A Trial of Mepolizumab Adjunctive Therapy for the Prevention of Asthma Exacerbations in Urban Children

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to see if treatment with a medication called Nucala® (mepolizumab), given along with standard asthma care, makes children less likely to have asthma attacks.

Detailed Description
-----------------
Asthma is a growing problem, especially in children. It causes frequent wheezing, shortness of breath, chest tightness, and cough. Asthma attacks, or exacerbations, are problems for children with asthma. The purpose of this study is to see if treatment with a medication called mepolizumab (Nucala®), given along with standard asthma care, makes children less likely to have asthma attacks. Mepolizumab is a new drug that is approved by the Food and Drug Administration (FDA) for use in children with asthma who are aged 12 years and older. Mepolizumab is given by injection. It is being studied by other researchers in children aged 6-11 years. All participants will be prescribed standard asthma medications by a clinician who is trained in asthma care. Medications will include controller medications, a rescue medication, and a medication for severe asthma attacks (prednisone). The amount of medication that participants receive may be increased or decreased during the study based on their symptoms and breathing test results. Study clinicians will treat all participants according to the same guidelines. These treatment guidelines are based on recommendations from a group of national experts in asthma. This study has been designed this way so that all participants will have safe and effective standard asthma care. In order to enroll in this study, participants must be willing to have their asthma managed by the study clinician during the entire study period. Participants must also be willing to bring study medications to all study visits. This study will include up to 20 study visits. Participant involvement in the study will endure for approximately 1 year. During the treatment period, participants will be placed in one of two treatment groups: Mepolizumab injection and guidelines-based asthma care or Placebo injection and guidelines-based asthma care. Participants will not be able to choose which group they are assigned. This assignment is random and by chance, much like flipping a coin. Participants will not know if they are receiving mepolizumab or placebo. Investigators will compare the study results between the participants of each group.

Official Title
-----------------
Mechanisms Underlying Asthma Exacerbations Prevented and Persistent With Immune-Based Therapy: A Systems Approach Phase 2 (ICAC-30)

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Biological: Mepolizumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Study applicant(s) that fulfill all of the inclusion criteria and none of the exclusion criteria are eligible for the study- Participant and/or parent guardian must be able to understand and provide informed consent and age-appropriate assent; Must have a primary place of residence in one of the pre-selected recruitment census tracts as outlined in the study's Manual of Procedures (MOP); Has had a diagnosis of asthma made >1 year prior to recruitment; --Those who received an asthma diagnosis by a clinician ≤1 year prior to recruitment must report that their respiratory symptoms were present for more than 1 year prior to recruitment. Has had ≥2 asthma exacerbations in the prior year (defined as a requirement for systemic corticosteroids and/or hospitalization); At Visit 0 (Screening), has the following requirement for asthma controller medication: For those ages 6 to 11 years, treatments with at least fluticasone 250 mcg dry powder inhaler (DPI) one puff twice daily or its equivalent and, For those ≥12 years of age, treatment with at least Advair 250/50 mcg dry powder inhaler (DPI), one puff twice daily or its equivalent. Has peripheral blood eosinophils ≥150 cells/µl obtained at Visit 0 (Screening) or in another Inner-City Asthma Consortium (ICAC) clinical research study within 6 months; Is able to perform spirometry at randomization (Visit for treatment assignment); Has documentation of current medical insurance with prescription coverage at randomization; and Has had varicella or the varicella vaccination. Exclusion Criteria: Individual(s) who meets any of the following criteria are not eligible for enrollment or randomization- Is not able or willing to give written informed consent or comply with the study protocol; Has concurrent (existing) medical problems that would require systemic corticosteroids or other immunomodulator treatments during the study; Is