A Safety and Efficacy Study of Mepolizumab in Subjects With Severe Asthma

Study Overview
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Brief Summary
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Mepolizumab, a humanized monoclonal antibody, has been developed as an add-on treatment for subjects with severe asthma with eosinophilic inflammation. Current asthma treatment guidelines offer minimal options for the severe asthmatic subjects on intensive therapy with frequent exacerbations. There is a significant unmet medical need to provide better treatment options for this segment of the asthma population. Thus, this study is designed to evaluate the efficacy and safety of mepolizumab in Chinese severe asthmatic subjects with eosinophilic inflammation. A total number of 300 subjects will be randomized in 1:1 ratio to receive either mepolizumab or placebo along with existing standard of care therapy. The maximum study duration will be 56 weeks.

Official Title
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A Randomized, Double Blind, Parallel Group Study of the Efficacy and Safety of Mepolizumab as Adjunctive Therapy in Patients With Severe Asthma With Eosinophilic Inflammation

Conditions
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Asthma

Intervention / Treatment
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* Drug: Mepolizumab 100 milligrams
* Drug: Placebo
* Drug: Salbutamol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who will be able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials. Subjects with at least 12 years of age at Visit 0 and a minimum weight of 40 kilograms. Persistent airflow obstruction as indicated by: For subjects >=18 years of age at visit 1, a pre-bronchodilator FEV1 <80 percent predicted (National Health and Nutrition Examination Survey [NHANES] III).;For subjects 12 to 17 years of age at Visit 1: A pre-bronchodilator FEV1 <90 percent predicted (NHANES III) recorded at Visit 1 or FEV1: Forced vital capacity (FVC) ratio <0.8 recorded at Visit 1. Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma as per Randomization Criteria 1 (Documented peripheral blood eosinophil count of >=300 cells per microliters that is related to asthma in the past 12 months prior to Visit 1 or a peripheral blood eosinophil count of >=150 cells per microliters at Visit 1 that is related to asthma). Regular treatment with high dose inhaled corticosteroid (ICS) in the 12 months prior to Visit 1, of which at least 9 months accumulated documented is required, the 3 months prior to Visit 1 is mandatory. With or without maintenance oral corticosteroids (OCS). ICS dose must be >=500 microgram per day fluticasone propionate (FP) or equivalent daily (for ICS/long-acting beta-2-agonists combination preparations, Seretide 50/250 micrograms twice daily and above or equivalent will meet this ICS criteria). (Maintenance OCS is defined as a prescribed regimen of a minimum average daily dose of prednisone 5 milligrams [or equivalent]). Current treatment with an additional controller medication, besides ICS, for at least 3 months. (Example given [e.g.], long-acting beta-2-agonist, leukotriene receptor antagonist [LTRA], or theophylline). Previously confirmed history of two or more exacerbations requiring treatment with systemic corticosteroid (intramuscular [IM], intravenous, or oral), in the 12 months prior to Visit 1, despite the use of high-dose ICS. For subjects receiving maintenance corticosteroid, the corticosteroid treatment for the exacerbations must have been a two-fold increase or greater in the dose for at least 3 days is required. A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1 percent, during the intervention period and for at least 4 months after the last dose of study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive pregnancy test before the first dose of study intervention. If urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the subject must be excluded from participation if the serum pregnancy result is positive. Follicle-stimulating hormone will be assessed to confirm child-bearing status as needed in non WOCBP. Exclusion Criteria: 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 Visit 1. Presence of a known pre-existing, clinically significant lung condition other than asthma, in the opinion of the Investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study. This includes current bacterial or viral infection of the upper or lower respiratory tract, 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. Clinically Significant is defined as any disease/condition that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. A chest X-ray that reveals evidence of clinically significant abnormalities not believed to be due to the presence of asthma. Bronchial Thermoplasty and Radiotherapy are excluded for 12 months prior to visit 1 and throughout the study. 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). Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice or cirrhosis. Subjects with ALT >2 times Upper Limit of Normal (ULN), bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent) Subjects who have known, pre-existing severe or clinically significant cardiovascular disease uncontrolled with standard treatment. Including but not limited to: known ejection fraction of <30 percent or severe heart failure meeting New York Heart Association Class IV classification or hospitalized in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III or angina diagnosed less than 3 months prior to Visit 1 or at Visit 1. QT interval corrected by Fridericia's formula (QTc[F]) >450 milliseconds (msec) or QTc(F) >480 msec for subjects with Bundle Branch Block at Visit 1 is exclusive. Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, hematological or any other system abnormalities that are uncontrolled with standard treatment. Current malignancy except for basal and squamous skin cancer. Subjects with other conditions that could lead to elevated eosinophils such as Hypereosiniophilic Syndromes, including Churg-Strauss Syndrome, or Eosinophilic Esophagitis. Subjects with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are also excluded. A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1. Alcohol abuse is defined as: an average weekly intake of greater than 21 units or an average daily intake of greater than three units (males), or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than two units (females). One unit was equivalent to a half-pint (220 milliliters) of beer or one (25 milliliters) measure of spirits or one glass (125 milliliters) of wine. A known immunodeficiency (e.g., human immunodeficiency virus - HIV), other than that explained by the use of corticosteroids taken as therapy for asthma. Subjects who have received omalizumab (Xolair) within 130 days of Visit 1. Subjects who have received any monoclonal antibodies (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1. Use of herbals within 7 days prior to visit 1, unless in the opinion of the Investigator and GlaxoSmithKline (GSK) Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. 