COVID19 SARS Vaccinations: Systemic Allergic Reactions to SARS-CoV-2 Vaccinations

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT04761822

Collaborator

Immune Tolerance Network (ITN) (Other), Rho Federal Systems Division, Inc. (Industry)

746

Enrollment

Locations

Arms

12.6

Actual Duration (Months)

25.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Background: Allergic reactions have been reported to occur after vaccination with both the Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine. Allergic reactions range from mild to severe and include life- threatening anaphylactic reactions, although no deaths have been reported with either vaccine.

This study is designed with two principal aims:

To estimate the proportions of systemic allergic reactions to the Pfizer-BioNTech COVID-19 Vaccine and the Moderna COVID-19 Vaccine in a High-Allergy/Mast Cell Disorder (HA/MCD) population, and
If the risk in the HA/MCD is demonstrable, to determine whether the proportions are higher in the HA/MCD in comparison to a representative population without severe allergies or mast cell disorders

Condition or Disease	Intervention/Treatment	Phase
SARS-CoV Infection COVID-19 Allergic Reaction Mast Cell Disorder	Biological: Moderna COVID-19 Vaccine Biological: Pfizer-BioNTech COVID-19 Vaccine Biological: Placebo	Phase 2

Detailed Description

This is a multicenter, randomized, initially blinded (masked), phase 2 trial to assess

SARS-CoV-2 vaccination reactions in two populations:

One population including individuals with a history of allergic reactions or Mast Cell Disorder (HA/MCD), and
One comparison population without severe allergies or mast cell disorders.

Approximately 2040 HA/MCD and 1360 comparison participants will be enrolled across participating sites in the United States. Approximately two-thirds of participants enrolled in each of the 2 groups will be female. This is because the vast majority of cases of anaphylaxis to the COVID-19 vaccines have occurred in women. Enrollment of participants who qualify only on the basis of reactions to multiple unrelated drugs will be limited to approximately 300.

Enrollment of the MCD group is anticipated to be at least 200 participants, and not more than 300 participants.

Participants in each population will be randomized 2:2:1:1 to receive the Pfizer-BioNTech COVID-19 Vaccine, Moderna COVID-19 Vaccine, placebo + Pfizer-BioNTech COVID-19 Vaccine, or placebo + Moderna COVID-19 Vaccine, if enrolled in the initial study period under protocol versions 1.0 -4.0. Participants enrolled under protocol version 5.0 will be randomized 2:1 to receive the Pfizer-BioNTech COVID-19 Vaccine or placebo + Pfizer-BioNTech COVID-19 Vaccine. If enrollment under protocol version 5.0 is robust and sustained, the active vaccine randomization may be changed to the Moderna COVID-19 Vaccine.

Participants randomized to one of the placebo groups will receive placebo as a first dose and will receive two doses of their assigned active vaccine at subsequent visits. During the first visit, all participants will be initially-blinded to whether they are receiving placebo or vaccine, and to which vaccine they are receiving (if enrolling under protocol versions 1.0 -4.0).

Due to the different dosing schedules for the Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine, it will become apparent to both the site staff and the study participant which vaccine has been assigned, once the second injection visit is scheduled. However, the blind over placebo versus vaccine will remain in effect until after the second visit. During a follow-up call, scheduled 3 days after the second injection, participants will be unblinded as to whether they received placebo or active vaccine.

However under protocol version 5.0, participants will be told if they received placebo as the first injection during the following up conducted 3 days after. Participants in this phase of the study will also know which company's vaccine they are receiving, as the vaccines are anticipated to be used sequentially and will also be noted in the consent form.

