Efficacy and Safety of Omalizumab in Children (6 - < 12 Years) With Moderate-severe, Inadequately Controlled Allergic Asthma

Study Overview
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Brief Summary
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A substance called immunoglobulin E (IgE), which is naturally produced by our body, has a key role in generating asthma attacks. In patients with allergies, there is an exaggerated production of IgE in response to specific substances such as pollens. Omalizumab is a new drug that inactivates IgE. This study tested the safety and efficacy of omalizumab against asthma attacks in children with allergic asthma.

Detailed Description
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This study was designed to provide one year efficacy and safety data for subcutaneous (SC) omalizumab, compared to placebo in children (6 to < 12 years) with moderate to severe persistent asthma who have inadequate asthma control despite treatment according to National Heart, Lung and Blood Institute (NHLBI) step 3 or 4 (at least medium dose inhaled corticosteroids with or without other controller asthma medications).

Official Title
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A 1 Year, Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicenter Evaluation of Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Omalizumab in Children (6 - < 12 Years) With Moderate-severe, Persistent, Inadequately Controlled Allergic Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Omalizumab
* Drug: Placebo
* Drug: Fluticasone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Parent or legal guardian was informed of the study procedures and medications and gave written informed consent. Outpatient males and females aged 6 - < 12 years on study entry, with body weight between 20 and 150 kg. Total serum IgE level ≥ 30 to ≤ 1300 IU. Diagnosis of allergic asthma ≥ 1 year duration, according to American Thoracic Society (ATS) criteria, and a screening history consistent with clinical features of moderate or severe persistent asthma according to National Heart Lung and Blood Institute (NHLBI) guidelines. Positive prick skin test to at least one perennial allergen, documented within the past 2 years or taken at Screening. A radioallergosorbent test (RAST) could have been performed for patients with a borderline skin prick test result after consultation with Novartis clinical personnel. Patients with ≥ 12% increase in forced expiratory volume in 1 second (FEV1) over starting value within 30 minutes of taking up to 4 puffs (4x100 µg) salbutamol (albuterol) or nebulized salbutamol up to 5 mg (or equivalent of alternative B2-agonist) documented within the past year, at screening, during the run-in period, or prior to randomization. Patients were not to take their long acting B2-agonist (LABA) medication within 12 hours of reversibility testing. Clinical features of moderate or severe persistent asthma (at least step 3) despite therapy at step 3 or 4 (at least medium dose inhaled corticosteroid (ICS) - fluticasone dry-powder inhaler (DPI) ≥ 200 mg/day or equivalent with or without other controller medications). Documented history of experiencing asthma exacerbations and demonstrated inadequate symptom control during the last 4 weeks of run-in despite receiving an equivalent dose of fluticasone DPI ≥ 200 mg/day total daily ex-valve dose. Exclusion criteria: Patients who received systemic corticosteroids for reasons other than asthma, beta-adrenergic antagonists by any route, anticholinergics within 24 hours of Screening, methotrexate, gold salts, cyclosporin or troleandomycin, or had received desensitization therapy with less than 3 months of stable maintenance doses prior to Screening. Patients with a history of food or drug related severe anaphylactoid or anaphylactic reaction, a history of allergy to antibiotics, with aspirin or other non-steroidal anti-inflammatory drugs (NSAID)-related asthma (unless the NSAID could be avoided), with active lung disease or acute sinusitis/chest infection, elevated serum IgE levels for other reasons, presence/history of a clinically significant uncontrolled systemic disease, cancer, abnormal, electrocardiogram (ECG) in the previous month, or platelets ≤ 100 x 109/L or clinically significant laboratory abnormalities at Screening.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 11 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omalizumab<br>Participants received omalizumab administered by subcutaneous injection every 2 or 4 weeks for a duration of 52 weeks. The omalizumab dose was based on the patient's body weight and total serum IgE level at Screening. The first 24 weeks of the treatment period was a fixed steroid phase where the steroid dose was maintained constant; in the following 28 weeks the steroid dose was adjustable, depending on the patient's condition. Following the 52-week treatment period, patients were followed up for an additional 16 weeks. | Drug: Omalizumab<br>* The omalizumab dose administered, based on the patient's body weight and total serum IgE level at Screening, and the number of injections and injection volume was determined from the dosing tables in the protocol. Omalizumab 75 to 375 mg was administered subcutaneous (SC) every 2 or 4 weeks depending on the dose.<br>Drug: Fluticasone<br>* Patients entered the study using their current formulation of any inhaled steroid (proprietary drug and device) ≥ 200 μg/day equivalent of fluticasone administered with a dry-powder inhaler.<br>|
