Safety of RIV4 Versus IIV4 in Pregnant Women

• ClinicalTrials.gov Identifier: NCT03969641
• Recruitment Status: Completed
• First Posted: May 31, 2019
• Results First Posted: December 27, 2022
• Last Update Posted: January 11, 2023
• Sponsor: Duke University
• Collaborators: Children's Hospital Medical Center, Cincinnati; Boston Medical Center; Centers for Disease Control and Prevention
• Information provided by (Responsible Party): Duke University

Tracking Information

• First Submitted Date: May 28, 2019
• First Posted Date: May 31, 2019
• Results First Submitted Date: September 21, 2022
• Results First Posted Date: December 27, 2022
• Last Update Posted Date: January 11, 2023
• Actual Study Start Date: September 5, 2019
• Actual Primary Completion Date: September 29, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 12, 2022)

Number of Pregnant Women Vaccinated With RIV4 Versus IIV4 With Adverse Birth Outcomes [ Time Frame: Birth outcomes were monitored within postnatal day 28. ]

As measured by the number of women experiencing one of the following:

• Adverse birth outcome is a composite of occurrence of at least one of the following: preterm birth, spontaneous abortion, fetal death, or neonatal death.
  • Preterm birth- born alive at less than 37 weeks and 0 days gestation
  • Spontaneous abortion (SAB)- pregnancy loss prior to 20 weeks 0 days
  • Fetal death- intrauterine death of fetus at or after 20 weeks 0 days
  • Neonatal death- infant death within first 28 days of life

Original Primary Outcome Measures (submitted: May 28, 2019)

Adverse birth outcomes in pregnant women vaccinated with RIV4 versus IIV4 [ Time Frame: 12 months ]

As measured by the proportion of women experiencing one of the following:

• Adverse birth outcome is a composite of occurrence of at least one of the following: preterm birth, spontaneous abortion, fetal death, or neonatal death.

Current Secondary Outcome Measures (submitted: December 12, 2022)

• Number of Pregnant Women With Preterm Birth After RIV4 Versus IIV4 Vaccination [ Time Frame: Birth outcomes were monitored through 36 weeks 6 days gestation. ]
  Preterm birth is defined as born alive at less than 37 weeks and 0 days gestation.
• Number of Pregnant Women With Fetal or Neonatal Death After RIV4 Versus IIV4 Vaccination [ Time Frame: Birth outcomes were monitored through postnatal day 28. ]
  Fetal death is defined as intrauterine death of fetus at or after 20 weeks 0 days. Neonatal death is defined as infant death within first 28 days of life.
• Number of Pregnant Women With Spontaneous Abortion After RIV4 Versus IIV4 Vaccination [ Time Frame: Birth outcomes were monitored through 19 weeks 6 days gestation. ]
  Spontaneous abortion (SAB) is defined as pregnancy loss prior to 20 weeks 0 days.
• Number of Pregnant Women With Moderate/Severe Solicited Reactogenicity Events (Local and Systemic) Within 8 Days After Vaccination With RIV4 Versus IIV4 [ Time Frame: Reactogenicity was measured for 8 days post-vaccination. ]
  Reactogenicity events include Injection Site Pain, Injection Site Redness, Injection Site Tenderness, Injection Site Swelling, Nausea, Vomiting, Diarrhea, Abdominal Pain, Headache, Chills/Shivering, Body Rash, Fever, Malaise (Fatigue), Myalgia (Body Aches), and Joint Pain.

Original Secondary Outcome Measures (submitted: May 28, 2019)

• Preterm birth after RIV4 versus IIV4 vaccination [ Time Frame: 12 months ]
  As measured by proportions of preterm birth after RIV4 versus IIV4 vaccination
• Combined fetal and neonatal death after RIV4 versus IIV4 vaccination [ Time Frame: 12 months ]
  As measured by proportions of combined fetal and neonatal death after RIV4 versus IIV4 vaccination
• Spontaneous abortion after RIV4 versus IIV4 vaccination [ Time Frame: 12 months ]
  As measured by proportions of spontaneous abortion after RIV4 versus IIV4 vaccination
• Pregnant women with moderate/severe solicited reactogenicity events (local and systemic) within 8 days after vaccination with RIV4 versus IIV4 [ Time Frame: 8 days ]
  As measured by proportions of moderate/severe solicited reactogenicity events in pregnant women vaccinated with RIV4 versus IIV4

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety of RIV4 Versus IIV4 in Pregnant Women
• Official Title: A Prospective, Randomized, Clinical Trial to Compare Adverse Birth Outcomes in Pregnant Women Receiving Quadrivalent Recombinant Influenza Vaccine (RIV4) Versus Quadrivalent Inactivated Influenza Vaccine (IIV4)

Brief Summary

This is a prospective, randomized clinical trial. During the study, pregnant women will be randomized (1:1) to receive RIV4 or IIV4. Vaccines will be administered by licensed providers.

Prior influenza vaccine history will be verified by medical record review when possible.

Injection-site (local) and systemic reaction data will be assessed on vaccination day and during the 8 days following vaccination using either identical web-based or paper diaries, depending on study participant preference.

