Sanofi H1N1 Influenza Vaccine Administered at Two Dose Levels in Adult and Elderly Populations

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and the body's immune response (body's defense against disease) to an experimental H1N1 influenza vaccine in healthy adult and elderly populations. The study will enroll up to 450 healthy adults ages 18 and older with no history of H1N1 infection or vaccination. Two hundred individuals will be 18-64 years old, and the other 200 will be greater than or equal to 65 years of age. Participants will be randomly assigned to 1 of 2 possible vaccine groups: group 1 will receive 15 mcg of H1N1 vaccine; group 2 will receive 30 mcg of H1N1 vaccine. Both groups will receive vaccine injections on days 0 and 21 in the arm muscle. Study procedures include: medical history, physical exam, maintaining a memory aid, and blood sample collection. Participants will be involved in study related procedures for approximately 7 months.

Detailed Description
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Recently, a novel swine-origin influenza A/H1N1 virus was identified as a significant cause of febrile respiratory illnesses in Mexico and the United States. It rapidly spread to many countries around the world, prompting the World Health Organization (WHO) to declare a pandemic on June 11, 2009. Data from several cohorts in different age groups that received licensed trivalent seasonal influenza vaccines suggest that these vaccines are unlikely to provide protection against the new virus. In addition, adults are more likely to have measurable levels of serum hemagglutination inhibition assay (HAI) or neutralizing antibody than are children. These data indicate the need to develop vaccines against the new H1N1 strain and suggest that different vaccine strategies (e.g., number of doses, need for adjuvant) may be appropriate for persons in different age groups. The primary safety objective of this study is to assess the safety of the unadjuvanted, inactivated H1N1 vaccine when administered at the 15 or 30 mcg dose. The primary immunogenicity objective is to assess the antibody response following a single dose of unadjuvanted, inactivated H1N1 vaccine, stratified by age of recipient, when administered at the 15 or 30 mcg dose. The secondary immunogenicity objective is to assess the antibody response following 2 doses of unadjuvanted, inactivated H1N1 vaccine, stratified by age of recipient, when administered at the 15 or 30 mcg dose. Participants will include up to 450 healthy adults age 18 and older who have no history of novel influenza H1N1 2009 infection or novel influenza H1N1 2009 vaccination. This is a randomized, double-blinded, Phase II study in healthy males and non-pregnant females designed to investigate the safety, reactogenicity, and immunogenicity of an inactivated influenza H1N1 virus vaccine at 2 dose levels. Subjects will be randomized into 2 dose groups, stratified by age (200 subjects per dose group with 100 subjects per age stratum, 18-64 or greater than or equal to 65 years of age) to receive intramuscular influenza H1N1 vaccine at 15 mcg (Group 1) or 30 mcg (Group 2). The H1N1 vaccine will be administered at Day 0 and Day 21. Following immunization, safety will be measured by assessment of adverse events through 21 days following the last vaccination (Day 42 for those receiving both doses and Day 21 for those who do not receive the second dose), serious adverse events and new-onset chronic medical conditions through 7 months post first vaccination (Day 201), and reactogenicity to the vaccine for 8 days following each vaccination (Day 0-7). Immunogenicity testing will include HAI and neutralizing antibody testing on serum obtained on the day of each vaccination (prior to vaccination), on Day 8-10 after each vaccination, and 21 days following the second vaccination (Day 42).

