Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations

National Institute of Allergy and Infectious Diseases (NIAID)478 enrolled

Overview

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.

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."

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

478

Conditions

Asthma

Interventions

OmalizumabBIOLOGICAL

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.

Inhaled Corticosteroid Boost Therapy (ICS)DRUG

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.

Placebo omalizumabBIOLOGICAL

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.

Eligibility

Sex: ALLMin age: 6 YearsMax age: 17 Years

Medical Language ↔ Plain English

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).

Locations (8)

National Jewish Health

Denver, Colorado, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Children's Memorial Hospital - Department of Allergy

Chicago, Illinois, United States

Boston University School of Medicine

Outcomes

Primary Outcomes

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).

Time frame: 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.

Time frame: 90 Day outcome period

Secondary Outcomes

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.

Data from ClinicalTrials.gov

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