Study Duration: Randomized and vaccinated participants will complete study participation in approximately 29 days if vaccinated with the Pfizer-BioNTech COVID-19 Vaccine, 36 days if vaccinated with the Moderna COVID-19 Vaccine. Participants enrolled under protocol versions 1.0 -4.0 will complete study participation in 50 or 64 days if administered placebo before receiving two doses of either the Pfizer-BioNTech COVID-19 Vaccine or the Moderna COVID-19 Vaccine, respectively and participants enrolled under protocol version 5.0 will complete participation in approximately 36 of 43 days, respectively, if they receive placebo first.

Study Design

Study Type:

Interventional

Actual Enrollment :

746 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

Due to the different dosing schedules for the Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine, it will become apparent to both the site staff and study participant which vaccine has been assigned, once their second injection is scheduled. Participants and the staff will be unblinded (unmasked) during the follow-up call 3 days after the second injection when a third appointment (for those who received a placebo injection first) is, or is not (active vaccinations only) scheduled.

Primary Purpose:

Treatment

Official Title:

Systemic Allergic Reactions to SARS-CoV-2 Vaccination

Actual Study Start Date :

Apr 7, 2021

Actual Primary Completion Date :

Apr 20, 2022

Actual Study Completion Date :

Apr 27, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Moderna COVID-19 Vaccine The Moderna COVID-19 Vaccine (0.5 mL) will be administered intramuscularly in the deltoid, as a series of two doses (0.5 mL each) administered 1 month (28 days) apart.	Biological: Moderna COVID-19 Vaccine Intramuscular injection Other Names: mRNA-1273
Experimental: Pfizer-BioNTech COVID-19 Vaccine The Pfizer-BioNTech COVID-19 Vaccine (0.3 mL) will be administered intramuscularly in the deltoid, as a series of two doses (0.3 mL each) administered 3 weeks (21 days) apart.	Biological: Pfizer-BioNTech COVID-19 Vaccine Intramuscular injection Other Names: BNT162b2
Experimental: Placebo +Moderna COVID-19 Vaccine Participants will receive placebo as a first dose followed by two doses of their assigned active vaccine at subsequent visits. 0.5 mL of placebo will be administered intramuscularly in the deltoid. The placebo dose will be followed by two doses of Moderna COVID-19 Vaccine, with the first dose administered 1 month later. The Moderna COVID-19 Vaccine (0.5 mL) will be administered intramuscularly in the deltoid, as a series of two doses (0.5 mL each) administered 1 month (28 days) apart.	Biological: Moderna COVID-19 Vaccine Intramuscular injection Other Names: mRNA-1273 Biological: Placebo Intramuscular injection Other Names: sterile, preservative-free 0.9% Sodium Chloride Injection
Experimental: Placebo+Pfizer-BioNTech COVID-19 Vaccine Participants will receive placebo as a first dose followed by two doses of their assigned active vaccine at subsequent visits. 0.3 mL of placebo will be administered intramuscularly in the deltoid. The placebo dose will be followed by two doses of Pfizer-BioNTech COVID-19 Vaccine, with the first dose administered 1 month later. The Pfizer-BioNTech COVID-19 Vaccine (0.3 mL) will be administered intramuscularly in the deltoid, as a series of two doses (0.3 mL each) administered 3 weeks (21 days) apart.	Biological: Pfizer-BioNTech COVID-19 Vaccine Intramuscular injection Other Names: BNT162b2 Biological: Placebo Intramuscular injection Other Names: sterile, preservative-free 0.9% Sodium Chloride Injection

