Study to Assess the Efficacy and Safety of Omalizumab Treatment on ICS Reduction for Severe IgE-mediated Asthma

Study Overview
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Brief Summary
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Assess efficacy and safety of omalizumab treatment during 12 months in order to reduce the use of inhaled corticosteroid (ICS) in pediatric and adult participants with severe Immunoglobulin E (IgE)-mediated asthma inadequately controlled with high doses of corticosteroids.

Detailed Description
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This was a multicentric, open label, randomized, parallel-group study with a 12-month treatment period. Participants were assigned to one of the 2 treatment groups, omalizumab plus budesonide/formoterol or budesonide/formoterol alone. The study comprised 4 phases: During the 4-week run-in phase adult participants received budesonide 800 mg and formoterol 24 mg. If a participant complied with all inclusion and exclusion criteria and had received the according-to-age run-in proposed doses during the last month, the participant continued to the stable-steroid phase. During the 16-week stable-steroid phase, adult and pediatric eligible participants were randomized to one of the two treatment groups. During the 8-week steroid-reduction phase, adult and pediatric participants reduced 25% of the budesonide baseline dose every 2 weeks, depending of the asthma control, until they reached a 100% reduction of the baseline dose. The clinical control of asthma was defined according to criteria (GINA 2012).

Official Title
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Multicentric, Open-label, Randomized, Parallel--group Study to Evaluate the Efficacy and Safety of Omalizumab in a 12- Month Period, in Patients With Severe IgE-mediated Asthma Inadequately Controlled With High Doses of Corticosteroids.

Conditions
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Severe IgE-mediated Asthma

