Omalizumab to Mepolizumab Switch Study in Severe Eosinophilic Asthma Patients

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02654145
• Collaborator: (none)
• Enrollment: 145
• Locations: 53
• Arm: 1
• Actual Duration (Months): 14.5
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Mepolizumab is an anti-interleukin-5 ( IL-5) monoclonal antibody that neutralizes IL-5 and reduces eosinophil counts in both sputum and blood. Omalizumab an anti-immunoglobulin E (IgE) monoclonal antibody (mAb) is effective in the treatment of moderate to severe allergic asthma. The aim of this study is to investigate whether subjects not optimally controlled on their current omalizumab treatment, who are eligible for therapy with mepolizumab can be effectively and safely switched to treatment with mepolizumab to improve asthma control. The study will provide data on the efficacy, safety, immunogenicity, and tolerability of mepolizumab when switched directly from omalizumab without any wash-out. The learnings from this study may help guide physicians when substituting one biologic with another for the treatment of patients with severe eosinophilic asthma.

The study will be a multi-centre, open-label single arm trial. Patients with severe eosinophilic asthma who are receiving omalizumab, but are not optimally controlled will be eligible to participate. Subjects will remain on their current maintenance therapy including omalizumab throughout the run-in period for a minimum of one week and up to 4 weeks. At Visit 2 (week 0) subjects will discontinue their omalizumab treatment and be switched to mepolizumab 100 mg subcutaneous (SC) every 4 weeks for 28 weeks. The treatment period is 32 weeks, including an Exit Visit/Early Withdrawal Visit, 4 weeks following the subject's last dose of mepolizumab.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Mepolizumab 100mg SC; Drug: Albuterol/salbutamol MDIs; Drug: Omalizumab	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 145 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-centre, Open Label, Single Arm, 32-week Treatment Study in Subjects With Severe Eosinophilic Asthma Not Optimally Controlled With Current Omalizumab Treatment Who Are Switched From Omalizumab to Mepolizumab 100mg Subcutaneous (Study Number 204471- the OSMO Study)
• Actual Study Start Date: Mar 17, 2016
• Actual Primary Completion Date: May 31, 2017
• Actual Study Completion Date: May 31, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Omalizumab switch to mepolizumab 100mg SC every 4 weeks Subjects with severe eosinophilic asthma who are receiving omalizumab will enter a run-in period for a minimum of one week and a up to 4 weeks. Subjects will remain on their current maintenance therapy throughout the run-in period, including omalizumab. At Visit 2 (week 0) subjects will discontinue omalizumab treatment and will be switched to receiving mepolizumab 100 mg SC every 4 weeks for 28 weeks. Except for omalizumab, subjects will remain on their current maintenance therapy throughout the open-label treatment period. Albuterol/salbutamol metered dose inhalers (MDIs) will be provided as rescue medication during treatment period.

Drug: Mepolizumab 100mg SC; At Visit 2 (Week 0) eligible subjects will receive mepolizumab 100mg SC into the upper arm or thigh every 4 weeks over a period of 28 weeks.; Drug: Albuterol/salbutamol MDIs; Albuterol/salbutamol metered dose inhalers (MDIs) will be provided as rescue medication during treatment period.; Drug: Omalizumab; Subjects receiving omalizumab will enter in a run-in period and will continue to receive omalizumab throughout the run-in period. At Visit 2 (week 0) subjects will discontinue omalizumab.

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in Asthma Control Questionnaire-5 (ACQ-5) Score at Week 32 [Baseline and at Week 32]

   The ACQ-5 is a five-item, self-completed questionnaire, which is used as a measure of asthma control of a participant. The five questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) enquire about the frequency and/or severity of symptoms over the previous week. The response options for all these questions range from zero (no impairment/limitation) to six (total impairment/ limitation) scale. ACQ-5 score range from 0 to 6. Higher scores indicates worsening of condition. Baseline was defined as the latest available assessment prior to first dose of mepolizumab. Change from Baseline at Week 32 was calculated as Week 32 value of ACQ-5 score minus Baseline value and was analyzed using Mixed Model Repeated Measures allowing for covariates of region, baseline maintenance OCS therapy, exacerbations in the year prior to the study (as ordinal variable) and visit.

