Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations

Study Overview
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Brief Summary
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The purpose of this trial is to compare the efficacy of 4 to 5 months of three treatments - omalizumab, corticosteroid therapy boost, and placebo - in reducing fall exacerbations in inner-city children and adolescents with allergic persistent asthma when initiated approximately 4 -6 weeks prior to the start of the first day of each participant's school year.

Detailed Description
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While the increase in the prevalence of asthma has abated, levels of asthma morbidity and mortality remain near record highs. An asthma exacerbation is a major factor contributing to morbidity, and even mortality in patients with asthma. Although current approaches to treatment have reduced these risks, asthma exacerbations are major problems for inner-city patients and their families, and prevention of these events continues to be a significant challenge. In children with asthma, there are predictable seasonal epidemics of exacerbations, especially during the fall season, otherwise known as the September epidemic.

Official Title
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Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations (ICAC-20)

Conditions
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Asthma

Intervention / Treatment
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* Biological: Omalizumab
* Drug: Inhaled Corticosteroid Boost Therapy (ICS)
* Biological: Placebo omalizumab
* Biological: Placebo fluticasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : Combined body weight (as measured at the screening visit) and total serum IgE level (as measured within 3 months of the screening visit) suitable for omalizumab (Xolair®) dosing; A diagnosis of asthma by a clinician made more than 1 year prior to recruitment; participants who received an asthma diagnosis by a clinician less than 1 year prior to recruitment must report that their respiratory symptoms were present for more than 1 year prior to recruitment; Having a requirement for at least 100 mcg fluticasone 100 mcg twice a day or equivalent at the Assumption of Care Visit AND who meet at least one of the following criteria: i. ≥1 asthma-related exacerbations, separated by at least two weeks, requiring treatment with a systemic corticosteroid course in the previous 12 months ii. ≥1 asthma-related overnight hospitalizations in the past 12 months. A positive prick skin-test to at least one perennial allergen (i.e. dust mite, cockroach, mold, cat, dog, rat, mouse) documented at the screening visit or at a ICAC study visit within 12 months of the screening visit; Primary place of residence is in one of the pre-selected recruitment census tracts; Able to perform spirometry; Parent or legal guardian is willing to sign the written informed consent (age appropriate) prior to initiation of any study procedure; Willing to sign the assent form, if age appropriate; A history of chickenpox or receipt of the chickenpox vaccine; Insurance which covers costs of medications; and Have not used and do not plan to restart any of the following medications in the 7 days prior to the first visit: tricyclic antidepressants, ketaconazole, or beta adrenergic blocker drugs (oral and/or topical). Exclusion Criteria: Participants who meet any of the following criteria are not eligible for enrollment but may be reassessed: Assigned to a treatment of less than 100 mcg fluticasone twice a day or equivalent at the Assumption of Care Visit; Pregnant or lactating. 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); Clinically significant laboratory abnormalities (not associated with the study indication) at the screening visit; Platelet count less than 100 x 10^9/L at the screening visit; Currently participating in another asthma-related pharmaceutical study or intervention study or who have participated in another asthma-related pharmaceutical study or intervention study in the month prior to Recruitment; Living with a foster parent: exception -not applicable if participant is able to provide consent; Does not have access to a phone (needed for scheduling appointments); Plan(s) to move from the area during the study period; Has previously been treated with omalizumab (Xolair®) within 1 year of recruitment; Currently receiving or has received hyposensitization therapy to any allergen in the past year prior to recruitment; Has received hyposensitization therapy to dust mite, Alternaria or cockroach for ≥ 6 months in the past 3 years prior to Recruitment; Has experienced a life-threatening