Outcome Measures

Primary Outcome Measures

Proportion of participants who experience a systemic allergic reaction to either dose of the Pfizer-BioNTech COVID-19 Vaccine [Within the 90-minute post- vaccination observation period]
Symptoms considered to be allergic will be graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale is Grade 1 (Mild) through 5, the higher the grade, the more severe the allergic reaction. Note- It is possible for a participant to have a reaction to: Either dose 1 or dose 2 of the assigned COVID-19 vaccine, but not to both doses, since a participant who has a reaction meeting qualifying criteria to dose 1 will not be eligible to receive the second dose; or, Neither dose of the assigned COVID-19 vaccine.
Proportion of participants who experience a systemic allergic reaction to either dose of the Moderna COVID-19 Vaccine [Within the 90-minute post- vaccination observation period]
Symptoms considered to be allergic will be graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale is Grade 1 (Mild) through 5, the higher the grade, the more severe the allergic reaction. Note- It is possible for a participant to have a reaction to: Either dose 1 or dose 2 of the assigned COVID-19 vaccine, but not to both doses, since a participant who has a reaction meeting qualifying criteria to dose 1 will not be eligible to receive the second dose; or, Neither dose of the assigned COVID-19 vaccine.

Secondary Outcome Measures

Proportion of participants who experience a severe (≥ Grade 3) systemic allergic reaction to either dose of each vaccine [Within the 90-minute post- vaccination observation period]
Symptoms considered to be allergic will be graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale is Grade 1 (Mild) through 5, the higher the grade, the more severe the allergic reaction. Note- It is possible for a participant to have a reaction to: Either dose 1 or dose 2 of the assigned COVID-19 vaccine, but not to both doses, since a participant who has a reaction meeting qualifying criteria to dose 1 will not be eligible to receive the second dose; or, Neither dose of the assigned COVID-19 vaccine.
Proportion of participants who experience an anaphylactic reaction per Brighton Collaboration Criteria to either dose of each vaccine [Within the 90-minute post- vaccination observation period]
Defined by Levels 1-3 per Brighton Collaboration Criteria. Brighton Collaboration case definition criteria for anaphylaxis. Brighton level 1 represents the highest level of diagnostic certainty that a reported case is a case of anaphylaxis, levels 2 and 3 represent successively lower levels of diagnostic certainty.
Proportion of participants who experience a systemic allergic reaction ≥Grade 2 to the first dose [Within the 90-minute post- vaccination observation period]
Symptoms considered to be allergic will be graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale is Grade 1 through 5, the higher the grade, the more severe the allergic reaction.
Proportion of participants who experience a systemic allergic reaction ≥Grade 2 to the second dose conditional on no systemic allergic reaction to the first dose [Within the 90-minute post- vaccination observation period]
Symptoms considered to be allergic will be graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale is Grade 1 through 5, the higher the grade, the more severe the allergic reaction.
Proportion of participants who experience a systemic allergic reaction ≥Grade 2 to the first dose after adjusting for placebo administration [Within the 90-minute post- vaccination observation period]
Symptoms considered to be allergic will be graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale is Grade 1 through 5, the higher the grade, the more severe the allergic reaction.
Proportion of participants who experience a systemic allergic reaction ≥Grade 2 within 48 hours of either dose of each vaccine [Within the 48 hours post- vaccination observation period]
Symptoms considered to be allergic will be graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale is Grade 1 through 5, the higher the grade, the more severe the allergic reaction.

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Individuals who meet all of the following criteria are eligible for enrollment as study participants:

Both groups (e.g., High-Allergy and Mast Cell Disorder (HA/MCD) Group and Comparison

Group):

Able to understand and provide informed consent
Male or non-pregnant female ≥12 years of age on the date of first study vaccination/placebo administration (protocol versions 1.0 - 4.0) OR male or non-pregnant female 5-17 years of age on the date of first study vaccination/placebo administration (protocol version 5.0)
Females of childbearing potential must have a negative pregnancy test prior to the first vaccination and placebo administration, if applicable.

--If a participant becomes pregnant after receiving a placebo dose but prior to receiving study vaccination, she will be discontinued from the study

Females of reproductive potential° and sexually active must agree to use FDA approved methods of birth control for the duration of the study. These include hormonal contraceptives, intrauterine device, double barrier contraception (i.e., condom plus diaphragm), or male partner with documented vasectomy.