Secondary Outcome Measures

1. Mean Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score at Week 32 [Baseline and at Week 32]

   The SGRQ Questionnaire is a well-established, self-completed tool, comprising of 50 questions with 76 weighted responses designed to measure Quality of Life in participants with diseases of airway obstruction. It consists of two parts; Part 1 produces the symptom score and Part 2 produces the activity and impact score. A Total score is also calculated which summarizes the impact of the disease on overall health status. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and zero indicates best possible health status. Baseline was defined as the latest available assessment prior to first dose of mepolizumab. Change from Baseline at Week 32 was calculated as Week 32 value of SGRQ score minus Baseline value and was analyzed using Mixed Model Repeated Measures allowing for covariates of region, baseline maintenance OCS therapy, exacerbations in the year prior to the study (as an ordinal variable) and visit.

2. The Rate of Clinically Significant Asthma Exacerbations Over 32 Weeks' Treatment [Up to Week 32]

   Clinically significant exacerbations of asthma were defined as worsening of asthma which requires use of systemic corticosteroids and/or hospitalization and/or Emergency Department (ED) visits. The frequency of clinically significant asthma exacerbations over 32 weeks' treatment was analyzed using Negative Binomial Regression via generalized estimating equations with a covariate of time period (pre-treatment versus on- and off treatment).

3. Ratio to Baseline in Blood Eosinophil Count at Week 32 [Baseline and at Week 32]

   Blood samples were collected at specific time points to measure blood eosinophils level for evaluation of pharmacodynamic effects in participants with a severe eosinophilic asthma phenotype when they were directly switched to mepolizumab. Baseline was defined as the latest available assessment prior to first dose of mepolizumab and ratio to Baseline at Week 32 was defined as Week 32 value divided by Baseline value and was analyzed using Mixed Model Repeated Measures allowing for covariates of region, Baseline maintenance oral corticosteroid (OCS) therapy, exacerbations in the year prior to the study (as an ordinal variable) and visit. The log transformation was applied to blood eosinophil counts prior to analysis. If a blood eosinophil count of zero was reported, it was imputed with half of the lowest possible blood eosinophil count, where applicable, prior to log transforming the data. The dispersion measure used was log standard error.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• At least 12 years of age at the time of signing the informed consent. For those countries where local regulations permit enrolment of adults only, subject recruitment will be restricted to those who are >= 18 years of age.

• Asthma: A physician diagnosis of asthma for >=2 years that meets the National Heart and Lung Institute guidelines.

• Forced expiratory volume in 1 second (FEV1): Persistent airflow obstruction as indicated by: For subjects >=18 years of age at Visit 1, a pre-bronchodilator FEV1 <80% predicted recorded at Visit 1, For subjects 12-17 years of age at Visit 1, a pre-bronchodilator FEV1 <90% predicted recorded at Visit 1 or FEV1/ Forced Vital Capacity (FVC) ratio <0.8 recorded at Visit 1

• Eosinophilic asthma: Airway inflammation characterized as eosinophilic in nature as indicated by one of the following: A peripheral blood eosinophil count of >=300 cells/microliter (uL) that is related to asthma demonstrated in the past 12 months prior to Visit 1 or a peripheral blood eosinophil count of >=150 cells/uL at Visit 1 that is related to asthma.