asthma exacerbation in the last 2 years requiring intubation, mechanical ventilation, or resulting in a hypoxic seizure; Home-schooled or in year round school; Are currently taking or who have taken any of the following medications within 4 weeks of the Screening Visit: monoamine oxidase inhibitors (phenelzine, tranylcypromine); tricyclic and tetracyclic antidepressants; beta adrenergic blocker drugs (both oral and topical); anticonvulsants(carbamazepine, phenobarbital, phenytoin, mephobarbital, primidone,ethosuximide, methsuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, valproic acid, divalproex sodium, zonisamide); protease inhibitors(ritonavir, indinavir, nelfinavir); calcium channel blockers (verapamil, diltiazem); modafinil; tamoxifen; non-nucleoside reverse transcriptase inhibitors; macrolide antibiotics*(erythromycin, clarithromycin, dirithromycin, troleandomycin); chloramphenicol; nefazodone; aprepitant; St. John's Wort (hypericum); Rifampin*; Azole antifungals* (ketoconazole, fluconazole,itraconazole); Sibutramine*; bergamottin* (constituent of grapefruit juice).*may be rescreened if this therapy is short-lived; 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. Participants who meet any of the following criteria are not eligible for assumption of care and may not be reassessed except where noted: A current severe hypersensitivity to milk; Individuals who were enrolled in the previous ICAC trial, Inner-City Anti-IgE Therapy for Asthma (ICATA,ICAC-NCT00377572); Individuals who have any medical illnesses that in the opinion of the investigators would a.) increase the risk the subject would incur by participating in the study; b.) interfere with the measured outcomes of the study; or c.) interfere with the performance of the study procedures. Examples of such diseases are: cystic fibrosis, bronchiectasis, type 1 diabetes, hemophilia, Von Willebrand disease, sickle cell disease, cerebral palsy, rheumatoid arthritis, lupus, psoriasis, hyperimmunoglobulin E syndrome, parasite infections, Wiskott-Aldrich Syndrome or allergic bronchopulmonary aspergillosis. Known hypersensitivity to any ingredients, including excipients (sucrose, histidine, polysorbate 20) of the study medication or drugs related to omalizumab (e.g. monoclonal antibodies, polyclonal gamma globulin) or fluticasone; Currently have diagnosed cancer, are currently being investigated for possible cancer, or who have a history of cancer; Do not primarily speak English (or Spanish at centers with Spanish speaking staff) The participant's caretaker does not primarily speak English (or Spanish at centers with Spanish speaking staff); not applicable if participant is able to provide consent. A history of severe(grade 3) anaphylactoid or anaphylactic reaction(s).

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 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: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omalizumab<br>Participants receive active omalizumab (Xolair®) injections and a placebo Flovent® Diskus® (fluticasone) inhaler. Each participant will receive omalizumab (Xolair®) subcutaneous injections at minimum dose of 0.016 mg/kg/IgE (immunoglobulin E) [IU/mL] every 2 or 4 weeks during the 4-5 months treatment period. In addition, all participants receive standardized specialist asthma care. | Biological: Omalizumab<br>* Participants received active omalizumab (Xolair(R)) injections and a placebo inhaler. Each participant received omalizumab (Xolair(R)) subcutaneous injections at minimum dose of 0.016 mg/kg/IgE (immunoglobulin E) [IU/mL] every 2 or 4 weeks during the 4-5 months treatment period. All participants received standardized specialist asthma care.<br>* Other names: Xolair®;Biological: Placebo fluticasone<br>* Self-administered placebo fluticasone (placebo Flovent ® Diskus®) inhalers identical in dose and guidance as active fluticasone. All participants will receive standardized specialist asthma care.<br>* Other names: Placebo Flovent® Diskus®;|
| Experimental: Inhaled Corticosteroid Boost Therapy (ICS)<br>Participants in this group, the Inhaled Corticosteroid (ICS) boost arm, receive active ICS and placebo omalizumab (Xolair®) injections. Self-administered fluticasone (Flovent ® Diskus®) inhalers sufficient to deliver the required 200 mcg or 500 mcg daily boost of fluticasone will be used. In addition, all participants receive standardized specialist asthma care. | Drug: Inhaled Corticosteroid Boost Therapy (ICS)<br>* Self-administered fluticasone (Flovent ® Diskus®) inhalers sufficient to deliver the required 200 mcg or 500 mcg daily boost of fluticasone. All participants will receive standardized specialist asthma care.<br>* Other names: Flovent® Diskus®;Biological: Placebo omalizumab<br>* Placebo was administered subcutaneously every 2 or 4 weeks over a period of 4 to 5 months. Doses (mg) and dosing frequency were determined by serum total immunoglobulin E (IgE) level (IU/mL) and body weight (kg). Also, participants continued with their conventional asthma therapy according to the National Asthma Education and Prevention Program (NAEPP, 2007) guidelines, under the management of an asthma specialist health care provider.<br>* Other names: Placebo Xolair®;|