Official Title
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A Phase II Study in Healthy Adult and Elderly Populations to Assess the Safety and Immunogenicity of an Unadjuvanted Sanofi Pasteur H1N1 Influenza Vaccine Administered at Two Dose Levels

Conditions
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Influenza

Intervention / Treatment
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* Biological: Inactivated H1N1 Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are males or non-pregnant females age 18 and older, inclusive. Women of child-bearing potential (not surgically sterile via tubal ligation, bilateral oophorectomy or hysterectomy or who are not postmenopausal for greater than or equal to 1 year) must agree to practice adequate contraception that may include, but is not limited to, abstinence, monogamous relationship with vasectomized partner, barrier methods such as condoms, diaphragms, spermicides, intrauterine devices, and licensed hormonal methods during the study for at least 30 days following the last vaccination. Are in good health, as determined by vital signs, medical history to ensure any existing medical diagnoses or conditions are stable and not considered clinically significant, and targeted physical examination based on medical history. A stable chronic medical condition is defined as no change in prescription medication, dose, or frequency of medication in the last 3 months and health outcomes of the specific disease are considered to be within acceptable limits in the last 6 months. Any change that is due to change of health care provider, insurance company etc, or that is done for financial reasons, as long as in the same class of medication will not be considered a violation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome will not be considered a violation of this inclusion criterion. Are able to understand and comply with planned study procedures. Provide written informed consent prior to initiation of any study procedures. Exclusion Criteria: Have a known allergy to eggs or other components of the vaccine (including gelatin, formaldehyde, octoxinol, thimerosal, and chicken protein). Have a positive urine or serum pregnancy test within 24 hours prior to vaccination (if female of childbearing potential), or women who are breastfeeding. Have immunosuppression as a result of an underlying illness or treatment, or use of anticancer chemotherapy or radiation therapy (cytotoxic) within the preceding 36 months. Have an active neoplastic disease or a history of any hematologic malignancy. Have long term use of glucocorticoids including oral, parenteral or high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months. (Nasal and topical steroids are allowed.) Have a diagnosis of schizophrenia, bipolar disease, or other major psychiatric diagnosis. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others, within the past 10 years. Are receiving psychiatric drugs (aripiprazole, clozapine, ziprasidone, haloperidol, molindone, loxapine, thioridazine, thiothixene, pimozide, fluphenazine, risperidone, mesoridazine, quetiapine, trifluoperazine, chlorprothixene, chlorpromazine, perphenazine, trifluopromazine, olanzapine, carbamazepine, divalproex sodium, lithium carbonate or lithium citrate). Subjects who are receiving a single antidepressant drug and are stable for at least 3 months prior to enrollment, without de-compensating symptoms will be allowed to be enrolled in the study. Have a history of receiving immunoglobulin or other blood product within the 3 months prior to vaccination in this study. Received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month prior to vaccination in this study or expect to receive an experimental agent during this study (prior to the Day 201 follow-up call - 180 days after the second vaccination). Have received any live licensed vaccines within 4 weeks or inactivated licensed vaccines within 2 weeks prior to vaccination in this study or plan receipt of such vaccines within 21 days following the second vaccination. This is inclusive of seasonal influenza vaccines. Have an acute or chronic medical condition that, in the opinion of the investigator, would render vaccination unsafe, or would interfere with the evaluation of responses. Have a history of severe reactions following previous immunization with influenza virus vaccines. Have an acute illness, including an oral temperature greater than 100.4 degrees Fahrenheit, within 3 days prior to vaccination. Have any condition that would, in the opinion of the site investigator, place them at an unacceptable risk of injury or render them unable to meet the requirements of the protocol. Participated in a novel influenza H1N1 2009 vaccine study in the past two years or have a history of novel influenza H1N1 2009 infection prior to enrollment. Have known active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection. Have a history of alcohol or drug abuse in the last 5 years. Plan to travel outside of North America in the time between the first vaccination and 42 days following the first vaccination. Have a history of Guillain-Barré Syndrome. Have any condition that the investigator believes may interfere with successful completion of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Group 2: H1N1 Vaccine 30 mcg<br>200 subjects (100 subjects ages 18-64 and 100 subjects greater than or equal to age 65) to receive 30 mcg of H1N1 vaccine on Days 0 and 21. | Biological: Inactivated H1N1 Vaccine<br>* Two doses of inactivated influenza H1N1 vaccine delivered intramuscularly as 15 or 30 mcg per dose.<br>|