• 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 18 years of age and older: ICS dose must be >=880 microgram (ug)/day fluticasone propionate (FP) (ex-actuator) or equivalent daily. For ICS/ Long-Acting Beta-2-Agonists (LABA) combination preparations, the highest approved maintenance dose in the local country will meet this ICS criterion. For subjects 12-17 years of age at Visit 1: ICS dose must be >=440 ug/day fluticasone propionate (FP) (ex-actuator) or equivalent daily, For ICS/LABA combination preparations, the highest 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.]

• Asthma symptoms not optimally controlled: An ACQ-5 score of >=1.5 recorded at Visit 1.

• Omalizumab Treatment: Receiving omalizumab, based on weight and IgE levels, for at least the 4 months prior to Visit 1.

• Exacerbation history: Previously confirmed history of two or more exacerbations requiring treatment with systemic corticosteroids (intramuscular, intravenous, or oral) in the 12 months prior to Visit 1 despite the use of high-dose ICS. For subjects receiving omalizumab for >=8 months, at least one exacerbation must have occurred while on omalizumab treatment. For subjects receiving maintenance oral corticosteroids, the corticosteroid treatment for the exacerbations must have been a two-fold dose increase or greater.

• Male or eligible Female: Females: a) Non-reproductive potential defined as :Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy, Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. b) Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until at least five terminal half-lives or until any continuing pharmacologic effect has ended, whichever is longer, after the last dose of study medication and completion of the Exit visit/Early Withdrawal visit.The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

• 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 (subjects that had localized carcinoma of the skin which was resected for cure will not be excluded).

• Liver disease: Subjects must not be enrolled in the study if :At screening (Visit 1) Alanine Transaminase (ALT) >2x Upper Limit of Normal (ULN); and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) 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.

• Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Visit 1. Chronic stable hepatitis C (e.g.,positive hepatitis C antibody test result at screening (Visit 1) or within 3 months prior to first dose of study treatment) are acceptable if subject otherwise meets entry criteria.

• Cardiovascular: Subjects 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

• Subjects with QT interval corrected (QTc) > 450 milliseconds (msec) or QTc > 480 msec in subjects with Bundle Branch Block at screening Visit 1.The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read. The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used.

• Other Concurrent Medical Conditions: Subjects 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: Subjects 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. Subjects with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are also to be excluded.

• Immunodeficiency: A known immunodeficiency (e.g., human immunodeficiency virus [HIV]), other than that explained by the use of corticosteroids taken as therapy for asthma.

• Other Monoclonal Antibodies: Subjects who have received any monoclonal antibody (other than omalizumab) to treat inflammatory disease within 5 half-lives of Visit 1.

• 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 subject who quit smoking at least 6 months prior to Screening Visit 1.

• Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.

• Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations.

• Hypersensitivity: Subjects with allergy/intolerance to a monoclonal antibody or biologic. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

• Investigator opinion: Omalizumab treatment has provided significant clinical benefit despite experiencing 2 exacerbations in the past 12 months, and potential benefit from a switch to mepolizumab would not outweigh the potential harm after omalizumab withdrawal for the subject.

• Previous participation: Previously participated in any study with mepolizumab and received investigational product (including placebo).

• Investigational Medications: Subjects 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 Screening (V1) (this also includes investigational formulations of marketed products).

