Safety of LAIV4 in Children With Asthma

• Sponsor: Vanderbilt University Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT03600428
• Collaborator: Centers for Disease Control and Prevention (U.S. Fed), Duke University (Other), Children's Hospital Medical Center, Cincinnati (Other)
• Enrollment: 152
• Locations: 3
• Arms: 2
• Actual Duration (Months): 17.1
• Patients Per Site: 50.7
• Patients Per Site Per Month: 3

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Asthma in Children; Vaccine Adverse Reaction; Vaccine Reaction; Asthma; Wheezing; Influenza	Biological: Live Attenuated Influenza Vaccine (LAIV); Biological: Inactivated Influenza Vaccine (IIV)	Phase 4

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 152 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Clinical Study of the Safety of Quadrivalent Live Attenuated Influenza Vaccine (LAIV4) in Children With Asthma of Varying Levels of Severity
• Actual Study Start Date: Oct 15, 2018
• Actual Primary Completion Date: Mar 20, 2020
• Actual Study Completion Date: Mar 20, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Live Attenuated Influenza Vaccine (LAIV) 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); 1 dose, 0.2 mL, intranasal administration
Active Comparator: Inactivated Influenza Vaccine (IIV) Participants will receive one dose of inactivated influenza vaccine via intramuscular injection (0.5 mL).	Biological: Inactivated Influenza Vaccine (IIV); 1 dose, 0.5 mL, intramuscular administration

Outcome Measures

Primary Outcome Measures

1. Comparison of the Proportion of Participants Experiencing an Asthma Exacerbation During the 42 Days After LAIV4 vs. IIV4 (Until Day 43). [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.

Secondary Outcome Measures

1. Comparison of the Proportion of Participants Experiencing an Asthma Exacerbation During the 14 Days After LAIV4 vs. IIV4 [Day 15]

   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.

2. 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). [Day 15]

   Cough, wheezing, tightness in chest, nighttime awakening and unscheduled albuterol use will all be assessed by parent self-report

3. 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 [Baseline, Day 15]

   For purposes of this measure, a clinically significant decrease in peak flow is defined as: a decrease of ≥20% in PEFR from baseline PEFR

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years to 11 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710
2	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
3	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University Medical Center
• Centers for Disease Control and Prevention
• Duke University
• Children's Hospital Medical Center, Cincinnati

Investigators

• Principal Investigator: Buddy Creech, MD, MPH, Vanderbilt University Medical Center

Study Documents (Full-Text)

• Study Protocol - Jul 3, 2019
• Statistical Analysis Plan - Mar 2, 2020

More Information

Publications

None provided.

• Responsible Party: Buddy Creech, Associate Professor of Pediatrics, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT03600428
• Other Study ID Numbers: 181211; 200-2012-50430 Task Order 0005
• First Posted: Jul 26, 2018
• Last Update Posted: Mar 16, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Buddy Creech, Associate Professor of Pediatrics, Vanderbilt University Medical Center: asthma; influenza vaccine; inactivated influenza vaccine; live attenuated influenza vaccine
• Additional relevant MeSH terms: Influenza, Human; Asthma; Respiratory Sounds; Vaccines

Study Results

Participant Flow

Arm/Group Title	Live Attenuated Influenza Vaccine (LAIV4)	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Participants will receive one dose of quadrivalent 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)). Quadrivalent Live Attenuated Influenza Vaccine (LAIV4): 1 dose, 0.2 mL, intranasal administration	Participants will receive one dose of quadrivalent inactivated influenza vaccine via intramuscular injection (0.5 mL). Quadrivalent Inactivated Influenza Vaccine (IIV4): 1 dose, 0.5 mL, intramuscular administration
Period Title: Overall Study
STARTED	79	73
15-day Follow-up	76	70
43-day Follow-up	74	68
COMPLETED	74	68
NOT COMPLETED	5	5