currently receiving immunotherapy; Is currently receiving treatment with omalizumab or has had omalizumab treatment within 6 months prior to planned participant randomization to treatment assignment; Is currently requiring greater than fluticasone 500 mcg administered twice daily plus a long-acting beta agonist (LABA) one puff twice daily or its equivalent, and/or --Individuals using oral corticosteroids daily or every other day for more than 14 days at the time of Visit 0 (Screening). Is currently pregnant or lactating, or plans to become pregnant during the time of study participation --Note: Females of child-bearing potential (post-menarche) must be abstinent or use a medically acceptable birth control method throughout the study (e.g. oral subcutaneous, mechanical, or surgical contraception). Has a known, pre-existing clinically important lung condition other than asthma; Has a current malignancy or previous history of cancer in remission for less than 12 months prior to randomization; Has known, pre-existing, unstable liver disease; Is a current smoker or has a smoking history of 10 or more pack years; Has a known immunodeficiency disease; Has other conditions that could lead to elevated eosinophils such as hypereosinophilic syndromes, including eosinophilic granulomatosis with polyangiitis; Has a known, active pre-existing parasitic infestation or is undergoing treatment for a parasitic infestation --Note: Once the individual has been successfully treated, the interested study applicant may be reevaluated for study eligibility. Positive for use of investigational drugs within 4 weeks of randomization; Has a past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the study clinician, May pose additional risks from participation in this study, May interfere with the participant's ability to comply with study requirements, or May impact the quality or interpretation of the data obtained from the study. In the event that the study applicant will not allow the study clinician, an asthma specialist, to manage their disease for the duration of the study or who are not willing to change their asthma medications to follow the protocol; Has a known history of allergic reaction to previous biologic therapy for asthma; or Has had a life threatening asthma exacerbation in the last 2 years requiring intubation, mechanical ventilation or resulting in a hypoxic seizure.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 17 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mepolizumab<br>Intervention: Mepolizumab plus guidelines-based standard of care asthma treatment. | Biological: Mepolizumab<br>* Mepolizumab administered every 4 weeks by subcutaneous injection at a dose of: 100 mg for participants ≥12 years of age and 40 mg for participants ages 6 to 11 years and weighing ≥40 kg. Note: Participants 6 to 11 years of age and weighing ≥40 kg who were enrolled in the study under previous versions of the protocol and were initially assigned a 100 mg dose will have their dose reduced to 40 mg. Participants 11 years of age will increase to the 100 mg dose if they become age 12 years during the study.<br>* Other names: anti-Interleukin 5 (IL5) antagonist monoclonal antibody;|
| Placebo Comparator: Placebo<br>Intervention: Placebo for mepolizumab plus guidelines-based standard of care asthma treatment. | Drug: Placebo<br>* Placebo administered every 4 weeks by subcutaneous injection at a dose of: 100 mg for participants ≥12 years of age and 40 mg for participants ages 6 to 11 years and weighing ≥40 kg. Note: Participants 6 to 11 years of age and weighing ≥40 kg who were enrolled in the study under previous versions of the protocol and were initially assigned a 100 mg dose will have their dose reduced to 40 mg. Participants 11 years of age will increase to the 100 mg dose if they become age 12 years during the study.<br>* Other names: Placebo for Mepolizumab;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Asthma Exacerbations During the Treatment Period | Exacerbations were defined as a prescription of a course of systemic corticosteroids by a clinician, initiation of a course of systemic corticosteroids by a participant, or as a hospitalization for asthma. If a participant initiated and completed a course of systemic corticosteroids without clinician involvement, this course was counted only if the study clinician agreed the treatment was warranted, and it met the following dosage: the course for prednisone, prednisolone, or methylprednisolone was at least 20 mg daily dose for 3 of 5 consecutive days. The course for dexamethasone was at least a 10 mg single daily dose. If a corticosteroid burst for the treatment of an asthma exacerbation was prescribed by a non-ICAC clinician, it was counted regardless of dose. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Asthma Severity Index (CASI) | Composite Asthma Severity Index (CASI) scores included 5 domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. The minimum composite score was 0 while the maximum was 20. The higher the score the more allergy symptoms a subject has. | Week 12, 24, 36, 48, 52 after randomization | 
