Influenza Vaccine in Pregnant Women

Study Overview
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Brief Summary
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In pregnant women, flu may cause complications like pneumonia (infection of the lungs) or hospitalization. In the United States (US) it is recommend that all women get flu vaccine if they are going to be pregnant or deliver during the flu season but only a few studies have measured a pregnant woman's immune response (the body's defense against the flu) after getting the flu vaccine. About 200, 18-39 year old, inclusive, pregnant women in their second or third trimester (from 14 weeks of gestation to term, inclusive) will be enrolled in this US based study. Participation will be about 8 months in duration. Women will be randomized (assigned by chance) to receive either Fluzone® or Fluarix®. Blood collection will occur on Day 0 and 28 days post vaccination.

Detailed Description
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Influenza is a significant cause of morbidity and mortality in the United States (US), resulting in an average of 226,000 hospitalizations and 36,000 deaths each year. Pregnant women and infants are at an increased risk for the complications of influenza. Severe disease, emergency department visits and hospitalizations occur frequently in pregnant women and infants which are considered high risk populations. In the US, routine vaccination with inactivated trivalent influenza vaccine (TIV) is recommended for pregnant women or those who deliver during the influenza season. Few studies exist on the safety and immunogenicity of administration of seasonal inactivated TIV despite long-standing recommendations. Although influenza vaccination has been recommended during pregnancy, the rates of immunization remain low, at about 13 percent. This is a multi-site randomized, double-blind clinical trial in 200 ambulatory, medically stable 18-39 year old, inclusive, pregnant women in their second or third trimester of pregnancy (from 14 weeks of gestation to term, inclusive). Study subjects will be randomized 1:1 to receive one dose of a 2008-2009 seasonal inactivated TIV, either Fluzone® or Fluarix® (100 pregnant women per vaccine group). Once enrolled, a blood sample will be collected and each subject will receive a single 0.5 mL dose of a 2008-2009 seasonal inactivated TIV, either Fluzone® or Fluarix®. The vaccination will occur on Day 0. Subjects will be observed for approximately 15 minutes after vaccination. All subjects will maintain a memory aid recording oral temperature, and systemic and local adverse events (AEs) for 7 days after each vaccination. Subjects will be encouraged to take their temperature around the same time each day. Subjects will have a phone call on Day 2 for review of memory aid, concomitant medication assessment, and assessment of AEs. Subjects will have a phone call on Day 8 for AE assessment, concomitant medication assessment and review of memory aid. At approximately Day 28 after the vaccination, subjects will return to the clinic for immunogenicity blood sample collection, concomitant medication assessment, and assessment of any AEs. A targeted physical exam will be conducted, if indicated. At approximately Day 180 or 6 months after vaccination, subjects will have a phone call for assessment for any serious adverse events (SAEs). Unsolicited non-serious AE data will be captured Day 0 through Day 28. Maternal SAE data will be captured throughout the study period (Day 0 through Day 180, approximately 6 months after dose of vaccine). Maternal and infant SAE data will be collected when obtaining data on pregnancy outcome. Serum for immunogenicity evaluations will be obtained prior to the dose of vaccine (at Day 0); and one month after vaccination (at Day 28). Pregnancy outcome data will be captured by a review of medical records and a phone call to the subject. Data include any complications during labor and delivery for both the mother as well as the neonate, to include premature delivery or delivery by emergency cesarean section. Neonatal assessments will include but not be limited to gestational age, birth weight, Apgar scores, congenital abnormalities, infection, hematological and metabolic complications, admission to nursery or Neonatal Intensive Care Unit and the need for respiratory support. Blood samples collected will be tested in a central laboratory for the levels of hemagglutination inhibition (HAI) and microneutralization (MN) antibodies.

Official Title
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A Randomized, Double-Blind Trial on the Safety and Immunogenicity of Inactivated Trivalent Influenza Vaccine in Pregnant Women