Baseline Characteristics

Arm/Group Title	Live Attenuated Influenza Vaccine (LAIV4)	Inactivated Influenza Vaccine (IIV4)	Total
Arm/Group Description	Participants will receive one dose of quadrivalent 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)). Quadrivalent Live Attenuated Influenza Vaccine (LAIV4): 1 dose, 0.2 mL, intranasal administration	Participants will receive one dose of quadrivalent inactivated influenza vaccine via intramuscular injection (0.5 mL). Quadrivalent Inactivated Influenza Vaccine (IIV4): 1 dose, 0.5 mL, intramuscular administration	Total of all reporting groups
Overall Participants	79	72	151
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	9.00	9.00	9.00
Age, Customized (Count of Participants)
5-11 years old	58 73.4%	55 76.4%	113 74.8%
12-17 years old	21 26.6%	17 23.6%	38 25.2%
Sex: Female, Male (Count of Participants)
Female	35 44.3%	28 38.9%	63 41.7%
Male	44 55.7%	44 61.1%	88 58.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 5.1%	3 4.2%	7 4.6%
Not Hispanic or Latino	75 94.9%	69 95.8%	144 95.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 2.5%	0 0%	2 1.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	25 31.6%	24 33.3%	49 32.5%
White	43 54.4%	42 58.3%	85 56.3%
More than one race	9 11.4%	6 8.3%	15 9.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	43 54.4%	42 58.3%	85 56.3%
Black	25 31.6%	24 33.3%	49 32.5%
Other	11 13.9%	6 8.3%	17 11.3%
Site (Count of Participants)
Vanderbilt	12 15.2%	8 11.1%	20 13.2%
Cincinnati	54 68.4%	53 73.6%	107 70.9%
Duke	13 16.5%	11 15.3%	24 15.9%
Asthma Severity Status (Count of Participants)
Mild	26 32.9%	19 26.4%	45 29.8%
Moderate or Severe	53 67.1%	53 73.6%	106 70.2%
Weight in kg (kilograms) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kilograms]	39.1	35.0	38.3
Height (inches) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [inches]	53.90	53.70	53.75
BMI (kg/m2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m2]	19.50	18.60	18.75
Received seasonal influenza vaccine in the past 12 months (Count of Participants)
No	42 53.2%	43 59.7%	85 56.3%
Yes	30 38%	26 36.1%	56 37.1%
Unknown	7 8.9%	3 4.2%	10 6.6%
History of nasal or sinus allergies (Count of Participants)
No	19 24.1%	27 37.5%	46 30.5%
Yes	56 70.9%	45 62.5%	101 66.9%
Unknown	4 5.1%	0 0%	4 2.6%
Influenza Season (Count of Participants)
2018-2019	27 34.2%	25 34.7%	52 34.4%
2019-2020	52 65.8%	47 65.3%	99 65.6%

Outcome Measures

1. Primary Outcome

Title	Comparison of the Proportion of Participants Experiencing an Asthma Exacerbation During the 42 Days After LAIV4 vs. IIV4 (Until Day 43).
Description	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.
Time Frame	Day 43

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Live Attenuated Influenza Vaccine (LAIV4)	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Participants received one dose of quadrivalent 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)). Quadrivalent Live Attenuated Influenza Vaccine (LAIV4): 1 dose, 0.2 mL, intranasal administration	Participants received one dose of quadrivalent inactivated influenza vaccine via intramuscular injection (0.5 mL). Quadrivalent Inactivated Influenza Vaccine (IIV4): 1 dose, 0.5 mL, intramuscular administration
Measure Participants	74	68
Asthma exacerbation within 43 days	8 10.1%	10 13.9%
No asthma exacerbation within 43 days	66 83.5%	58 80.6%

2. Secondary Outcome

Title	Comparison of the Proportion of Participants Experiencing an Asthma Exacerbation During the 14 Days After LAIV4 vs. IIV4
Description	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.
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Live Attenuated Influenza Vaccine (LAIV4)	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Participants received one dose of quadrivalent 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)). Quadrivalent Live Attenuated Influenza Vaccine (LAIV4): 1 dose, 0.2 mL, intranasal administration	Participants received one dose of quadrivalent inactivated influenza vaccine via intramuscular injection (0.5 mL). Quadrivalent Inactivated Influenza Vaccine (IIV4): 1 dose, 0.5 mL, intramuscular administration
Measure Participants	76	70
Asthma exacerbation within 14 days	3 3.8%	4 5.6%
No asthma exacerbation within 14 days	73 92.4%	66 91.7%

