The Effect of Prophylactic Antipyretics on Immune Responses and Fever After 2014-2015 and 2015-2016 Inactivated Influenza Vaccine

• ClinicalTrials.gov Identifier: NCT02212990
• Recruitment Status: Completed
• First Posted: August 11, 2014
• Last Update Posted: February 7, 2018
• Sponsor: Duke University
• Collaborator: Centers for Disease Control and Prevention
• Information provided by (Responsible Party): Duke University

Study Description

Brief Summary:

This study aims to conduct a double-blind, placebo-controlled study to assess the effect of prophylactic antipyretics on the immune responses and rates of fever after inactivated influenza vaccine (IIV) in children 6 through 47 months of age.

In this study, 160 healthy children, 6 through 47 months of age, including some children at risk of febrile seizure, will be randomized to one of three different treatment arms. Children will receive either blinded therapy with prophylactic acetaminophen or placebo immediately following and every 4 to 6 hours in the 24 hours after receipt of a dose of IIV or open-label ibuprofen every 6 to 8 hours in the 24 hours after receipt of a dose of IIV. Children will be followed for the occurrence of fever, fussiness, changes in appetite and sleep patterns, and use of medical services on the day of and for two days following vaccination. Antibody to influenza antigens contained in the respective 2014-2015 and 2015-2016 vaccines as measured by hemagglutination inhibition (HAI) antibody will be assessed at baseline and four weeks following vaccination. The proportions of children experiencing fever, having solicited side effects, using medical services, demonstrating a serologic response corresponding to seroprotection and seroconversion to each of the IIV antigens will be determined for groups of children in each of the three treatment arms. Likewise geometric mean HAI titers (GMTs) and corresponding 95% confidence intervals for each IIV antigen will be calculated for the three treatment arms. The investigators hope to learn whether or not prophylactic antipyretics affect the immune response and fever rates following IIV.

Condition or disease	Intervention/treatment	Phase
Fever	Other: Acetaminophen Arm; Other: Placebo Arm; Other: Ibuprofen Arm	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 104 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Clinical Immunization Safety Assessment (CISA): A Study to Assess the Effect of Prophylactic Antipyretics on Immune Responses and Fever After 2014-2015 and 2015-2016 Inactivated Influenza Vaccine (IIV) Administered to Children 6 Through 47 Months of Age
• Study Start Date: September 2014
• Actual Primary Completion Date: March 2016
• Actual Study Completion Date: March 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Acetaminophen Arm; Acetaminophen Suspension 160mg / 5mL Oral dose immediately following IIV and every 4 to 6 hours up to 24 hours (Maximum 5 oral doses)	Other: Acetaminophen Arm; Blinded Therapy
Placebo Comparator: Placebo Arm; Placebo Suspension Oral dose immediately following IIV and every 4 to 6 hours up to 24 hours (Maximum 5 oral doses)	Other: Placebo Arm; Blinded Therapy
Active Comparator: Ibuprofen Arm; Ibuprofen Suspension 100mg / 5mL Oral dose immediately following IIV and every 6 to 8 hours up to 24 hours (Maximum 4 oral doses)	Other: Ibuprofen Arm; Open Label Therapy

Outcome Measures

Primary Outcome Measures :

1. Seroconversion [ Time Frame: One month following the last dose of IIV ]
   Seroconversion (an HAI titer ≥ 1:40 four weeks post- vaccination if the baseline titer is < 1:10 or a four-fold rise in HAI titer if the baseline titer is ≥ 1:10) for each IIV antigen

Secondary Outcome Measures :

1. Seroprotection [ Time Frame: One month following the last dose of IIV ]
   Seroprotection (the proportion of subjects with an HAI titer >1:40) to each IIV antigen
2. Geometric mean HAI titer [ Time Frame: One month following the last dose of IIV ]
   Geometric mean HAI titer (GMT) and 95% confidence interval for each IIV antigen

Other Outcome Measures:

1. Fever [ Time Frame: Days 0, 1, and 2 following IIV ]
   Proportions of children with fever (≥ 38°C and ≥ 39°C) on days 0, 1, and 2 following IIV
2. Systemic symptoms following IIV [ Time Frame: Days 0, 1, and 2 following IIV ]
   Proportions of children with fussiness, appetite change, or altered sleep on days 0, 1, and 2 following IIV
3. Receipt of medical attention [ Time Frame: Days 0, 1, and 2 following IIV ]
   Proportions of children receiving medical attention on days 0, 1, and 2 following IIV

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 47 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. The child must be 6 through 47 months of age.
2. The child must weigh 5.4 kilograms.
3. The child must be receiving IIV this season.
4. If the child is two years of age or older and needs two doses of influenza vaccine this season the parent/guardian intends for the child to receive IIV for the second dose.
5. The parent/guardian must be willing and capable of providing written informed consent for the child.
6. The parent/guardian must be available for follow-up and must at minimum have telephone access.
7. The parent/guardian must agree to sign a medical release for the child so that study personnel may obtain medical information about the child's health (if needed).