Conditions
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Influenza

Intervention / Treatment
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* Biological: Fluzone®
* Biological: Fluarix®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant female between the ages of 18 and 39 years, inclusive. Is from 14 weeks of gestation to term, inclusive. Is in good health, as determined by vital signs (heart rate <100 bpm; blood pressure: systolic <140 mm Hg; diastolic less than or equal to 90 mm Hg; oral temperature <100.0 degrees Fahrenheit), medical history to ensure stable medical condition and a targeted physical examination based on medical history (if indicated). A stable medical condition is defined as health outcomes of the specific disease are considered to be within acceptable limits in the last 3 months. Able to understand and comply with planned study procedures. Provides written informed consent prior to initiation of any study procedures. Agrees to sign medical release for herself and her infant(s) to allow study staff to gather pregnancy outcome data, if needed per clinical site policy. Exclusion Criteria: Receipt of the 2008-2009 seasonal influenza vaccine [trivalent inactivated vaccine (TIV) or Flumist] prior to enrollment into the study. Has a known allergy to eggs, egg proteins, latex allergy or allergy to other components in the vaccines (i.e. formaldehyde, polyethylene glycol p-isooctylphenyl ether, sucrose, gelatin, polysorbate 80). Has a history of severe reactions following immunization with contemporary influenza virus vaccines. Has received any other licensed vaccines within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) prior to vaccination in this study or expects to receive a licensed product prior to Visit 4 (Day 28 visit) (except for inactivated influenza vaccine which may be received 2 weeks post vaccination with study product). Measles, mumps, rubella vaccine is permitted post-partum. Has a moderate-to-severe acute illness and/or an oral temperature greater than or equal to 100.0 degrees Fahrenheit, within 72 hours prior to vaccination. (This may result in a temporary delay of vaccination). Immunosuppression as a result of an underlying illness or treatment, or use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months. Has an active neoplastic disease, a history of any hematologic malignancy, current bleeding disorder, or taking anticoagulants. Long term use of oral or parenteral steroids, high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (nasal and topical steroids are allowed) or has received steroids for treatment of pre-term labor during this pregnancy. Has a history of receiving immunoglobulin or other blood product (with exception of Rhogam) within the 3 months prior to vaccination in this study. Has a diagnosis of a current and uncontrolled major psychiatric disorder. The subject is receiving listed psychiatric drugs (aripiprazole, clozapine, ziprasidone, haloperidol, molindone, loxapine, thioridazine, thiothixene, pimozide, fluphenazine, risperidone, mesoridazine, quetiapine, trifluoperazine, trifluopromazine, chlorprothixene, chlorpromazine, perphenazine, olanzapine, carbamazepine, divalproex sodium, lithium carbonate or lithium citrate). Subjects who are receiving an antidepressant drug and are stable for at least 3 months prior to enrollment without decompensating are allowed enrollment into the study. Known active human immunodeficiency virus, hepatitis B, or hepatitis C infection. History of alcohol or drug abuse in the 1 year prior to enrollment. Has a history of Guillain-Barré syndrome. Has a seizure disorder or is on an anti-seizure medication for a seizure disorder. Has received an experimental/investigational agent (vaccine, drug, biologic, device, blood product, or medication) during this pregnancy prior to enrollment, or expects to receive an experimental/investigational agent prior to Visit 4 (Day 28 visit). Has an acute or chronic medical condition that, in the opinion of the investigator would interfere with the evaluation of responses (this includes, but is not limited to: known chronic liver disease, significant renal disease, transplant recipients, uncontrolled diabetes, juvenile diabetes (Type 1) or advanced diabetes with renal and eye disease; diabetes controlled by diet or oral agents is acceptable). Has any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 2, Fluarix®<br>Single 0.5 mL intramuscular injection of Fluarix®. | Biological: Fluarix®<br>* Single 0.5 mL injection of the 2008-2009 seasonal inactivated trivalent influenza vaccine administered intramuscularly in the deltoid. Fluarix® contains less than 1 microgram (trace or a very small amount) thimerosal per shot.<br>|
| Experimental: Arm 1, Fluzone®<br>Single 0.5 mL intramuscular injection of Fluzone®. | Biological: Fluzone®<br>* Single 0.5 mL injection of the 2008-2009 seasonal inactivated trivalent influenza vaccine administered intramuscularly in the deltoid. Fluzone® does not contain thimerosal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Serum Hemagglutination Inhibition Assay (HAI) Antibody Titer Greater Than or Equal to 40 Against Each Antigen Included in the 2008-2009 Seasonal Inactivated Trivalent Influenza Vaccine (TIV) | Blood was collected for HAI assay at Day 0 prior to vaccination and again at 28 days following vaccination. The HAI assay was conducted with the three antigens in the 2008-2009 seasonal inactivated TIV: Influenza B antigen, H1N1 antigen, and H3N2 antigen. | Day 0 prior to and Day 28 after receiving single dose. | 
| Number of Participants Reporting Maternal Complications of Pregnancy, Labor and Delivery. | Participants were contacted after delivery, and medical records reviewed, to collect complications experienced during pregnancy, labor and delivery. The data collection process followed a prospectively-defined list of complications reported for this outcome measure, some of which may have also been reported as serious adverse events if otherwise meeting those requirements. | At time of delivery. | 
| Number of Participants Reporting Neonatal Complications. | Participants were contacted after delivery, and medical records reviewed, to collect neonatal complications. The data collection process followed a prospectively-defined list of complications reported for this outcome measure, some of which may have also been reported as serious adverse events if otherwise meeting those requirements. | At time of delivery. | 
