Safety and Immunogenicity of Simultaneous Tdap and IIV in Pregnant Women (Tdap/IIV)

• ClinicalTrials.gov Identifier: NCT02783170
• Recruitment Status: Completed
• First Posted: May 26, 2016
• Results First Posted: May 21, 2019
• Last Update Posted: June 11, 2019
• Sponsor: Duke University
• Collaborators: Children's Hospital Medical Center, Cincinnati; Centers for Disease Control and Prevention
• Information provided by (Responsible Party): Duke University

Study Description

Brief Summary:

This is a pilot, prospective, randomized, open-label clinical trial. During the study, pregnant women will be randomized (1:1) to receive co-administration of a single intramuscular (IM) 0.5 mL dose of US-licensed inactivated influenza vaccine (IIV) and a single intramuscular (IM) 0.5 mL dose of US-licensed Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap) or sequential administration of the vaccines (IIV followed by Tdap ~ 21 days later). Vaccines will be administered by licensed study personnel.

Prior Tdap/Td/TT and 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 7 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 the Tdap and Influenza at time points that include: prior to vaccination(s), ~21 days post vaccination(s), and at delivery. Additionally, cord blood serum will be analyzed for the same antibody titers.

Pregnant women will be followed with comprehensive obstetric and neonatal outcomes obtained from medical record review.

Condition or disease	Intervention/treatment	Phase
Pregnancy	Biological: Tetanus, Diphtheria, and Pertussis Vaccine; Biological: 2016-2017 Quadrivalent Inactivated Influenza Vaccine; Biological: 2017-2018 Quadrivalent Inactivated Influenza Vaccine	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 81 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Prospective, Randomized, Open-label Clinical Trial to Assess the Safety and Immunogenicity of Simultaneous vs Sequential Administration of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccine and Inactivated Influenza Vaccine in Pregnant Women - Pilot
• Study Start Date: September 2016
• Actual Primary Completion Date: April 3, 2018
• Actual Study Completion Date: May 10, 2018

Arms and Interventions

Arm	Intervention/treatment
Simultaneous vaccination arm; In the study arm,subjects will receive both Tdap and IIV vaccines during study visit 1.	Biological: Tetanus, Diphtheria, and Pertussis Vaccine; Other Name: Tdap; Biological: 2016-2017 Quadrivalent Inactivated Influenza Vaccine; Other Names: Flu vaccine; 2016-2017 Flu vaccine; Biological: 2017-2018 Quadrivalent Inactivated Influenza Vaccine; Other Names: Flu vaccine; 2017-2018 Flu vaccine
Sequential vaccination arm; In this study arm, subjects will receive the IIV vaccine during study visit 1. Approximately 3 weeks later, they will receive the Tdap vaccine during study visit 4.	Biological: Tetanus, Diphtheria, and Pertussis Vaccine; Other Name: Tdap; Biological: 2016-2017 Quadrivalent Inactivated Influenza Vaccine; Other Names: Flu vaccine; 2016-2017 Flu vaccine; Biological: 2017-2018 Quadrivalent Inactivated Influenza Vaccine; Other Names: Flu vaccine; 2017-2018 Flu vaccine