• Pregnancy: Subjects who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the time of study participation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Birmingham	Alabama	United States	35209
2	GSK Investigational Site	Riverside	California	United States	92506
3	GSK Investigational Site	Roseville	California	United States	95661
4	GSK Investigational Site	San Diego	California	United States	92123
5	GSK Investigational Site	Upland	California	United States	91786
6	GSK Investigational Site	Baltimore	Maryland	United States	21224
7	GSK Investigational Site	Piscataway	New Jersey	United States	08854
8	GSK Investigational Site	Rochester	New York	United States	14642
9	GSK Investigational Site	Charlotte	North Carolina	United States	28277
10	GSK Investigational Site	Durham	North Carolina	United States	27705
11	GSK Investigational Site	East Providence	Rhode Island	United States	02914
12	GSK Investigational Site	Richmond	Virginia	United States	23229
13	GSK Investigational Site	Williamsburg	Virginia	United States	23188
14	GSK Investigational Site	Florencio Varela	Buenos Aires	Argentina	1888
15	GSK Investigational Site	Florida	Buenos Aires	Argentina	1602
16	GSK Investigational Site	La Plata	Buenos Aires	Argentina	1900
17	GSK Investigational Site	Quilmes	Buenos Aires	Argentina	B1878FNR
18	GSK Investigational Site	Rosario	Santa Fe	Argentina	2000
19	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1426ABP
20	GSK Investigational Site	Erpent		Belgium	5101
21	GSK Investigational Site	Calgary	Alberta	Canada	T2N 4Z6
22	GSK Investigational Site	Sherwood Park	Alberta	Canada	T8H 0N2
23	GSK Investigational Site	Vancouver	British Columbia	Canada	V5Z 1M9
24	GSK Investigational Site	Ajax	Ontario	Canada	L1S 2J5
25	GSK Investigational Site	Mississauga	Ontario	Canada	L5A 3V4
26	GSK Investigational Site	Toronto	Ontario	Canada	M4V 1R2
27	GSK Investigational Site	Toronto	Ontario	Canada	M5T 3A9
28	GSK Investigational Site	Windsor	Ontario	Canada	N8X 2G1
29	GSK Investigational Site	Montreal	Quebec	Canada	H3T1E2
30	GSK Investigational Site	Bordeaux cedex		France	33076
31	GSK Investigational Site	Grenoble cedex 9		France	38043
32	GSK Investigational Site	Lyon cedex 04		France	69317
33	GSK Investigational Site	Marseille Cedex 20		France	13915
34	GSK Investigational Site	Montpellier cedex 5		France	34295
35	GSK Investigational Site	Nantes cedex 1		France	44093
36	GSK Investigational Site	Paris Cedex 18		France	75877
37	GSK Investigational Site	Toulouse Cedex 9		France	31059
38	GSK Investigational Site	Neu-Isenburg	Hessen	Germany	63263
39	GSK Investigational Site	Hannover	Niedersachsen	Germany	30173
40	GSK Investigational Site	Leipzig	Sachsen	Germany	04357
41	GSK Investigational Site	Berlin		Germany	10717
42	GSK Investigational Site	Berlin		Germany	12203
43	GSK Investigational Site	Dordrecht		Netherlands	3318 AT
44	GSK Investigational Site	Rotterdam		Netherlands	3045 PM
45	GSK Investigational Site	Laredo	Cantabria	Spain	39770
46	GSK Investigational Site	Barcelona		Spain	08035
47	GSK Investigational Site	Hospitalet de Llobregat		Spain	08907
48	GSK Investigational Site	Murcia		Spain	30003
49	GSK Investigational Site	Pozuelo De Alarcón/Madrid		Spain	28223
50	GSK Investigational Site	Santiago De Compostela. La Coruña.		Spain	15706
51	GSK Investigational Site	Valencia		Spain	46017
52	GSK Investigational Site	Göteborg		Sweden	SE-413 45
53	GSK Investigational Site	Stockholm		Sweden	SE-141 86

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Statistical Analysis Plan - May 8, 2017
• Study Protocol - Mar 23, 2016

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02654145
• Other Study ID Numbers: 204471; 2015-003697-32
• First Posted: Jan 13, 2016
• Last Update Posted: Aug 19, 2019
• Last Verified: Aug 1, 2019

• 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: mepolizumab; Omalizumab; SGRQ; severe eosinophilic asthma; ACQ; exacerbations
• Additional relevant MeSH terms: Asthma; Pulmonary Eosinophilia; Omalizumab; Albuterol

Study Results

Participant Flow

Recruitment Details	Participants with severe eosinophilic asthma who were receiving omalizumab, but were not optimally controlled were enrolled in this open-label study and received mepolizumab 100 milligrams (mg) subcutaneously (SC) every 4 weeks for 32 weeks with last dose on Week 28. The study was conducted at 46 centers from 17 March 2016 to 31 May 2017.
Pre-assignment Detail	Screening was performed at Visit 1 (Week -1). A total of 206 participants were screened of which 54 participants were screen failures. Seven additional participants were reported as pre-screen failures. The remaining 145 participants received at least one dose of mepolizumab.