Maternal serum samples will be collected for antibody titers relevant to Influenza at time points that include: prior to vaccination and ~29 days post vaccination. When feasible, maternal blood at delivery and cord blood serum will be analyzed for the same antibody titers.

Pregnant women will be followed through delivery with comprehensive obstetric and neonatal outcomes obtained from medical record review for 90 days of life.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention

Condition

• Safety
• Adverse Event Following Immunisation
• Birth Outcomes

Intervention

• Biological: Quadrivalent Recombinant Influenza Vaccine
  The first recombinant inactivated influenza vaccine (RIV) using an insect baculovirus expression system and recombinant DNA technology
  Other Name: Flublok Quadrivalent
• Biological: Quadrivalent Inactivated Influenza Vaccine
  Standard inactivated influenza vaccine (IIV) manufactured involving the use of embryonated hen eggs.
  Other Name: Flulaval

Study Arms

• Experimental: RIV4
  The first recombinant inactivated influenza vaccine (RIV) using an insect baculovirus expression system and recombinant DNA technology
  Intervention: Biological: Quadrivalent Recombinant Influenza Vaccine
• Active Comparator: IIV4
  Standard inactivated influenza vaccine (IIV) manufactured involving the use of embryonated hen eggs.
  Intervention: Biological: Quadrivalent Inactivated Influenza Vaccine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 21, 2022): 384
• Original Estimated Enrollment (submitted: May 28, 2019): 360
• Actual Study Completion Date: September 29, 2021
• Actual Primary Completion Date: September 29, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Pregnant, as determined by medical history
2. Age ≥ 18 years of age at enrollment
3. Intention of receiving influenza vaccine based on ACIP-CDC guidelines
4. Willing to provide written informed consent prior to initiation of any study procedures
5. Gestational age at vaccination ≤ 34 weeks 0 days based on reconciliation of last menstrual period and ultrasound dating. Estimated due date (EDD) and Gestational Age (GA-EDD) will be based on reconciliation of "sure" first day of the last menstrual period (LMP) and earliest dating ultrasound. If the LMP is uncertain, then the earliest dating ultrasound will be used to determine EDD and GA. If the ultrasound derived-EDD is in agreement with sure-LMP derived EDD, then the LMP-derived EDD is used to determine GA. If the ultrasound derived EDD is not in agreement with the LMP-derived EDD, the ultrasound-derived EDD is used to determine GA.
6. English or Spanish literate
7. Intention of being available for entire study period and complete all relevant study procedures, including follow-up phone calls and collection of delivery information.

Exclusion Criteria:

1. Influenza vaccine receipt during 2019-2020 or 2020-2021 influenza season prior to study enrollment.
2. Participation in this study in 2019-2020 influenza season
3. Any condition that may interfere with assessment of local injection site reactions, e.g. obscuring tattoos
4. Known or suspected immunosuppression as a result of an underlying illness or treatment
5. Use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months
6. Use of oral or parenteral corticosteroids (≥ 20mg/day prednisone equivalent) or high-dose inhaled glucocorticoid for ≥ 14 consecutive days within the preceding 30 days
7. Has an active neoplastic disease (excluding non-melanoma skin cancer), a history of any hematologic malignancy, current bleeding disorder, or taking anticoagulants (a daily aspirin is acceptable)
8. Has a history of receiving immunoglobulin or other blood product (with exception of Rh immunoglobulin) within the 3 months prior to study vaccination.
9. History of febrile illness (> 100.4°F or 38°C) within the past 24 hours prior to study vaccination
10. Contraindication to IIV or RIV receipt including history of severe allergic reaction after a previous dose of any influenza vaccine; or to a vaccine component, including egg protein
11. History of Guillain-Barré syndrome within 6 weeks of a prior dose of any influenza vaccine
12. Receipt of any licensed vaccine within 7 days prior to study vaccination or intention of receiving any vaccines during 8-day post-vaccination period
13. Receipt of live vaccine during current pregnancy
14. Signs or symptoms of active preterm labor, defined as regular uterine contractions with cervical change (dilation/effacement)
15. Known multi-fetal gestation or fetal congenital anomaly, e.g. genetic abnormality or major congenital malformation based on antenatal ultrasound
16. Anyone who is already enrolled or plans to enroll in another randomized clinical trial with any drug, vaccine or medical device. Co-enrollment in observational or behavioral intervention studies are allowed at any time
17. Any condition which, in the opinion of the investigators, may pose a health risk to the participant or interfere with the evaluation of the study objectives.
18. Anyone who is a relative of any research study personnel or is an employee supervised by study staff

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03969641
• Other Study ID Numbers: Pro00101707
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Duke University
• Original Responsible Party: Same as current
• Current Study Sponsor: Duke University
• Original Study Sponsor: Same as current

Collaborators

• Children's Hospital Medical Center, Cincinnati
• Boston Medical Center
• Centers for Disease Control and Prevention

Investigators

• Principal Investigator: Geeta K Swamy, MD; Duke University
• Principal Investigator: Karen R Broder, MD; Centers for Disease Control and Prevention

• PRS Account: Duke University
• Verification Date: January 2023