3. Secondary Outcome

Title	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).
Description	Cough, wheezing, tightness in chest, nighttime awakening and unscheduled albuterol use will all be assessed by parent self-report
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Live Attenuated Influenza Vaccine (LAIV4)	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Participants received one dose of quadrivalent 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)). Quadrivalent Live Attenuated Influenza Vaccine (LAIV4): 1 dose, 0.2 mL, intranasal administration	Participants received one dose of quadrivalent inactivated influenza vaccine via intramuscular injection (0.5 mL). Quadrivalent Inactivated Influenza Vaccine (IIV4): 1 dose, 0.5 mL, intramuscular administration
Measure Participants	76	70
No	18 22.8%	20 27.8%
Yes	58 73.4%	50 69.4%
No	55 69.6%	42 58.3%
Yes	21 26.6%	28 38.9%
No	41 51.9%	44 61.1%
Yes	35 44.3%	26 36.1%

4. Secondary Outcome

Title	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).
Description	Cough, wheezing, tightness in chest, nighttime awakening and unscheduled albuterol use will all be assessed by parent self-report
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Live Attenuated Influenza Vaccine (LAIV4)	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Participants received one dose of quadrivalent 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)). Quadrivalent Live Attenuated Influenza Vaccine (LAIV4): 1 dose, 0.2 mL, intranasal administration	Participants received one dose of quadrivalent inactivated influenza vaccine via intramuscular injection (0.5 mL). Quadrivalent Inactivated Influenza Vaccine (IIV4): 1 dose, 0.5 mL, intramuscular administration
Measure Participants	76	70
None	26 32.9%	22 30.6%
Mild	35 44.3%	29 40.3%
Moderate	14 17.7%	15 20.8%
Severe	1 1.3%	4 5.6%
None	51 64.6%	39 54.2%
Mild	19 24.1%	18 25%
Moderate	5 6.3%	12 16.7%
Severe	1 1.3%	1 1.4%
None	58 73.4%	45 62.5%
Mild	12 15.2%	21 29.2%
Moderate	5 6.3%	3 4.2%
Severe	1 1.3%	1 1.4%

5. Secondary Outcome

Title	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
Description	For purposes of this measure, a clinically significant decrease in peak flow is defined as: a decrease of ≥20% in PEFR from baseline PEFR
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Live Attenuated Influenza Vaccine (LAIV4)	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Participants received one dose of quadrivalent 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)). Quadrivalent Live Attenuated Influenza Vaccine (LAIV4): 1 dose, 0.2 mL, intranasal administration	Participants received one dose of quadrivalent inactivated influenza vaccine via intramuscular injection (0.5 mL). Quadrivalent Inactivated Influenza Vaccine (IIV4): 1 dose, 0.5 mL, intramuscular administration
Measure Participants	76	70
No PEFR decrease >= 20% from baseline within 14 days	36 45.6%	37 51.4%
PEFR decreased >= 20% from baseline within 14 days	39 49.4%	33 45.8%
Unknown	1 1.3%	0 0%

Adverse Events

Time Frame	Within 42 days (until day 43) after vaccination.
Adverse Event Reporting Description	Adverse events (AEs), including serious adverse events (SAEs) were recorded on the memory aid and included the need for new prescription or nonprescription medications for the control of asthma, an unscheduled healthcare provider visit or consultation, any other clinically significant event at any point during the study period. The definition of SAEs matched the definition from clinicaltrials.gov.
Arm/Group Title	Live Attenuated Influenza Vaccine (LAIV4)		Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Participants received one dose of quadrivalent 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)). Quadrivalent Live Attenuated Influenza Vaccine (LAIV4): 1 dose, 0.2 mL, intranasal administration		Participants received one dose of quadrivalent inactivated influenza vaccine via intramuscular injection (0.5 mL). Quadrivalent Inactivated Influenza Vaccine (IIV4): 1 dose, 0.5 mL, intramuscular administration
All Cause Mortality
	Live Attenuated Influenza Vaccine (LAIV4)		Inactivated Influenza Vaccine (IIV4)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/74 (0%)		0/68 (0%)
Serious Adverse Events
	Live Attenuated Influenza Vaccine (LAIV4)		Inactivated Influenza Vaccine (IIV4)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/74 (0%)		0/68 (0%)
Other (Not Including Serious) Adverse Events
	Live Attenuated Influenza Vaccine (LAIV4)		Inactivated Influenza Vaccine (IIV4)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/74 (10.8%)		10/68 (14.7%)
Respiratory, thoracic and mediastinal disorders
Asthma Exacerbation	8/74 (10.8%)		10/68 (14.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.