/54 (5.6%)
Injection site reaction	2/54 (3.7%)		3/54 (5.6%)
Peripheral swelling	2/54 (3.7%)		1/54 (1.9%)
Malaise	0/54 (0%)		2/54 (3.7%)
Infections and infestations
Bronchitis	10/54 (18.5%)		7/54 (13%)
Nasopharyngitis	7/54 (13%)		7/54 (13%)
Rhinitis	6/54 (11.1%)		5/54 (9.3%)
Upper respiratory tract infection	2/54 (3.7%)		8/54 (14.8%)
Sinusitis	4/54 (7.4%)		2/54 (3.7%)
Urinary tract infection	0/54 (0%)		5/54 (9.3%)
Influenza	1/54 (1.9%)		3/54 (5.6%)
Oral herpes	2/54 (3.7%)		2/54 (3.7%)
Cystitis	2/54 (3.7%)		1/54 (1.9%)
Gastroenteritis	2/54 (3.7%)		1/54 (1.9%)
Arthritis infective	2/54 (3.7%)		0/54 (0%)
Gastroenteritis viral	2/54 (3.7%)		0/54 (0%)
Onychomycosis	2/54 (3.7%)		0/54 (0%)
Respiratory tract infection	0/54 (0%)		2/54 (3.7%)
Injury, poisoning and procedural complications
Contusion	1/54 (1.9%)		3/54 (5.6%)
Skin abrasion	0/54 (0%)		2/54 (3.7%)
Metabolism and nutrition disorders
Decreased appetite	3/54 (5.6%)		0/54 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/54 (7.4%)		4/54 (7.4%)
Pain in extremity	2/54 (3.7%)		6/54 (11.1%)
Myalgia	3/54 (5.6%)		4/54 (7.4%)
Back pain	3/54 (5.6%)		3/54 (5.6%)
Musculoskeletal chest pain	0/54 (0%)		3/54 (5.6%)
Musculoskeletal pain	2/54 (3.7%)		0/54 (0%)
Nervous system disorders
Headache	7/54 (13%)		7/54 (13%)
Dizziness	3/54 (5.6%)		4/54 (7.4%)
Hypoaesthesia	1/54 (1.9%)		3/54 (5.6%)
Paraesthesia	0/54 (0%)		3/54 (5.6%)
Presyncope	3/54 (5.6%)		0/54 (0%)
Somnolence	2/54 (3.7%)		0/54 (0%)
Reproductive system and breast disorders
Erectile dysfunction	2/54 (3.7%)		0/54 (0%)
Vaginal haemorrhage	0/54 (0%)		2/54 (3.7%)
Respiratory, thoracic and mediastinal disorders
Asthma	5/54 (9.3%)		2/54 (3.7%)
Dyspnoea	2/54 (3.7%)		3/54 (5.6%)
Nasal obstruction	2/54 (3.7%)		3/54 (5.6%)
Rhinorrhoea	4/54 (7.4%)		1/54 (1.9%)
Cough	4/54 (7.4%)		0/54 (0%)
Epistaxis	2/54 (3.7%)		1/54 (1.9%)
Oropharyngeal pain	2/54 (3.7%)		1/54 (1.9%)
Skin and subcutaneous tissue disorders
Pruritus	7/54 (13%)		4/54 (7.4%)
Urticaria	5/54 (9.3%)		0/54 (0%)
Alopecia	0/54 (0%)		4/54 (7.4%)
Rash	2/54 (3.7%)		2/54 (3.7%)
Eczema	2/54 (3.7%)		0/54 (0%)
Erythema	2/54 (3.7%)		0/54 (0%)
Hyperhidrosis	0/54 (0%)		2/54 (3.7%)
Vascular disorders
Hypertension	2/54 (3.7%)		1/54 (1.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.