Arm/Group Title	Mepolizumab 100 mg SC
Arm/Group Description	Eligible participants received mepolizumab 100 mg SC doses into the upper arm or thigh every 4 weeks over a period of 32 weeks, with the last dose administered at Week 28, along with their current maintenance therapy except omalizumab.
Period Title: Overall Study
STARTED	145
COMPLETED	138
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Mepolizumab 100 mg SC
Arm/Group Description	Eligible participants received mepolizumab 100 mg SC doses into the upper arm or thigh every 4 weeks over a period of 32 weeks, with the last dose administered at Week 28, along with their current maintenance therapy except omalizumab.
Overall Participants	145
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.6 (13.83)
Sex: Female, Male (Count of Participants)
Female	86 59.3%
Male	59 40.7%
Race/Ethnicity, Customized (Count of Participants)
Asian- Central/South Asian Heritage	2 1.4%
Asian- East Asian Heritage	1 0.7%
Asian- South East Asian Heritage	2 1.4%
Black or African American heritage	11 7.6%
White- Arabic/ North African Heritage	4 2.8%
White- White/Caucasian/European Heritage	124 85.5%
Multiple-Black/African American and White Heritage	1 0.7%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in Asthma Control Questionnaire-5 (ACQ-5) Score at Week 32
Description	The ACQ-5 is a five-item, self-completed questionnaire, which is used as a measure of asthma control of a participant. The five questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) enquire about the frequency and/or severity of symptoms over the previous week. The response options for all these questions range from zero (no impairment/limitation) to six (total impairment/ limitation) scale. ACQ-5 score range from 0 to 6. Higher scores indicates worsening of condition. Baseline was defined as the latest available assessment prior to first dose of mepolizumab. Change from Baseline at Week 32 was calculated as Week 32 value of ACQ-5 score minus Baseline value and was analyzed using Mixed Model Repeated Measures allowing for covariates of region, baseline maintenance OCS therapy, exacerbations in the year prior to the study (as ordinal variable) and visit.
Time Frame	Baseline and at Week 32

Outcome Measure Data

Analysis Population Description

Intent to treat - all participants who received at least one dose of mepolizumab

Arm/Group Title	Mepolizumab 100 mg SC
Arm/Group Description	Eligible participants received mepolizumab 100 mg SC doses into the upper arm or thigh every 4 weeks over a period of 32 weeks, with the last dose administered at Week 28, along with their current maintenance therapy except omalizumab.
Measure Participants	145
Least Squares Mean (Standard Error) [Scores on a scale]	-1.45 (0.107)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is for Difference (Mepo-Placebo) calculated based on the Historical Placebo estimate of -0.55 (Standard Error: 0.05), which was estimated from a meta-analysis of studies NCT01000506 and NCT01691521 using all Placebo participants.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.90
	Confidence Interval	(2-Sided) 95%; -1.13 to -0.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference (Mepo-Placebo) calculated based on the Historical Placebo estimate of -0.55 (Standard Error: 0.05), which was estimated from a meta-analysis of studies NCT01000506 and NCT01691521 using all Placebo participants.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p- value for Difference (Mepo-Placebo) calculated based on the Historical Placebo estimate of -0.11 (Standard Error: 0.14), which was estimated from a meta-analysis of studies NCT01691521 and NCT02281318 using Placebo participants who previously used
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.34
	Confidence Interval	(2-Sided) 95%; -1.68 to -1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference (Mepo-Placebo) calculated based on the Historical Placebo estimate of -0.11 (Standard Error: 0.14), which was estimated from a meta-analysis of studies NCT01691521 and NCT02281318 using Placebo participants who previously used Xolair.