| Number of Participants Reporting Serious Adverse Events (SAE) | Serious adverse events included any untoward medical occurrence that resulted in death of the mother, fetus or infant; was life threatening to mother, fetus or infant; was a persistent/significant disability/incapacity; required in-patient hospitalization or prolongation thereof; was a congenital anomaly/birth defect in fetus or infant; or may have jeopardized the mother, fetus or infant, or required intervention to prevent one of the outcomes. All events are included regardless of association to vaccination. | Through 6 months post vaccination. | 
| Number of Participants Reporting Unsolicited Non-serious Adverse Events Considered Associated With Vaccination | Unsolicited non-serious adverse events were collected from participants at follow up contacts, either by phone or in clinic, through 28 days after vaccination. Association to vaccination was determined by a clinician licensed to make a medical diagnosis and listed on the site's Federal Drug Administration's Form 1572. | Day 0 through Day 28 post vaccination. | 
| Number of Participants Reporting Solicited Injection Site Reactions at Each Severity Based on the Functional Grading Scale | Participants recorded a daily maximum severity at which local reactions of pain, tenderness and swelling were experienced. Mild reactions had no interference with daily activities, moderate reactions interfered with daily activity, and severe reactions were defined as preventing daily activity. Participants are reported at the highest severity experienced across the 8 days. | Days 0-7 after vaccination. | 
| Number of Participants Reporting Measured Injection Site Reactions of Swelling and Redness at Each Grade | Participants recorded a daily measured value of swelling and redness, if present. The protocol defined grading of small, medium and large, with small as less than 20 mm, medium as 20-50 mm and large as greater than 50 mm. Participants are counted at the largest measured grade experienced across the 8 day period after vaccination. | Days 0-7 after vaccination. | 
| Number of Participants Reporting Solicited Systemic Symptoms at Each Severity Based on the Functional Grading Scale | Participants recorded a daily maximum severity at which systemic symptoms of feverishness, malaise, myalgia, headache and nausea were experienced. Mild reactions had no interference with daily activities, moderate reactions interfered with daily activity, and severe reactions were defined as preventing daily activity. Participants are reported at the highest severity experienced across the 8 days. | Days 0-7 after vaccination. | 
| Number of Participants Reporting Fever Based on the Protocol-defined Grading Scale for Oral Temperature | Participants recorded a daily oral temperature on a memory aid for 8 days (Days 0-7) after vaccination. The protocol defined mild fever as oral temperatures 37.8 to less than 38 degree Celsius, moderate fever as 38 to less than 39 degrees Celsius and severe fever as oral temperatures of 39 degrees Celsius or higher. Participants are reported at the highest severity experienced across the 8 days. | Days 0-7 after vaccination. | 
| Hemagglutination Inhibition Assay (HAI) Geometric Mean Titer (GMT) Against Each Antigen in the 2008-2009 Seasonal Influenza Trivalent Influenza Vaccine | Blood was collected for HAI assay at Day 0 prior to vaccination and again at 28 days following vaccination. The HAI assay was conducted with the three antigens in the 2008-2009 seasonal inactivated TIV: Influenza B antigen, H1N1 antigen, and H3N2 antigen. | Day 0 prior to and Day 28 after receiving single dose. | 
| Number of Participants With a Four-fold or Greater Rise in HAI Antibody Titer Against Each Antigen in the 2008-2009 Seasonal Influenza Trivalent Influenza Vaccine | Blood was collected for HAI assay at Day 0 prior to vaccination and again at 28 days following vaccination. The HAI assay was conducted with the three antigens in the 2008-2009 seasonal inactivated TIV: Influenza B antigen, H1N1 antigen, and H3N2 antigen. A participant met the threshold of a four-fold increase in titer if the Day 0 titer was less than 10 (the assay's lowest level of detection) and the Day 28 titer was 40 or greater, or the Day 0 titer was greater than or equal to 10, and the Day 28 titer was an increase by four-fold or more. | Day 0 prior to and Day 28 receiving a single dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Serum Microneutralization Antibody Titer of Greater Than or Equal to 40 Against Each Antigen in the 2008-2009 TIV | Blood was collected for microneutralization assay at Day 0 prior to vaccination and again at 28 days following vaccination. The microneutralization assay was to be conducted with the three antigens in the 2008-2009 seasonal inactivated TIV: Influenza B antigen, H1N1 antigen, and H3N2 antigen. | Day 0 prior to and Day 28 after receiving a single dose. | 
| Number of Participants With a Four-fold or Greater Rise in Microneutralization Antibody Titer Against Each Antigen in the 2008-2009 TIV | Blood was collected for microneutralization assay at Day 0 prior to vaccination and again at 28 days following vaccination. The microneutralization assay was to be conducted with the three antigens in the 2008-2009 seasonal inactivated TIV: Influenza B antigen, H1N1 antigen, and H3N2 antigen. The threshold of a four-fold increase in titer would be met if the Day 0 titer was less than 10 (the assay's lowest level of detection) and the Day 28 titer was 40 or greater, or the Day 0 titer was greater than or equal to 10, and the Day 28 titer was an increase by four-fold or more. | Day 0 prior to and Day 28 receiving a single dose. | 
| Microneutralization Assay Geometric Mean Antibody Titers Against Each Antigen in the 2008-2009 TIV | Blood was collected for microneutralization assay at Day 0 prior to vaccination and again at 28 days following vaccination. The microneutralization assay was to be conducted with the three antigens in the 2008-2009 seasonal inactivated TIV: Influenza B antigen, H1N1 antigen, and H3N2 antigen. | Day 0 prior to and Day 28 after receiving a single dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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influenza, trivalent, vaccine, pregnant women