Intervention / Treatment
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* Drug: Omalizumab
* Drug: Budesonide
* Drug: Formoterol
* Drug: Budesonide
* Drug: Formoterol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male and female between 6 and 55 years old. If female, participant of childbearing potential must use a safe and efficacious birth control method. Asthma is considered as not well-controlled if participant has 3 or more of the following conditions: Persistent day symptoms with current therapy twice at week or more, (siblings, dyspnea, cough, chest pain, thoracic oppression). One or more night-time awakenings over the last 4 weeks. Any limitation of age-appropriated habitual activities. Need of rescue medication (short acting β2 agonist) for two or more occasions per week during the last 4 weeks before screening and 2 consecutive weeks within the 4 weeks before selection. Peak expiratory flow (PEF) or VEF1 <80% predicted or personal best (if known) this is not mandatory for pediatric participants (under 18 years old). Despite continuous treatment with high-dose inhaled corticosteroids (ICS) or oral corticosteroids (OCS) (CSO≥ 1 mg/kg/day) with or without controllers (As per GINA 2012 definition), the subject is receiving high doses of ICS (budesonide or its equivalent) and a long-acting β2-agonists(LABA) (formoterol) for the past 12 weeks at visit 0. At last one documented asthma exacerbation (defined as increase asthma symptoms requiring systemic corticosteroid rescue therapy) that requires visits to the emergency room or to be hospitalized in the past 12 months. It is also considered asthma exacerbation a non-planned visit that required rescue medication (β2-agonists and/or steroid nebulization every 20 minutes or β2-agonists inhaler shots every 20 minutes). Positive skin test or in vitro reactivity to a perennial aeroallergen, documented during the 12 months previous screening. IgE total concentration ranging from 30 to 1500 UI/ml. Body weight between 20 to 150 kg Exclusion Criteria Pregnant or lactating female or without safe and efficacious birth control method if of childbearing potential. Currently smokers or history of smoking 10 or more packs per year. Ex-smokers with a history of more than 10 years of smoking. As an exception, a participant with this criterion will be considered as eligible if the FEV1 reversibility of the first spirometry reaches 12%. Active lung disease other than asthma. Use of methotrexate, gold salts, troleandomycin, cyclosporine, immunosuppressants, gammaglobulin or any other type of monoclonal antibody used during the 6 months prior to the initial visit. Use of omalizumab during the 4 months prior to de screening visit. History of renal disease, cardiovascular disease, metabolic disease, hematologic disease, gastrointestinal disease, as well as immunodeficiency or cerebrovascular disease currently under treatment but not-controlled. History of hepatic, neurologic, oncologic or autoimmune disease. Participant under suspicion of having cancer. Participants with history of hypersensitivity to sucrose, histidine, polysorbate 20 as well as to monoclonal antibodies or gammaglobulin. Hypersensitivity to omalizumab or its excipients. Abnormal values of the blood chemistry laboratory tests, over 2 times the upper limit normal, that are considered clinically significant. Underage participant or any participant under vulnerable conditions who does not live with their parents or legal guardian.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 55 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omalizumab + budesonide and formoterol<br>Participants will receive Omalizumab every 2 or 4 weeks depending on IgE level and body weight and will also receive budesonide and formoterol according to maximum daily dose. | Drug: Omalizumab<br>* Subcutaneous injection dose according to the IgE level and body weight.<br>Drug: Budesonide<br>* Budesonide (400 μg, 200 μg or 100 μg) tablets taken orally according to maximum daily dose.<br>Drug: Formoterol<br>* Formoterol 12ug tablets taken orally according to maximum daily dose.<br>Drug: Budesonide<br>* Budesonide (400 μg, 200 μg or 100 μg). Patients were instructed to take the inhaled budesonide doses every 12 hours following the specific administration instructions as per the manufactures' prescription information.<br>|
| Active Comparator: Budesonide and formoterol<br>Participants will receive budesonide and formoterol according to maximum daily dose. | Drug: Budesonide<br>* Budesonide (400 μg, 200 μg or 100 μg) tablets taken orally according to maximum daily dose.<br>Drug: Formoterol<br>* Formoterol 12ug tablets taken orally according to maximum daily dose.<br>Drug: Budesonide<br>* Budesonide (400 μg, 200 μg or 100 μg). Patients were instructed to take the inhaled budesonide doses every 12 hours following the specific administration instructions as per the manufactures' prescription information.<br>Drug: Formoterol<br>* Formoterol 12ug. Patients were instructed to take the inhaled formoterol doses every 12 hours following the specific administration instructions as per the manufactures' prescription information.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Mean Prescribed Budesonide Dose (μg) at Baseline | prescribed budesonide dose (in μg) at Baseline in intention to treat population and in intention to treat population | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Hospital Admissions Due to Asthma Exacerbation | A hospital admission is defined as admissions to hospital involving a stay of at least 24 hours. | 12 month treatment duration | 
| Days Missed in School/Work Due to Asthma Exacerbation Episodes | Participants /parent/legal guarding reported number of missed days of school or work at each study visit via diaries. | 12 month treatment duration | 
| Control of Asthma Symptoms- Daytime Symptoms | The clinical control of asthma was defined according to the following criteria (GINA 2012): 1-Daytime symptoms: none or less than twice a week 2-Limitations of daily activities: none 3-Nocturnal symptoms or awakening because of asthma: none 4-Need of relief or rescue medication: none or less than twice a week 5-Lung function (PEF or FEV1) without administration of bronchodilator: normal | 12 month treatment duration | 
| Control of Asthma Symptoms | The clinical control of asthma was defined according to the following criteria (GINA 2012): 1-Daytime symptoms: none or less than twice a week 2-Limitations of daily activities: none 3-Nocturnal symptoms or awakening because of asthma: none 4-Need of relief or rescue medication: none or less than twice a week 5-Lung function (PEF or FEV1) without administration of bronchodilator: normal | 12 month treatment duration | 
| Control of Asthma Symptoms- Rescue Medication Use | The clinical control of asthma was defined according to the following criteria (GINA 2012): 1-Daytime symptoms: none or less than twice a week 2-Limitations of daily activities: none 3-Nocturnal symptoms or awakening because of asthma: none 4-Need of relief or rescue medication: none or less than twice a week 5-Lung function (PEF or FEV1) without administration of bronchodilator: normal | 12 month treatment duration | 
| Participants Requiring Oral Systemic Corticosteroids During the 12 Month Study Duration | Number of days of concomitant medications use reported by participants at all visits via diaries. | 12 month treatment duration | 
| Asthma Control Questionnaire (ACQ) at Baseline | The Asthma Control Questionnaire (ACQ) has six questions to be answered by the participants, each with a 7 point scale (0-good control, 6-poor control), and one question where the actual pre-bronchodilator Forced expiratory volume in 1 second (FEV1) value expressed in % of predicted FEV1 was classified to scores from 0 (> 95% of predicted) to 6 (< 50% of predicted). The overall score is the average of the 7 questions; a minimum overall score of 0 = good control of asthma whereas a maximum overall score of 6 = poor control of asthma. | Baseline | 
| Asthma Quality of Life Questionnaire (AQLQ) at Baseline | The quality of life will be measured by the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]) score for adults and the pediatric version of the AQLQ(S) for pediatric participants (PAQLQ[S]) . The AQLQ(S) and PAQLQ(S0 contain 4 domains (activity limitations, symptoms, emotional function, and environmental stimuli), with a total of 32 items; each item is measured in a 7-point Likert scale of 1 to 7 (1 = severe impairment, 7 = no impairment). All items are weighted equally. Mean score is calculated across all items within each domain and the overall score is the mean score of the 32 items. | Baseline |