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 visit 1 (this also includes investigational formulations of marketed products). Subjects with allergy/intolerance to a monoclonal antibody or biologic. Subjects who are pregnant or breastfeeding. Subjects should not be enrolled if they plan to become pregnant during the time of study participation. Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations. Previously participated in any study with mepolizumab and received investigational product (including placebo). A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator. Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study. Re-screening of subjects will be allowed only upon approval by the medical monitor.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible subjects will be randomized in 1:1 ratio to receive either mepolizumab or placebo along with existing standard of care therapy during the treatment period.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subjects receiving Mepolizumab<br>Eligible subjects will randomized in 1:1 ratio to Mepolizumab group or Placebo group. Subjects in Mepolizumab group will receive Mepolizumab 100mg subcutaneously into the upper arm or thigh every 4 weeks during the total treatment period of 52 weeks in addition to their baseline SOC of asthma treatment. Subjects will be provided with salbutamol MDIs as a rescue medication to be used on an needed basis in this study. | Drug: Mepolizumab 100 milligrams<br>* Mepolizumab will be given as a lyophilized cake in sterile vials for individual use. The vial will be reconstituted with Sterile Water for Injection, just prior to use.<br>Drug: Salbutamol<br>* Salbutamol MDI will be given as a rescue medication to be used on an as needed basis in this study.<br>|
| Placebo Comparator: Subjects receiving Placebo<br>Eligible subjects in placebo group will receive placebo (0.9 percent sodium chloride) matching to Mepolizumab administered subcutaneously into the upper arm or thigh every 4 weeks during the total treatment period of 52 weeks in addition to their baseline SOC of asthma treatment. Subjects will be provided with salbutamol MDIs as a rescue medication to be used on an as needed basis in this study. | Drug: Placebo<br>* Placebo will be given as 0.9 percent sodium chloride solution.<br>Drug: Salbutamol<br>* Salbutamol MDI will be given as a rescue medication to be used on an as needed basis in this study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of clinically significant exacerbations of asthma | Clinically significant exacerbations are defined as worsening of asthma which requires use of systemic corticosteroids and/or hospitalizations and/or Emergency Department (ED) visits. | Up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first clinically significant exacerbations | Clinically significant exacerbations are defined as worsening of asthma which requires use of systemic corticosteroids and/or hospitalizations and/or ED visits. | Up to Week 52 | 
| Mean change from Baseline in St. George's Respiratory Questionnaire (SGRQ) at Week 52 | 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 subjects 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 and Week 52 | 
| Number of exacerbations requiring hospitalization or ED visits | An exacerbation is defined as worsening of asthma requiring the use of systemic corticosteroids and/or emergency department visit, or hospitalization. The number of exacerbations requiring hospitalization including intubation and admittance to an Intensive care unit (ICU) or ED visits will be evaluated. | Up to Week 52 | 
| Number of exacerbations requiring hospitalization | An exacerbation is defined as worsening of asthma requiring the use of systemic corticosteroids and/or emergency department visit, or hospitalization. | Up to Week 52 | 
| Mean change from Baseline in clinic prebronchodilator forced expiratory volume in 1 second (FEV1) at Week 52 | FEV1 is the volume of air that can be forced out in one second after taking a deep breath. FEV1 will be measured via spirometer at Baseline and Week 52. | Baseline and Week 52 | 
| Number of subjects with adverse events including systemic (i.e., allergic [type I hypersensitivity] and other systemic) and injection site reactions | AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of subjects with adverse events including systemic and injection site reactions will be reported. | Up to Week 52 | 
| Number of subjects with abnormal hematology parameters | Hematology parameters which will be assessed include platelet count, red blood cell (RBC) count, hemoglobin, hematocrit; RBC indices: mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH); white blood cell (WBC) count with differential: neutrophils, lymphocytes, monocytes, eosinophils and basophils. | Up to Week 52 | 
| Number of subjects with abnormal clinical chemistry parameters | Clinical chemistry parameters which will be assessed include blood urea nitrogen, potassium, aspartate amino transferase (serum glutamic oxaloacetic transaminase), total and direct bilirubin, creatinine, sodium, alanine amino transferase (serum glutamic pyruvic transaminase), total protein, glucose, calcium, alkaline phosphatase and albumin. | Up to Week 52 | 
| Number of subjects with abnormal systolic blood pressure (SBP) and diastolic blood pressure (DBP) | SBP and DBP will be measured in a sitting position after 5 minutes rest. | Up to Week 52 | 
| Number of subjects with abnormal pulse rate | Pulse rate measurement will be measured in a sitting position after 5 minutes rest. | Up to Week 52 | 
| Number of subjects with abnormal electrocardiogram (ECG) findings | Twelve-lead ECG measurements will be obtained after the subject has rested in the supine position for 5 minutes. | Up to Week 52 | 
| Number of subjects with anti-mepolizumab antibody positive results | Number of subjects with positive anti-mepolizumab antibody results will be determined. | Up to Week 52 | 
| Change from Baseline in blood eosinophil ratio | Blood eosinophil counts will be recorded as part of standard hematological assessments. | Baseline and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eosinophilic inflammation, Mepolizumab, Asthma