| Experimental: Group 1: H1N1 Vaccine 15 mcg<br>200 subjects (100 subjects ages 18-64 and 100 subjects greater than or equal to age 65) to receive 15 mcg of H1N1 vaccine on Days 0 and 21. | Biological: Inactivated H1N1 Vaccine<br>* Two doses of inactivated influenza H1N1 vaccine delivered intramuscularly as 15 or 30 mcg per dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Vaccine-associated Serious Adverse Events (SAEs) | Serious adverse events included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required in-patient hospitalization or prolongation thereof; resulted in a congenital anomaly/birth defect; or may have jeopardized the participant or required intervention to prevent one of these outcomes. Association to vaccination was determined by a study clinician licensed to make medical diagnoses. | Day 0 through Day 180 after last vaccination | 
| Number of Participants Reporting Solicited Local Reactions Based on the Functional Grading Scale After the First Vaccination | Participants maintained a memory aid to record daily the occurrence of local reactions of pain, tenderness and swelling for 8 days after vaccination (Day 0-7) based on their interference with daily activities. Participants are counted if they reported experiencing the symptom at any severity on any of the 8 days. | Day 0-7 after first vaccination | 
| Number of Participants Reporting Solicited Local Reactions Based on the Functional Grading Scale After the Second Vaccination | Participants maintained a memory aid to record daily the occurrence of local reactions of pain, tenderness and swelling for 8 days after vaccination (Day 0-7) based on their interference with daily activities. Participants are counted if they reported experiencing the symptom at any severity on any of the 8 days. | Day 0-7 after second vaccination | 
| Number of Participants Reporting Measured Injection Site Reactions of Swelling and Redness After the First Vaccination | Participants maintained a memory aid to record daily the occurrence of local reactions of swelling and redness for 8 days after vaccination (Day 0-7). If the reaction was present, the maximum diameter was measured in millimeters (mm). Participants are counted if they reported experiencing the reaction with any measurement greater than 0 mm on any of the 8 days. | Day 0-7 after first vaccination | 
| Number of Participants Reporting Measured Injection Site Reactions of Swelling and Redness After the Second Vaccination | Participants maintained a memory aid to record daily the occurrence of local reactions of swelling and redness for 8 days after vaccination (Day 0-7). If the reaction was present, the maximum diameter was measured in millimeters (mm). Participants are counted if they reported experiencing the reaction with any measurement greater than 0 mm on any of the 8 days. | Day 0-7 after second vaccination | 
| Number of Participants Reporting Solicited Systemic Reactions Based on the Functional Grading Scale After the First Vaccination | Participants maintained a memory aid to record daily the occurrence of systemic symptoms of feverishness, malaise, myalgia, headache, and nausea for 8 days after vaccination (Day 0-7) based on their interference with daily activities. Participants are counted if they reported experiencing the symptom at any severity on any of the 8 days. | Day 0-7 after first vaccination | 
| Number of Participants Reporting Solicited Systemic Reactions Based on the Functional Grading Scale After the Second Vaccination | Participants maintained a memory aid to record daily the occurrence of systemic symptoms of feverishness, malaise, myalgia, headache, and nausea for 8 days after vaccination (Day 0-7) based on their interference with daily activities. Participants are counted if they reported experiencing the symptom at any severity on any of the 8 days. | Day 0-7 after second vaccination | 
| Number of Participants Reporting Fever After the First Vaccination | Participants were provided with a thermometer and a memory aid on which to record daily oral temperatures for 8 days after vaccination (Day 0-7). The protocol defined fever as oral temperature of 38.0 degrees Celsius or higher. Participants are counted as experiencing fever if they reported oral temperatures of 38.0 degrees Celsius or higher on any of the 8 days. | Day 0-7 after first vaccination | 
| Number of Participants Reporting Fever After the Second Vaccination | Participants were provided with a thermometer and a memory aid on which to record daily oral temperatures for 8 days after vaccination (Day 0-7). The protocol defined fever as oral temperature of 38.0 degrees Celsius or higher. Participants are counted as experiencing fever if they reported oral temperatures of 38.0 degrees Celsius or higher on any of the 8 days. | Day 0-7 after second vaccination | 
| Number of Participants in the 18-64 Year Age Stratum With 4-fold or Greater HAI Antibody Titer Increases Against Influenza H1N1 2009 Virus at 8-10 Days Following 1 Dose of Vaccine | Blood was collected from all participants prior to vaccination and at the 8-10 day follow up visit for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. A participant met the threshold of a 4-fold rise in titer if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 8-10 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 8-10 titer was an increase by 4-fold or more. | Baseline and Day 8-10 after first vaccination | 
| Number of Participants in the 65 Years and Older Age Stratum With 4-fold or Greater HAI Antibody Titer Increases Against Influenza H1N1 2009 Virus at 8-10 Days Following 1 Dose of Vaccine | Blood was collected from all participants prior to vaccination and at the 8-10 day follow up visit for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. A participant met the threshold of a 4-fold rise in titer if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 8-10 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 8-10 titer was an increase by 4-fold or more. | Baseline and Day 8-10 after first vaccination | 
| Number of Participants in the 18-64 Year Age Stratum With 4-fold or Greater HAI Antibody Titer Increases Against Influenza H1N1 2009 Virus at 21 Days Following 1 Dose of Vaccine | Blood was collected from all participants prior to vaccination and at the 21 day follow up visit for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. A participant met the threshold of a 4-fold rise in titer if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 8-10 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 8-10 titer was an increase by 4-fold or more. | Baseline and Day 21 after first vaccination | 