| Participant Quality of Life Measured Using the Physician Global Assessment Tool | The Physician Global Assessment Tool was used to assess the quality of life of the subjects during treatment. The questionnaire is one question that asks the physician to evaluate how the participant's quality of life changed over the course of treatment. There are seven possible options ranging from significantly worse to significantly improved. | Week 56 | 
| Participant Quality of Life Measured Using the Patient Global Assessment, at Visit 14 | The Patient Global Assessment Tool was used to assess the quality of life of the subjects during treatment. The questionnaire is one question that asks the participant to evaluate how their quality of life changed over the course of treatment. There are seven possible options ranging from significantly worse to significantly improved. | Week 56 | 
| Lung Function as Assessed by Spirometry | A generalized mixed model was used to analyze spirometry parameter at each visit where the lung function was collected. The ratio of the forced expiratory volume to the forced vital capacity of the lungs (FEV1/FVC) is the outcome that measured lung function. | Weeks 12, 24, 36, 48, 52 after randomization | 
| Lung Function as Assessed by Impulse Oscillometry | A generalized mixed model was used to analyze impulse oscillometry parameter at each visit where the lung function was collected. The Percent Predicted FEV1 (%) is the outcome that measured lung function. | Weeks 12, 24, 36, 48, 52 after randomization | 
| Rate of Exacerbations (Mepolizumab vs. Placebo) During the Treatment Period for Participants Who Did Not Fit the FDA-approved Dosing Table for Omalizumab Therapy. | Looking at the rate of exacerbations similarly to the primary endpoint. This outcome measure also took into consideration FDA- approved dosing of omalizumab. The FDA-approved dosing table is based off of age, weight and pre-treatment Serum IGE | Up to 12 months | 
| Rate of Exacerbations (Mepolizumab vs. Placebo) During the Treatment Period for Participants Who Fit the FDA-approved Dosing Table. | Looking at the rate of exacerbations similarly to the primary endpoint. This outcome measure also took into consideration FDA- approved dosing of omalizumab. The FDA-approved dosing table is based off of age, weight and pre-treatment Serum IGE | Up to 12 months | 
| Time to First Asthma Exacerbation | A Cox PH model was also used to model the time to first asthma exacerbation during the treatment period. The Cox PH model included treatment arm as the primary exposure but was also adjusted for study site, number of exacerbations in year prior to study (2 or 3+), peripheral blood eosinophils (above or below 400 cells/μl), BMI (above or below 95th percentile for age) and total serum IgE (above or below 540 kUA/L). | Up to 12 months | 
| Number of Reported Adverse Events (AEs), Including Their Severity | The number of AEs by severity was used to assess safety. Please refer to the Adverse Event tables for specifics. | Week 4 (Treatment Initiation) to Week 56 (Completion of Treatment) | 
| Number of Reported Adverse Events (AEs), Including Their Treatment Relatedness | The number of AEs by relationship to study drug was used to assess safety. Please refer to the Adverse Event tables for specifics. | Week 4 (Treatment Initiation) to Week 56 (Completion of Treatment) | 
| Number of Reported Serious Adverse Events (SAEs) Inclusive of Severity. Please Refer to the Adverse Event Tables for Specifics. | The number of SAEs by severity and relationship to study drug was used to assess safety. | Week 4 (Treatment Initiation) to Week 56 (Completion of Treatment) | 
| Number of Reported Serious Adverse Events (SAEs) Inclusive of Treatment Relatedness. Please Refer to the Adverse Event Tables for Specifics. | The number of SAEs by relationship to study drug was used to assess safety. | Week 4 (Treatment Initiation) to Week 56 (Completion of Treatment) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
urban setting, children and adolescents, double-masked, placebo-controlled randomized trial, asthma exacerbations (attacks), mepolizumab adjunctive therapy, asthma exacerbations prevention, difficult-to-control exacerbation-prone asthma