| Placebo Comparator: Placebo<br>Placebo was administered by subcutaneous injection every 2 or 4 weeks depending on the dosing schedule in the protocol for a total of 52 weeks. The first 24 weeks of the treatment period was a fixed steroid phase where the steroid dose was maintained constant; in the following 28 weeks the steroid dose was adjustable, depending on the patient's condition. Following the 52-week treatment period, patients were followed up for an additional 16 weeks. | Drug: Placebo<br>* Placebo was administered subcutaneous (SC) every 2 or 4 weeks depending on the dosing schedule in the protocol.<br>Drug: Fluticasone<br>* Patients entered the study using their current formulation of any inhaled steroid (proprietary drug and device) ≥ 200 μg/day equivalent of fluticasone administered with a dry-powder inhaler.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Clinically Significant Asthma Exacerbations Per Patient in the 24-week Fixed-dose Steroid Treatment Period | A clinically significant asthma exacerbation was defined as a worsening of asthma symptoms, as judged clinically by the investigator, requiring doubling of the baseline inhaled corticosteroid dose and/or treatment with systemic rescue corticosteroids for at least 3 days. The exacerbations rate per patient was derived using Poisson model adjusted by time at risk and the following covariates: country, exacerbation history, and dose schedule. A patient's person-days at risk was taken as the total amount of time (in days) he/she spent in the 24-week fixed-dose steroid treatment period. | Baseline to end of the fixed-dose steroid treatment period (Week 24) | 
| Percentage of Participants With at Least 1 Adverse Event | See Adverse Events module for details. | Baseline to end of the study (Week 68) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Nocturnal Asthma Symptom Score From Baseline to the End (Last 4 Weeks) of the 24-week Fixed-dose Steroid Treatment Period | Nocturnal asthma symptom was measured daily on a scale of 0 to 4 in response to the question How did you sleep last night?, with 0 as the best response and 4 as the worst response. The mean of the last 4 weeks of the 24-week fixed-dose steroid treatment period was calculated; for patients who discontinued prematurely, the mean of the last 28 days before discontinuation was calculated. A negative change in mean score indicated improvement. | Baseline to the end (last 4 weeks) of the 24-week fixed-dose steroid treatment period | 
| Rate of Clinically Significant Asthma Exacerbations Per Patient in the 52-week Treatment Period | A clinically significant asthma exacerbation was defined as a worsening of asthma symptoms, as judged clinically by the investigator, requiring doubling of the baseline inhaled corticosteroid dose and/or treatment with systemic rescue corticosteroids for at least 3 days. The exacerbations rate per patient was derived using Poisson model adjusted by time at risk and the following covariates: country, exacerbation history, and dose schedule. A patient's person-days at risk was taken as the total amount of time (in days) he/she spent in the 52-week treatment period. | Baseline to end of the treatment period (Week 52) | 
| Change in Mean Daily Number of Puffs of Asthma Rescue Medication From Baseline to the End (Last 4 Weeks) of the 24-week Fixed-dose Steroid Treatment Period | Patients were instructed to record the number of puffs of rescue medication they took twice daily in a diary. The mean daily number of puffs during the last 4 weeks of the 24-week fixed-dose steroid treatment period was calculated; for patients who discontinued prematurely, the mean of the last 28 days before discontinuation was calculated. A negative change in mean daily number of puffs indicated reduced use of rescue medication. | Baseline to the end (last 4 weeks) of the 24-week fixed-dose steroid treatment period | 
| Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24) | PAQLQ measures functional problems that are most troublesome to children with asthma. PAQLQ has 23 questions in 3 domains (activity limitation=5, emotional function=8, symptoms=10). Patients responded to each question on a 7-point Likert scale. Overall PAQLQ score is mean of 23 questions; each domain score is mean of questions in that domain. Minimum possible value is 1 (maximum impairment); maximum possible value is 7 (no impairment). Positive change indicated improvement. The analysis included country, baseline PAQLQ value, and dosing schedule (2-weekly/4-weekly) as factors and covariates. | Baseline to the end of the 24-week fixed-dose steroid treatment period (Week 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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allergic, asthma, atopic, omalizumab, immunoglobulin E, IgE, anti-IgE