Menopause is defined as at least 12 consecutive months without menses; if in question, a follicle stimulating hormone of ≥25 U/mL must be documented.
Hysterectomy, bilateral oophorectomy, or bilateral tubal ligation must be documented, as applicable; if documented, women with these conditions are not required to use additional contraception.

High-Allergy and Mast Cell Disorder (HA/MCD) Group:

Individuals who meet at least one of the following criteria are eligible for enrollment in the HA/MCD group:

History of a severe allergic reaction to food(s), allergen immunotherapy, insect venom(s), or latex with use of epinephrine within the last 15 years
History of an Emergency Department visit with convincing evidence of a systemic allergic reaction (consistent with CoFAR Grade 3 or higher) to food(s), allergen immunotherapy, insect venom(s), or latex within the last 15 years
History of documented, immediate allergic reactions to 2 or more unrelated drugs within the last 15 years
A convincing clinical history, or a history that is accompanied by a positive skin test, of an immediate reaction to a drug, vaccine, or latex within the last 15 years
History of physician-diagnosed idiopathic anaphylaxis requiring epinephrine or an Emergency Department visit in the last 15 years
History of a physician-diagnosed mast cell disorder (e.g., mastocytosis, mast cell activation syndrome [MCAS], or hereditary alpha-tryptasemia). MCAS must meet consensus criteria as defined below:

Criterion A: Typical clinical signs of severe, recurrent (episodic) systemic Mast Cell Activation are present (often in form of anaphylaxis)

---Definition of systemic: involving at least 2 organ systems

Criterion B: Involvement of Mast Cell (MC) is documented by biochemical studies

--- Preferred marker: increase in serum tryptase level from the individual's baseline to plus 20% + 2 ng/ml

Criterion C: Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production or drugs blocking mediator release or effects of MC-derived mediators
NOTE: All 3 Mast Cell Activation Syndrome (MCAS) criteria (A + B + C) must be fulfilled to call a condition MCAS.

Comparison Group:

Individuals who meet all of the following criteria are eligible for enrollment in the comparison group:

No history of allergic asthma or atopic dermatitis within the last 10 years
No history of chronic spontaneous urticaria, or angioedema
No history of allergic reactions to foods or insect venoms
No history of allergic reactions to drugs or vaccines
No history of anaphylaxis
No history of a mast cell disorder (e.g., mastocytosis, mast cell activation syndrome [MCAS], or hereditary alpha- tryptasemia)

Exclusion Criteria:

Individuals who meet any of these criteria are not eligible for enrollment as study participants:

Inability or unwillingness of a participant and/or parent/legal guardian to give written informed consent and/or assent, as applicable, or to comply with study protocol
Weight less than 15 kg (33 lbs)
Prior receipt of any doses of the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) Vaccine, Moderna COVID-19 Vaccine, or any other COVID-19 vaccine
History of a severe reaction to any component of the Pfizer-BioNTech COVID-19 Vaccine or Moderna COVID-19 Vaccine
History of contact dermatitis with confirmed patch test reaction to Prevalence of polyethylene glycol (PEG)
History of reaction to Doxil®
Known exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and still within the quarantine window
Symptoms consistent with acute COVID-19 infection or known COVID-19 infection (positive Polymerase chain reaction [PCR] or antigen test) and still within the quarantine window
Have an acute illness, including body temperature greater than 100.4 degrees Fahrenheit, within 14 days of the first study vaccination/placebo administration or 3 days prior to each subsequent vaccination
History of autoimmune or other disorders requiring systemic immune modulators
History of acute urticaria within 28 days of randomization
Pregnant
Have received any vaccines within 14 days of the first study vaccination/placebo administration or plan to receive other vaccines during the study period
Had any allergen immunotherapy administration within 24 hours prior to vaccination/placebo administration or plan to receive within 24 hours after vaccination/placebo administration
Have received a biologic therapy within 6 months of randomization
Use of systemic steroids for any reason within 28 days of randomization
Use of Zileuton® within 14 days of randomization
Use of any monoclonal antibody agent for treatment or prevention of COVID-19 within 3 months of randomization
Coronary artery disease, peripheral or cerebral vascular disease, unstable angina, or cardiac arrhythmia, other than supraventricular tachycardia (SVT)
Medically unstable hypertension
Current use of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, monoamine oxidase (MAO) inhibitors, tricyclic anti-depressants or other agents that could interfere with the treatment of anaphylaxis, in the opinion of the investigator
Unstable asthma within 3 months of randomization or symptomatic asthma on the day of vaccination, as assessed by the site investigator
Have past or current medical problems or findings from physical exam or laboratory testing not listed above, which in the opinion of the investigator, may pose additional risks from participation in the study or which may interfere with the ability to comply with study requirements --This includes individuals with underlying conditions or other medications that, in the opinion of the investigator, may increase risk in the event of an anaphylactic reaction or lead to complications following administration of epinephrine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona Health Sciences, College of Medicine Tucson, Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine	Tucson	Arizona	United States	85724
2	Arkansas Children's, University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72202
3	University of California, Los Angeles Medical Center	Los Angeles	California	United States	90095
4	Stanford Medicine, Sean N. Parker Center for Allergy & Asthma Research	Stanford	California	United States	94040
5	National Jewish Health	Denver	Colorado	United States	80206
6	University Health, University of Miami Health System	Miami	Florida	United States	33136
7	University of South Florida Asthma Allergy and Immunology Clinical Research Unit	Tampa	Florida	United States	33613
8	Emory University School of Medicine, Emory Healthcare: Emory Clinic Allergy and Immunology	Atlanta	Georgia	United States	30324
9	Sinus and Allergy Center of Northwestern University	Chicago	Illinois	United States	60611
10	NorthShore University HealthSystem, Dermatology Clinical Trials Unit	Skokie	Illinois	United States	60077
11	University of Iowa Health Care	Iowa City	Iowa	United States	52242
12	Johns Hopkins Bayview Medical Center	Baltimore	Maryland	United States	21224
13	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
14	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
15	University of Michigan Health	Ann Arbor	Michigan	United States	48109
16	Henry Ford Hospital and Health System	Detroit	Michigan	United States	48202
17	Saint Louis University Care Center for Specialized Medicine	Saint Louis	Missouri	United States	63104
18	Mount Sinai Hospital, Department of Medicine, Division of Clinical Immunology	New York	New York	United States	10029
19	Columbia University Irving Medical Center	New York	New York	United States	10032
20	Rochester Regional Health	Rochester	New York	United States	14607
21	North Carolina Translational and Clinical Sciences Institute-Clinical & Translational Research Center (CTRC) at the University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
22	Cleveland Clinic, Allergy & Clinical Immunology	Cleveland	Ohio	United States	44195
23	Penn State Health Allergy, Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
24	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
25	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
26	Baylor College of Medicine Medical Center	Houston	Texas	United States	77030
27	University of Virginia Health System: Department of Medicine, Division of Allergy and Immunology	Charlottesville	Virginia	United States	22908
28	Virginia Commonwealth University, Department of Internal Medicine, Division of Rheumatology, Allergy & Immunology	Richmond	Virginia	United States	23298
29	University of Wisconsin Asthma Allergy Pulmonary Research	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Rho Federal Systems Division, Inc.

Investigators

Study Chair: James R. Baker Jr., MD, Mary H. Weiser Food Allergy Center and Michigan Nanotechnology Institute for Medicine and the Biological Sciences
Study Chair: Rebecca S. Gruchalla, MD, PhD, Division of Allergy and Immunology Departments of Internal Medicine and Pediatrics, University of Texas Southwestern
Study Chair: N. Franklin Atkinson Jr., MD, Graduate Training Program in Clinical Investigation Associate TP Director, Allergy-Immunology Johns Hopkins Asthma & Allergy Center