| Placebo Comparator: Placebo<br>The placebo group receive placebo omalizumab (Xolair®) injections and placebo Flovent® Diskus® (fluticasone) inhaler. In addition, all participants receive standardized specialist asthma care. | Biological: Placebo omalizumab<br>* Placebo was administered subcutaneously every 2 or 4 weeks over a period of 4 to 5 months. Doses (mg) and dosing frequency were determined by serum total immunoglobulin E (IgE) level (IU/mL) and body weight (kg). Also, participants continued with their conventional asthma therapy according to the National Asthma Education and Prevention Program (NAEPP, 2007) guidelines, under the management of an asthma specialist health care provider.<br>* Other names: Placebo Xolair®;Biological: Placebo fluticasone<br>* Self-administered placebo fluticasone (placebo Flovent ® Diskus®) inhalers identical in dose and guidance as active fluticasone. All participants will receive standardized specialist asthma care.<br>* Other names: Placebo Flovent® Diskus®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of One or More Asthma Exacerbations (All Treatment Steps [Steps 2-5]) | Asthma exacerbation defined as a prescribed course of systemic steroids by a clinician or initiation of a course of systemic steroids by a participant or a hospitalization during the fall outcome period (90 day period beginning on the first day of the participant's school year) to prevent a serious asthma outcome. If a participant initiates and completes a course of systemic steroids without clinician involvement, this course will be counted only if it meets the following minimum dosage: prednisone, prednisolone, or methylprednisolone at ≥ 20mg per day for 3 of any 5 consecutive days; or dexamethasone at ≥10mg per day for ≥1 day. Odds ratio comparing Placebo and Omalizumab arms across all treatment steps (Steps 2-5). | 90 Day outcome period | 
| Occurrence of One or More Asthma Exacerbations (Treatment Steps 2-4) | Asthma exacerbation defined as a prescription of a course of systemic steroids by a clinician or initiation of a course of systemic steroids by a participant or a hospitalization during the fall outcome period (90 day period beginning on the first day of the participant's school year) to prevent a serious asthma outcome. If a participant initiates and completes a course of systemic steroids without clinician involvement, this course will be counted only if it meets the following minimum dosage: prednisone, prednisolone, or methylprednisolone at ≥20mg per day for 3 of any 5 consecutive days; or dexamethasone at ≥10mg per day for ≥1 day. Odds ratio comparing Inhaled corticosteroid boost therapy (ICS) and Omalizumab arms at Treatment Steps 2-4. | 90 Day outcome period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virus-induced Exacerbations as Measured by an Exacerbation That is Associated With a Virus Detected Using the Nasal Mucus Samples | Asthma exacerbation:defined by a prescribed course of systemic steroids by a clinician or initiation of a course of systemic steroids by a participant or a hospitalization during the fall outcome period (90 day period beginning on the 1st day of the participant's school year) to prevent a serious asthma outcome. If a participant initiates and completes a course of systemic steroids without clinician involvement, this course will be counted only if it meets the following minimum dosage: prednisone, prednisolone, or methylprednisolone at ≥ 20mg per day for 3 of any 5 consecutive days; or dexamethasone at ≥ 10mg per day for ≥1 day. Exacerbations were then associated with viral respiratory infections based on nasal mucus samples collected monthly. Nasal mucus samples were categorized as having exacerbations or not having exacerbations. Participants could potentially be counted in each group, as participants could have samples with exacerbations and samples without exacerbations. | 90 Day outcome period | 