Exclusion Criteria:

1. History of receipt of current year's licensed influenza vaccine.
2. Planned receipt of the live attenuated nasally administered influenza vaccine this year
3. History of a severe allergic reaction (e.g. anaphylaxis) to any component of influenza vaccine, including egg protein, formaldehyde, octylphenol ethoxylate, gelatin, or thimerosal if using thimerosal containing vaccine.
4. History of a severe allergic reaction (e.g. anaphylaxis) following a prior dose of influenza vaccine.
5. History of an allergic reaction following acetaminophen or ingredients in the acetaminophen product.
6. History of an allergic reaction following ibuprofen or ingredients in the ibuprofen product.
7. History of an allergic reaction following aspirin or other pain reliever or fever reducer.
8. History of liver disease.
9. Currently taking the blood thinning drug warfarin (Coumadin) or other blood thinners.
10. History of recent or planned heart surgery within the past 3 months or next 3 months.
11. History of stomach ulcer or bleeding problem.
12. Currently already routinely taking prescription or nonprescription non-steroidal anti-inflammatory drugs or NSAIDs (aspirin, ibuprofen, naproxen, or others)
13. Received any other licensed vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to vaccination in this study or expects to receive a licensed vaccine during the 28 days following the last influenza vaccination in this study. Concomitant vaccinations are not allowed.
14. Routine immunizations are delayed or will be delayed by not being able to receive a concomitantly administered vaccine or a needed vaccine in the 28 days following the last influenza vaccination in this study.
15. Received an experimental/investigational agent (vaccine, drug, biologic, device, blood product, or medication) within 28 days prior to vaccination in this study, or expects to receive an experimental/investigational agent within the follow-up time period (28 days after the last vaccination in this study).
16. A moderate to severe acute illness and/or a reported temperature greater than or equal to 100.0°F (37.8°C) within 72 hours prior to first dose of IIV or an axillary temperature greater than or equal to 100.0°F (37.8°C) at the time of enrollment. (This may result in a temporary delay of vaccination. For those needing a second dose of IIV, a moderate to severe acute illness and/or a reported temperature greater than or equal to 100.0°F (37.8°C) within 72 hours prior to second dose of IIV may result in a temporary delay of vaccination).
17. Receipt of an antipyretic medication (acetaminophen or ibuprofen) within 72 hours prior to the first dose of IIV (This may result in a temporary delay of vaccination) or is already planning to administer a prophylactic antipyretic medication on the day of and the day following any dose of IIV (this exclusion does not apply if the caretaker indicates he/she might administer antipyretics after vaccination to reduce a fever).
18. Immunosuppression as a result of an underlying illness or treatment, or use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months.
19. Long term (at least 14 days of prednisone 2 mg/kg/day or equivalent other glucocorticoid), any parenteral steroids, high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (topical and nasal steroids are allowed).
20. History of Guillain-Barré syndrome within 6 weeks of a prior dose of influenza vaccine.
21. Has any condition that would, in the opinion of the site investigator, place the participant at an unacceptable risk of injury or render the participant unable to meet the requirements of the protocol.

Contacts and Locations

Locations

United States, North Carolina

Duke University Health System

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Duke University

Centers for Disease Control and Prevention

Investigators

• Principal Investigator: Emmanuel B Walter, MD, MPH; Duke Unviersity School of Medicine
• Principal Investigator: Karen Broder, MD; Centers for Diseaes Control and Prevention

More Information

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT02212990
• Other Study ID Numbers: Pro00056213; 200-2012-53663 ( Other Grant/Funding Number: Centers for Disease Control and Prevention )
• First Posted: August 11, 2014
• Last Update Posted: February 7, 2018
• Last Verified: April 2016

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Duke University:

Fever; Antipyretics; Acetaminophen; Ibuprofen; Influenza vaccine; Influenza; Body temperature changes; Signs and symptoms

Additional relevant MeSH terms:

Influenza, Human; Fever; Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Body Temperature Changes; Acetaminophen; Ibuprofen; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Antipyretics; Anti-Inflammatory Agents, Non-Steroidal; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action