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Injection-site Reactions Post Tdap and IIV4 Administration [ Time Frame: 8 days post vaccine administration ]
   Percentage of injection-site reactions will be compared in simultaneous and sequential groups as determined by self-assessment via memory aid
2. Percentage of Participants With Systemic Reactions Post Tdap and IIV4 Administration - Visit 1 [ Time Frame: 8 days post vaccine administration ]
   Percentage of systemic reactions will be compared in simultaneous and sequential groups as determined by self-assessment via memory aid
3. Percentage of Participants With Systemic Reactions Post Tdap and IIV4 Administration - Visit 4 [ Time Frame: 8 days post vaccine administration ]
   Percentage of systemic reactions will be compared in simultaneous and sequential groups as determined by self-assessment via memory aid
4. Pertussis Serum Antibody Levels, as Measured by Geometric Mean Titers [ Time Frame: Pre-vaccination and approximately 21 days post vaccination and at Delivery ]
   Measurement of serum antibody levels to pertussis antigens, in maternal blood pre- and post-vaccination, maternal blood at delivery and infant cord blood obtained at delivery
5. Percentage of Subjects With Seroprotection as Determined by Diphtheria Serum Antibody Levels (Defined as ≥ 0.1 IU/mL) [ Time Frame: Pre vaccination and approximately 21 days post vaccination and at Delivery ]
   Measurement of serum antibody levels to diphtheria toxoids, in maternal blood pre- and post-vaccination, maternal blood at delivery and infant cord blood obtained at delivery
6. Percentage of Subjects With Seroprotection as Determined by Tetanus Serum Antibody Levels (Defined as ≥ 0.1 IU/mL) [ Time Frame: 21 days post vaccination ]
   Measurement of serum antibody levels to tetanus toxoids, in maternal blood pre- and post-vaccination, maternal blood at delivery and infant cord blood obtained at delivery
7. Percentage of Subjects With Seroprotection as Determined by Influenza Serum Antibody Levels (≥1:40) (Pre- and Post-immunization) and Seroconversion (4-fold Rise From Baseline or a Change From <1:10 to ≥1:40) ) [ Time Frame: Pre and 21 days post vaccination and at Delivery ]
   Measurement of serum antibody levels to influenza antigens in maternal blood and infant cord blood obtained at delivery
8. Percentage of Subjects Recruited Enrollment Period [ Time Frame: Approximately 1 year ]
   Percentage of subjects recruited during 4 month enrollment period
9. Feasibility as Measured by Participant Retention (Percentage of Participants Who Complete All Visits) [ Time Frame: Approximately 1 year ]
   Percentage of participants that completed all in-person and delivery visits
10. Feasibility Reported as Percentage of Reactogenicity Data Collected [ Time Frame: Approximately 1 year ]
    Percentage of reactogenicity data days reported (days reported / total possible days)
11. Feasibility Reported as Percentage of Adequate Biospecimens Collected [ Time Frame: Approximately 1 year ]
    Percentage of samples collected (sample timepoints collected / total possible sample timepoints)
12. Feasibility Reported as Percentage of Timely Collected Biospecimens [ Time Frame: Approximately 1 year ]
    Timeliness is defined as collected within the visit window

Secondary Outcome Measures :

1. Number of Participants With Adverse Maternal Outcomes [ Time Frame: Up to the 6-week postpartum visit ]
   The number of participants with adverse maternal outcomes at delivery. Missing data is data not collected or unavailable.
2. Number of Participants With Adverse Infant Outcomes Based on Medical Record Review [ Time Frame: approximately 2 months ]
   Number of participants with adverse infant outcomes. Missing data is data not collected or unavailable.
3. Percentage of Participants With Clinical Chorioamnionitis [ Time Frame: at the time of delivery ]
   Percentage of participants with clinical chorioamnionitis
4. Percentage of Participants With Histologic Chorioamnionitis on Surgical Pathology Examination of Placental Tissue [ Time Frame: after delivery, approximately up to 2 weeks ]
   Percentage of participants with histologic chorioamnionitis on surgical pathology examination of placental tissue
5. Feasibility as Measured by Percentage of Blood Samples in Testable Condition [ Time Frame: Approximately 1 year ]
   Percentage of blood samples received in testable condition (sufficient volume and quality)
6. Feasibility as Measured by Percentage of Blood Samples in With Sufficient Volume for Testing [ Time Frame: Approximately 1 year ]
   Percentage of blood samples received with sufficient volume for testing
7. Feasibility as Measured by Percentage of Testable Blood Samples Completed [ Time Frame: Approximately 1 year ]
   Percentage of testable (sufficient volume and quality) blood samples completed

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Pregnant, as determined by medical history; 18 - 45 years of age inclusive
2. Intention of receiving Tdap and IIV vaccines based on Advisory Committee on Immunization Practices (ACIP) recommendations
3. Willing to provide written informed consent prior to initiation of any study procedures
4. Singleton gestation ≥ 26 weeks 0 days gestation - ≤32 weeks 0 days gestation at the time of Visit 1 vaccination 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 a "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.
5. English or Spanish literate
6. 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. For subjects enrolling during the 2016-2017 influenza season: IIV/LAIV receipt during 2016-2017 influenza season prior to study enrollment

2. For subjects enrolling during the 2017-2018 influenza season: IIV/LAIV receipt during 2017-2018 influenza season prior to study enrollment

   2. Tdap/Td/TT receipt during current pregnancy prior to study enrollment 3. Has immunosuppression as a result of an underlying illness or treatment, or use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months.