| Severity of Asthma Symptoms Associated With a Viral Infection:Omalizumab vs. Placebo | Severity asthma symptoms is defined as the highest value among the following 3 variables: number of days with wheezing, tightness in the chest, or cough; number of nights with disturbed sleep as a result of asthma; and number of days on which a participant had to slow down or discontinue play/physical activities over a two week period associated with a viral infection. This outcome looks at the effect by group on number of days with asthma symptoms and infections. The hypothesis behind this outcome measure is that omalizumab will change virology; thus, the the intent of this measure was to assess the comparator group of placebo against omalizumab | 90 Day outcome period | 
| Number of Exacerbations Evaluated Monthly With Viral Respiratory Infections: Omalizumab vs. Placebo | Asthma exacerbation is defined as a prescribed course of systemic steroids by a clinician or initiation of a course of systemic steroids by a participant or a hospitalization during the fall outcome period (90 day period beginning on the first day of the participant's school year) to prevent a serious asthma outcome. If a participant initiates and completes a course of systemic steroids without clinician involvement, this course will be counted only if it meets the following minimum dosage: prednisone, prednisolone, or methylprednisolone at ≥20mg per day for 3 of any 5 consecutive days; or dexamethasone at ≥10mg per day for ≥1 day. The hypothesis behind this outcome measure is that omalizumab will change virology; thus, the intent of this measure was to assess the comparator group of placebo against omalizumab. | 90 Day outcome period | 
| Composite Asthma Severity Index (CASI), Treatment Steps 2-5: Omalizumab vs. Placebo | CASI scores include 5 domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. To calculate CASI, the 5 domain scores are summed to determine a final score, which can range from 0 to 20, with 0 being no severity of asthma and 20 being extremely severe asthma. | 90 Day outcome period | 
| Composite Asthma Severity Index (CASI), Treatment Steps 2-4: Omalizumab vs. ICS | CASI scores include 5 domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. To calculate CASI, the 5 domain scores are summed to determine a final score, which can range from 0 to 20, with 0 being no severity of asthma and 20 being extremely severe asthma. | 90 Day outcome period | 
| Spirometry Measurements: Forced Expiratory Volume in 1 Second (FEV1) % Predicted, Treatment Steps 2-5:Omalizumab vs. Placebo | FEV1 is air volume exhaled in 1 second during spirometry. Asthma severity classification for trial: mild--pre-bronchodilator FEV1 ≥ 80% predicted requiring no/ low-moderate dose of inhaled glucocorticoids; moderate--pre-bronchodilator FEV1 <80% predicted requiring no/ low-moderate dose of inhaled glucocorticoids; severe--requiring high-dose inhaled glucocorticoids with/without continuous/near continuous oral glucocorticoids, or uncontrolled despite treatment. FEV1 percent of predicted value is FEV1 converted to a percentage of normal, based on height, weight, and race. | 90 Day outcome period | 
| Spirometry Measurements: Forced Expiratory Volume in 1 Second (FEV1) % Predicted , Treatment Steps 2-4: Omalizumab vs. ICS | FEV1 is air volume exhaled in 1 second during spirometry. Asthma severity classification for trial: mild--pre-bronchodilator FEV1 ≥ 80% predicted requiring no/ low-moderate dose of inhaled glucocorticoids; moderate--pre-bronchodilator FEV1 <80% predicted requiring no/ low-moderate dose of inhaled glucocorticoids; severe--requiring high-dose inhaled glucocorticoids with/without continuous/near continuous oral glucocorticoids, or uncontrolled despite treatment. FEV1 percent of predicted value is FEV1 converted to a percentage of normal, based on height, weight, and race. | 90 Day outcome period | 
| Spirometry Measurements: FEV1:FVCx100, Treatment Steps 2-5: Omalizumab vs. Placebo | The FEV1 (forced expiratory volume 1))/ FVC (forced vital capacity) ratio is used to evaluate airways obstructions since pure restrictive ventilatory defects cause an equal reduction in the FEV1 and the FVC. An FEV1/FVC ratio below 80% indicates airflow obstruction. Normal FEV1/FVC: 8 - 19 years of age=85%. | 90 Day outcome period | 
| Spirometry Measurements: FEV1:FVCx100, Treatment Steps 2-4: Omalizumab vs. ICS | The FEV1 (forced expiratory volume 1))/ FVC (forced vital capacity) ratio is used to evaluate airways obstructions since pure restrictive ventilatory defects cause an equal reduction in the FEV1 and the FVC. An FEV1/FVC ratio below 80% indicates airflow obstruction. Normal FEV1/FVC: 8 - 19 years of age=85%. | 90 Day outcome period | 