2. Secondary Outcome

Title	Mean Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score at Week 32
Description	The SGRQ Questionnaire is a well-established, self-completed tool, comprising of 50 questions with 76 weighted responses designed to measure Quality of Life in participants with diseases of airway obstruction. It consists of two parts; Part 1 produces the symptom score and Part 2 produces the activity and impact score. A Total score is also calculated which summarizes the impact of the disease on overall health status. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and zero indicates best possible health status. Baseline was defined as the latest available assessment prior to first dose of mepolizumab. Change from Baseline at Week 32 was calculated as Week 32 value of SGRQ score minus Baseline value and was analyzed using Mixed Model Repeated Measures allowing for covariates of region, baseline maintenance OCS therapy, exacerbations in the year prior to the study (as an ordinal variable) and visit.
Time Frame	Baseline and at Week 32

Outcome Measure Data

Analysis Population Description

Intent to treat - all participants who received at least one dose of mepolizumab

Arm/Group Title	Mepolizumab 100 mg SC
Arm/Group Description	Eligible participants received mepolizumab 100 mg SC doses into the upper arm or thigh every 4 weeks over a period of 32 weeks, with the last dose administered at Week 28, along with their current maintenance therapy except omalizumab.
Measure Participants	145
Least Squares Mean (Standard Error) [Scores on a scale]	-19.0 (1.64)

3. Secondary Outcome

Title	The Rate of Clinically Significant Asthma Exacerbations Over 32 Weeks' Treatment
Description	Clinically significant exacerbations of asthma were defined as worsening of asthma which requires use of systemic corticosteroids and/or hospitalization and/or Emergency Department (ED) visits. The frequency of clinically significant asthma exacerbations over 32 weeks' treatment was analyzed using Negative Binomial Regression via generalized estimating equations with a covariate of time period (pre-treatment versus on- and off treatment).
Time Frame	Up to Week 32

Outcome Measure Data

Analysis Population Description

Intent to treat - all participants who received at least one dose of mepolizumab

Arm/Group Title	Mepolizumab 100 mg SC
Arm/Group Description	Eligible participants received mepolizumab 100 mg SC doses into the upper arm or thigh every 4 weeks over a period of 32 weeks, with the last dose administered at Week 28, along with their current maintenance therapy except omalizumab.
Measure Participants	145
Number [Exacerbation rate per year]	1.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Generalised Estimating Equations
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.28 to 0.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis performed using generalized estimating equation (GEE) model assuming a negative binomial distribution with a covariate of treatment period (pre-treatment , on- and off-treatment), logarithm of time as an offset variable

4. Secondary Outcome

Title	Ratio to Baseline in Blood Eosinophil Count at Week 32
Description	Blood samples were collected at specific time points to measure blood eosinophils level for evaluation of pharmacodynamic effects in participants with a severe eosinophilic asthma phenotype when they were directly switched to mepolizumab. Baseline was defined as the latest available assessment prior to first dose of mepolizumab and ratio to Baseline at Week 32 was defined as Week 32 value divided by Baseline value and was analyzed using Mixed Model Repeated Measures allowing for covariates of region, Baseline maintenance oral corticosteroid (OCS) therapy, exacerbations in the year prior to the study (as an ordinal variable) and visit. The log transformation was applied to blood eosinophil counts prior to analysis. If a blood eosinophil count of zero was reported, it was imputed with half of the lowest possible blood eosinophil count, where applicable, prior to log transforming the data. The dispersion measure used was log standard error.
Time Frame	Baseline and at Week 32