| Number of Participants in the 65 Years and Older Age Stratum With 4-fold or Greater HAI Antibody Titer Increases Against Influenza H1N1 2009 Virus at 21 Days Following 1 Dose of Vaccine | Blood was collected from all participants prior to vaccination and at the 21 day follow up visit for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. A participant met the threshold of a 4-fold rise in titer if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 8-10 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 8-10 titer was an increase by 4-fold or more. | Baseline and Day 21 after first vaccination | 
| Number of Participants in the 18-64 Year Age Stratum With a Serum Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater Against Influenza H1N1 2009 Virus Prior to and at 8-10 Days Following 1 Dose of H1N1 Vaccine | Blood was collected from all participants prior to vaccination and at the 8-10 day follow up visit for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 1:40 or greater. | Day 0 prior to and Day 8-10 after first vaccination | 
| Number of Participants in the 65 Years and Older Age Stratum With a Serum Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater Against Influenza H1N1 2009 Virus Prior to and at 8-10 Days Following 1 Dose of H1N1 Vaccine | Blood was collected from all participants prior to vaccination and at the 8-10 day follow up visit for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 1:40 or greater. | Day 0 prior to and Day 8-10 after first vaccination | 
| Number of Participants in the 18-64 Year Age Stratum With a Serum Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater Against Influenza H1N1 2009 Virus at 21 Days Following 1 Dose of H1N1 Vaccine | Blood was collected from all participants at the 21 day follow up visit for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 1:40 or greater. | Day 21 after first vaccination | 
| Number of Participants in the 65 Years and Older Age Stratum With a Serum Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater Against Influenza H1N1 2009 Virus at 21 Days Following 1 Dose of H1N1 Vaccine | Blood was collected from all participants at the 21 day follow up visit for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 1:40 or greater. | Day 21 after first vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in the 18-64 Year Age Stratum With 4-fold or Greater HAI Antibody Titer Increases Against Influenza H1N1 2009 Virus at 8-10 and 21 Days Following 2 Doses of H1N1 Vaccine | Blood was collected from all participants prior to the initial vaccination as well as 8-10 and 21 days after the second vaccination for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. A participant met the threshold of a 4-fold rise in titer if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 21 post vaccination 2 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 21 post vaccination 2 titer was an increase by 4-fold or more. | Baseline and Day 8-10 and 21 after the second vaccination | 
| Number of Participants in the 65 Years and Older Age Stratum With 4-fold or Greater HAI Antibody Titer Increases Against Influenza H1N1 2009 Virus at 8-10 Days Following 2 Doses of H1N1 Vaccine | Blood was collected from all participants prior to the initial vaccination and 8-10 days after the second vaccination for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. A participant met the threshold of a 4-fold rise in titer if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 21 post vaccination 2 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 21 post vaccination 2 titer was an increase by 4-fold or more. | Baseline and Day 8-10 after the second vaccination | 
| Number of Participants in the 65 Years and Older Age Stratum With 4-fold or Greater HAI Antibody Titer Increases Against Influenza H1N1 2009 Virus at 21 Days Following 2 Doses of H1N1 Vaccine | Blood was collected from all participants prior to the initial vaccination and 21 days after the second vaccination for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. A participant met the threshold of a 4-fold rise in titer if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 21 post vaccination 2 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 21 post vaccination 2 titer was an increase by 4-fold or more. | Baseline and Day 21 after the second vaccination | 
| Number of Participants in the 18-64 Year Age Stratum With a Serum Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater Against Influenza H1N1 2009 Virus at 8-10 and 21 Days Following 2 Doses of H1N1 Vaccine | Blood was collected from all participants at Day 8-10 and Day 21 post second vaccination for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 1:40 or greater. | Day 8-10 and Day 21 after the second vaccination | 
| Number of Participants in the 65 Years and Older Age Stratum With a Serum Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater Against Influenza H1N1 2009 Virus at 8-10 Days Following 2 Doses of H1N1 Vaccine | Blood was collected from all participants at Day 8-10 post second vaccination for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 1:40 or greater. | Day 8-10 after the second vaccination | 
| Number of Participants in the 65 Years and Older Age Stratum With a Serum Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater Against Influenza H1N1 2009 Virus at 21 Days Following 2 Doses of H1N1 Vaccine | Blood was collected from all participants at Day 21 post second vaccination for testing in the HAI assay with Influenza H1N1 2009 virus as the assay antigen. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 1:40 or greater. | Day 21 after the second vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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H1N1, influenza A viruses, vaccine, elderly