   4. Has an active neoplastic disease (excluding non-melanoma skin cancer), a history of any hematologic malignancy, current bleeding disorder, or taking anticoagulants (daily low dose aspirin may be acceptable).

   5. Has a history of receiving immunoglobulin or other blood product (with exception of Rhogam) within the 3 months prior to enrollment in this study.

   6. Known to have pre-existing diabetes mellitus or an autoimmune disorder. 7. Febrile illness within the last 24 hours or an oral temperature >/= 100.4°F (>/= 38.0°C) prior to IIV or Tdap administration 8. Contraindication to IIV receipt including history of severe allergic reaction after a previous dose of any influenza vaccine; or to a vaccine component, including egg protein 9. Contraindication to Tdap receipt including history of severe allergic reaction after a previous dose of any tetanus toxoid-, diphtheria toxoid-, or pertussis antigen-containing vaccine or encephalopathy within 7 days of administration of a previous dose of a pertussis antigen-containing vaccine that is not attributable to another identifiable cause 10. Arthus-type hypersensitivity reaction following a prior dose of a tetanus toxoid-containing vaccine within the last 10 years 11. Any condition that may interfere with assessment of local injection site reactions, e.g. lymphadenectomy or obscuring tattoos 12. History of Guillain-Barré syndrome within 6 weeks of a prior dose of any tetanus toxoid-, diphtheria toxoid- or pertussis antigen-containing vaccine or influenza vaccine 13. Known or suspected impairment of immunologic function including infection with HIV, hepatitis B or C 14. Use of immunosuppressive or cytotoxic drugs except receipt of oral or parenteral (intravenous, subcutaneous or intramuscular) corticosteroids 30 or more days prior to enrollment. Persons who have used oral or parenteral corticosteroids within 12 months prior to enrollment may be enrolled if the longest course of therapy was less than 14 consecutive days and no dose was given within 30 days of enrollment. Intraarticular, bursal, tendon, or epidural injections of corticosteroids are permissible if the most recent injection was 30 or more days prior to enrolment. Persons applying topically corticosteroid in either upper arm (i.e. injection site) may be enrolled 1 or more days after their therapy is completed. Corticosteroids administered topically at non-injection sites, by inhalation or intranasally are permissible 15. Receipt of any licensed vaccine within 14 days prior to study vaccination or planning receipt of any vaccines (except study vaccines) prior to Visit 7 follow up.

   16. Receipt of live vaccine during current pregnancy. 17. High risk for preterm birth (active preterm labor, short cervix, cervical cerclage, receipt of antenatal corticosteroids for fetal lung maturity prior to Visit 1) 18. Antenatal ultrasound diagnosis of fetal growth restriction, defined as < 10th percentile estimated fetal weight for gestational age 19. Known fetal congenital anomaly, e.g. genetic abnormality or malformation based on antenatal ultrasound 20. Any condition which, in the opinion of the investigators, may pose a health risk to the subject or interfere with the evaluation of the study objectives.

   21. Anyone who is a relative of any research study personnel 22. Anyone who is an employee of any research study personnel 23. Anyone who is already enrolled or plans to enroll in another clinical trial with an investigational product. Co-enrollment in observational or behavioral intervention studies are allowed at any time.

   24. Previous participation in the study.

Contacts and Locations

Locations

United States, Georgia

Centers for Disease Control and Prevention

Atlanta, Georgia, United States

United States, North Carolina

Duke University

Durham, North Carolina, United States, 27705

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

Sponsors and Collaborators

Duke University

Children's Hospital Medical Center, Cincinnati

Centers for Disease Control and Prevention

Investigators

• Principal Investigator: Geeta Swamy, MD; Duke University

  Study Documents (Full-Text)

Documents provided by Duke University:

Study Protocol and Statistical Analysis Plan  [PDF] December 5, 2017

More Information

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT02783170
• Other Study ID Numbers: Pro00071192
• First Posted: May 26, 2016
• Results First Posted: May 21, 2019
• Last Update Posted: June 11, 2019
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Duke University:

Tdap vaccine; Flu vaccine; vaccines in pregnancy; immunizations in pregnancy; Whooping Cough; Pertussis; Influenza

Additional relevant MeSH terms:

Vaccines; Immunologic Factors; Physiological Effects of Drugs