| Asthma Control Test Scores: Asthma Control Test (ACT), Treatment Steps 2-5: Omalizumab vs. Placebo | Outcome measure description: The Asthma Control Test (ACT) is a validated tool to assess asthma control (over the last 4 weeks) in patients ≥12 yrs old. It is comprised of 5 questions assessing symptoms, use of rescue medications, and the impact of asthma on everyday functioning. All questions are scored on a 5-point Likert scale (higher score indicating better control). Total scores can range from 5-25. A score of ≤19 is indicative of not well-controlled asthma. The minimally important difference is 3 points. | 90 Day outcome period | 
| Asthma Control Test Scores: Asthma Control Test (ACT), Treatment Steps 2-4: Omalizumab vs. ICS | The Asthma Control Test (ACT) is a validated tool to assess asthma control (over the last 4 weeks) in patients ≥12 yrs old. It is comprised of 5 questions assessing symptoms, use of rescue medications, and the impact of asthma on everyday functioning. All questions are scored on a 5-point Likert scale (higher score indicating better control). Total scores can range from 5-25. A score of ≤19 is indicative of not well-controlled asthma. The minimally important difference is 3 points. | 90 Day outcome period | 
| Asthma Control Test Score: Child Asthma Control Test (C-ACT), Treatment Steps 2-5: Omalizumab vs. Placebo | The Childhood Asthma Control Test (C-ACT) is a validated tool to assess overall asthma control (over the last 4 weeks) in patients ages 4 to 11 years. Scores can range from 0 to 27. A score of 19 or less is indicative of asthma that is not well controlled. The minimally important difference in C-ACT scores is not defined | 90 Day outcome period | 
| Asthma Control Test Score: Child Asthma Control Test (C-ACT), Treatment Steps 2-4: Omalizumab vs. ICS | The Childhood Asthma Control Test (C-ACT) is a validated tool to assess overall asthma control (over the last 4 weeks) in patients ages 4 to 11 years. Scores can range from 0 to 27. A score of 19 or less is indicative of asthma that is not well controlled. The minimally important difference in C-ACT scores is not defined. | 90 Day outcome period | 
| Work Disruptions Due to Child's Asthma, Treatment Steps 2-5: Omalizumab vs. Placebo | The ratio of the work hours missed due to child's asthma over the numbers of work hours in the past 14 days among caretakers working. | 90 Day outcome period | 
| Work Disruptions Due to Child's Asthma, Treatment Steps 2-4: Omalizumab vs. ICS | The ratio of the work hours missed due to child's asthma over the numbers of work hours in the past 14 days among caretakers working | 90 Day outcome period | 
| School Absences (Percent), Treatment Steps 2-5:Omalizumab vs. Placebo | The ratio of the number of school days missed over the numbers of school days in session | 90 Day outcome period | 
| School Absences (Percent), Treatment Steps 2-4: Omalizumab vs. ICS | The ratio of the number of school days missed over the numbers of school days in session | 90 Day outcome period | 
| Percent Adherence to Asthma Medication, Treatment Steps 2-5: Omalizumab vs. Placebo | Adherence to the study regimen and other asthma treatments, assessed as percent of expected dose taken, by means of study interviews and study physician corroboration. | 90 Day outcome period | 
| Percent Adherence to Asthma Medication, Treatment Steps 2-4: Omalizumab vs. ICS | Adherence to the study regimen and other asthma treatments, assessed as percent of expected dose taken, by means of study interviews and study physician corroboration. | 90 Day outcome period | 
| Comparison of Home Allergen (Cockroach) Exposure and Asthma Exacerbations: Omalizumab Versus Placebo | Residential environmental exposure to cockroach allergen of participants in the context of the risk of asthma exacerbations and effect of omalizumab versus placebo (control) on asthma exacerbations was explored. Presence of cockroach allergen in household dust samples was assessed. Exacerbation defined as: participant required either 1.)a prescribed course of systemic steroids by a clinician2.)initiation of a course of systemic steroids or 3.)a hospitalization during the fall outcome period (90 day period beginning on the first day of the participant's school year) to prevent a serious asthma outcome. In cases that a participant initiated and completed a course of systemic steroids without clinician involvement, the course was counted as an exacerbation only with fulfillment of the following minimum dosage: prednisone, prednisolone, or methylprednisolone at ≥20mg per day for 3 of any 5 consecutive days; or dexamethasone at ≥10mg per day for ≥1 day). | 90 Day outcome period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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persistent allergic asthma, asthma exacerbations reduction, Xolair® (omalizumab), Flovent® Diskus® (fluticasone), placebo, inhaled corticosteroid therapy, anti-immunoglobulin E therapy, anti-IgE therapy