Safety of LAIV4 in Children With Asthma

Study Overview
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Brief Summary
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This is a prospective randomized, open label clinical trial in approximately 300 children aged 5-11 years with a physician diagnosis of persistent asthma. Participants will be randomized 1:1 to receive either a single intranasal dose of licensed quadrivalent LAIV (LAIV4) or an intramuscular injection of quadrivalent IIV4 (IIV4).

Detailed Description
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The study will be conducted at three sites: Vanderbilt University Medical Center (Lead site), Cincinnati Children's Hospital Medical Center (contributing site), and Duke University Medical Center (contributing site) during the 2018-2019 influenza season. Participants will be randomized 1:1 to receive either a single intranasal dose of licensed quadrivalent LAIV (LAIV4) or an intramuscular injection of quadrivalent IIV4 (IIV4), stratifying by asthma severity (mild vs. moderate-to-severe). Vanderbilt will enroll about 100 participants, Cincinnati will enroll about 110 participants, and Duke will enroll about 90 participants. After enrollment, participants will be followed for 43 days via 5 additional phone, email, or text visits to monitor systemic reactogenicity, asthma symptoms and exacerbations, and serious adverse events. The primary objective is to compare proportions of participants with asthma exacerbations during the 42 days after LAIV4 versus IIV4. Because of the potential for increased risk of wheezing after LAIV, the use of LAIV in persons with asthma has been an area of vaccine safety research for many years; the safety issue remains unresolved. A clinical study to assess the safety of LAIV4 in children with asthma could expand the evidence base and inform clinical decision-making and public health policy.

Official Title
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Clinical Study of the Safety of Quadrivalent Live Attenuated Influenza Vaccine (LAIV4) in Children With Asthma of Varying Levels of Severity

Conditions
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Asthma in Children, Vaccine Adverse Reaction, Vaccine Reaction, Asthma, Wheezing, Influenza

Intervention / Treatment
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* Biological: Live Attenuated Influenza Vaccine (LAIV)
* Biological: Inactivated Influenza Vaccine (IIV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children between 5-11 years of age, inclusive, at enrollment Participant must have a current diagnosis of persistent asthma (Physician diagnosis of asthma and current prescribed use of a long-acting controller medication. For purposes of this study, we have considered controller medications to be any single or combination use of long-acting medications used to prevent asthma exacerbations and to achieve long-term control of asthma (as compared to short-acting rescue medication).) Parent(s) or legal guardian(s) must provide written, informed consent and participant must provide assent as appropriate for age prior to initiation of study procedures and according to local IRB requirements Parent(s) or legal guardian(s) and participant must be willing and able to comply with planned study procedures and be available for all study visits Is in good health, other than their asthma, as determined by medical history English or Spanish literate (only English-speaking participants will be included at the Cincinnati and Duke sites) Intention of being available for entire study period and complete all relevant study procedures, including follow-up using at least one of the following methods: phone calls, text messages, or emails Exclusion Criteria: Acute illness and/or a reported oral temperature of ≥ 100.4°F within 72 hours prior to enrollment (this may result in a temporary delay of vaccination) Use of antipyretic medication during the preceding 24 hours that might mask a fever (this may result in a temporary delay of vaccination) History of a severe allergic reaction (e.g., anaphylaxis) after a previous dose of any influenza vaccine or after any component of the influenza vaccine, including egg protein. Receipt of any licensed vaccine within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to vaccination or planned receipt of any licensed vaccine within 42 days after vaccination Receipt of current year's (2018-2019 influenza season) licensed influenza vaccine for children 9-11 years (only). (Clarification: Children aged 5-8 years are permitted to be enrolled if they have received zero or one dose of the 2018-2019 influenza season vaccine, and require two doses of the 2018-2019 influenza vaccine.) Received an investigational agent (licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication) in the 28 days prior to enrollment or planned receipt before 42 days after vaccination Have immunosuppression as a result of an underlying illness or treatment, or use of anticancer chemotherapy or radiation therapy within the preceding 36 months Have taken ≥20mg/day of prednisone or its equivalent, for 14 days or more within the past 28 days Have known active neoplasm or a history of any hematologic malignancy Has had a previous exacerbation of their asthma symptoms requiring systemic steroids within the prior 28 days, or has had a life-threatening exacerbation of asthma in the past two years (e.g. hypoxic seizure, mechanical ventilation) Received influenza antiviral medication within 48 hours prior to study vaccination History of Guillian-Barré syndrome within 6 weeks of previous influenza vaccination Have any condition that, in the opinion of the investigator, would interfere with the evaluation of the responses or would place the participant at unacceptable risk of injury Has a positive urine or serum pregnancy test within 24 hours prior to vaccination in a post-menarchal female. LAIV is not recommended for use in pregnant females. Currently taking aspirin or aspirin-containing products Any parent(s) or legal guardian(s) who is an immediate relative of study staff or is an employee supervised by study staff.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Live Attenuated Influenza Vaccine (LAIV)<br>Participants will receive one dose of live attenuated influenza vaccine via intranasal spray (administer approximately one half of the contents of the single-dose intranasal sprayer into each nostril, each sprayer contains 0.2 mL of vaccine)). | Biological: Live Attenuated Influenza Vaccine (LAIV)<br>* 1 dose, 0.2 mL, intranasal administration<br>|
| Active Comparator: Inactivated Influenza Vaccine (IIV)<br>Participants will receive one dose of inactivated influenza vaccine via intramuscular injection (0.5 mL). | Biological: Inactivated Influenza Vaccine (IIV)<br>* 1 dose, 0.5 mL, intramuscular administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the Proportion of Participants Experiencing an Asthma Exacerbation During the 42 Days After LAIV4 vs. IIV4 (Until Day 43). | For this study, asthma exacerbation will be defined as: any acute episode of progressively worsening shortness of breath (dyspnea), cough, wheezing, chest tightness, and/or respiratory distress during the 42 days (until day 43) after influenza vaccination for which the patient seeks unscheduled medical attention (e.g., healthcare provider office or Emergency Department visit or hospitalization) or receives a new prescription for systemic corticosteroids. | Day 43 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the Proportion of Participants Experiencing an Asthma Exacerbation During the 14 Days After LAIV4 vs. IIV4 | For this study, asthma exacerbation will be defined as: any acute episode of progressively worsening shortness of breath (dyspnea), cough, wheezing, chest tightness, and/or respiratory distress during the 14 days (until day 15) after influenza vaccination for which the patient seeks unscheduled medical attention (e.g., healthcare provider office or Emergency Department visit or hospitalization) or receives a new prescription for systemic corticosteroids. | Day 15 | 
| Comparison of the Proportion of Participants With Asthma Symptoms and Unscheduled Albuterol Use During the 14 Days After Receipt of LAIV4 or IIV4 (Each is Assessed Separately). | Cough, wheezing, tightness in chest, nighttime awakening and unscheduled albuterol use will all be assessed by parent self-report | Day 15 | 
| Comparison of the Proportion of Participants Who Experience a Clinically Significant Decrease in Peak Flow Measurement From Baseline During the 14 Days After LAIV4 or IIV4 | For purposes of this measure, a clinically significant decrease in peak flow is defined as: a decrease of ≥20% in PEFR from baseline PEFR | Baseline, Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma, influenza vaccine, inactivated influenza vaccine, live attenuated influenza vaccine