Outcome Measure Data

Analysis Population Description

Intent to treat- all participants who received at least one dose of mepolizumab

Arm/Group Title	Mepolizumab 100 mg SC
Arm/Group Description	Eligible participants received mepolizumab 100 mg SC doses into the upper arm or thigh every 4 weeks over a period of 32 weeks, with the last dose administered at Week 28, along with their current maintenance therapy except omalizumab.
Measure Participants	145
Least Squares Mean (Standard Error) [Ratio]	0.22 (0.106)

Adverse Events

Time Frame	The on-treatment adverse events (AEs) and on-treatment serious AEs (SAEs) are the AEs which happened on/after the first dose of mepolizumab date and before/on last dose of mepolizumab date + 28 days (up to 32 weeks).
Adverse Event Reporting Description	AEs and SAEs were collected in intent-To-Treat Population which comprised of all participants who received at least one dose of Mepolizumab.
Arm/Group Title	Mepolizumab 100 mg SC
Arm/Group Description	Eligible participants received mepolizumab 100 mg SC doses into the upper arm or thigh every 4 weeks over a period of 32 weeks, with the last dose administered at Week 28, along with their current maintenance therapy except omalizumab.
All Cause Mortality
	Mepolizumab 100 mg SC
	Affected / at Risk (%)	# Events
Total	0/145 (0%)
Serious Adverse Events
	Mepolizumab 100 mg SC
	Affected / at Risk (%)	# Events
Total	16/145 (11%)
Cardiac disorders
Coronary artery disease	1/145 (0.7%)	1
Gastrointestinal disorders
Abdominal pain upper	1/145 (0.7%)	1
Dental cyst	1/145 (0.7%)	1
General disorders
Chest discomfort	1/145 (0.7%)	1
Hepatobiliary disorders
Cholecystitis	1/145 (0.7%)	1
Infections and infestations
Cellulitis	2/145 (1.4%)	2
Pneumonia	2/145 (1.4%)	2
Influenza	1/145 (0.7%)	1
Sepsis	1/145 (0.7%)	1
Tooth infection	1/145 (0.7%)	1
Nervous system disorders
Cerebrovascular accident	1/145 (0.7%)	1
Syncope	1/145 (0.7%)	1
Transient ischaemic attack	1/145 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	7/145 (4.8%)	9
Hypoxia	1/145 (0.7%)	1
Lung disorder	1/145 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Mepolizumab 100 mg SC
	Affected / at Risk (%)	# Events
Total	107/145 (73.8%)
Gastrointestinal disorders
Nausea	11/145 (7.6%)	12
Diarrhoea	9/145 (6.2%)	11
Abdominal pain upper	6/145 (4.1%)	8
General disorders
Fatigue	14/145 (9.7%)	20
Asthenia	6/145 (4.1%)	8
Chest pain	6/145 (4.1%)	10
Injection site reaction	5/145 (3.4%)	23
Infections and infestations
Viral upper respiratory tract infection	24/145 (16.6%)	33
Bronchitis	19/145 (13.1%)	23
Influenza	11/145 (7.6%)	14
Rhinitis	11/145 (7.6%)	11
Sinusitis	8/145 (5.5%)	10
Gastroenteritis viral	5/145 (3.4%)	5
Urinary tract infection	5/145 (3.4%)	7
Musculoskeletal and connective tissue disorders
Arthralgia	14/145 (9.7%)	20
Back pain	13/145 (9%)	15
Myalgia	7/145 (4.8%)	8
Musculoskeletal pain	6/145 (4.1%)	7
Neck pain	6/145 (4.1%)	8
Nervous system disorders
Headache	41/145 (28.3%)	89
Dizziness	5/145 (3.4%)	6
Respiratory, thoracic and mediastinal disorders
Cough	11/145 (7.6%)	13
Rhinitis allergic	10/145 (6.9%)	12
Dyspnoea	7/145 (4.8%)	15
Dysphonia	5/145 (3.4%)	5
Oropharyngeal pain	5/145 (3.4%)	5

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.