Open-Label Study of H5 Vaccine in Participants of Protocol 04-077

Study Overview
=================
Brief Summary
-----------------
This study may provide safety information on a flu vaccine given to children and may provide immunogenicity information to add to what was collected in a previous flu vaccine study. Participants will include 55 healthy children, ages 2-10, who participated in 04-077 and received a placebo injection instead of the flu vaccine or were incompletely immunized. The study has 2 purposes: to make sure there are no serious side effects in children and to see how the immune systems react to the vaccine. Study procedures include up to 4 study visits, up to 9 follow-up phone calls, 2 blood samples to be collected during visits 1 and 3, and up to 3 vaccine injections in the arm or thigh muscle. Parents will be given a memory aid card to record side effects, temperatures, and medications. Parents will have the option for the child to receive a 3rd dose of vaccine if offered, at month 6. This booster shot will require a 6-month visit and participation for an additional 6 months.

Detailed Description
-----------------
The recent emergence of novel influenza virus strains in human populations has encouraged efforts to develop vaccines for a potential pandemic. The objectives of this study are to evaluate the safety of intramuscular (IM) subvirion inactivated H5N1 vaccine in healthy children aged 2 through 10 years and to determine the immunogenicity profile of IM subvirion inactivated H5N1 vaccine in healthy children approximately 1 month following receipt of the second of 2 doses of vaccine. Study endpoints include: adverse event (AE) and serious adverse event (SAE) information (solicited in-clinic and via memory aids, concomitant medications, and periodic targeted physical assessments, as indicated); proportion of subjects achieving a serum hemagglutination inhibition antibody titer of 1:40 against the influenza A/H5N1 virus 28 days after receipt of second dose of vaccine (approximately Day 56); geometric mean titer and the frequency of 4-fold or greater increases in hemagglutination inhibition antibody titers 28 days after receipt of second dose of vaccine (approximately Day 56); and development of serum antibody responses against antigenically drifted variants of influenza H5N1 virus. This study is linked to DMID protocol 06-0072. Up to 55 healthy children, aged 2 through 10 years, who previously participated in DMID 04-077, will be eligible for enrollment in this multimember, open-label, phase I/II clinical trial to receive at least 2 and up to 3 doses of an inactivated influenza A/H5N1 vaccine at a 45-micrograms dose. The vaccine dosage level that will be used in this study was chosen based upon safety and immunogenicity data collected previously in adults and children. The injection volume of the 90-micrograms dose is 1 mL for the vaccine being used in this study, but this is considered unacceptable in this age group. Therefore, the 45-micrograms dose (0.5 ml volume) has been selected. Twenty three subjects who were previously enrolled and assigned to placebo in the DMID 04-077 study (A Randomized, Double-Blinded, Placebo-Controlled, Phase I/II, Study of the Safety, Reactogenicity, and Immunogenicity of Intramuscular Inactivated Influenza A/H5N1 Vaccine in Healthy Children Aged 2 Years Through 9 Years) along with up to 32 subjects from a single site who were incompletely immunized are eligible for enrollment in this study. Vaccine will be administered into the deltoid or (if age appropriate) thigh muscle. All subjects will receive 2 doses of the vaccine approximately 28 days apart. At month 6, subjects' parent(s) or guardian(s) will be called to assess the subjects for serious adverse events. Blood collection for immunogenicity studies will be at the discretion of the parent(s) or legal guardian(s). Should data evaluating a third dose of the influenza A/H5N1 vaccine show enhanced immunogenicity in pediatric subjects participating in DMID 04-077, parents/guardians of subjects who received vaccine will be offered the possibility of a third dose for their participating children.

Official Title
-----------------
Open-Label Study of Intramuscular Inactivated Influenza A/H5N1 Vaccine in Healthy Children Aged 2 Years to 10 Years

Conditions
-----------------
Influenza

Intervention / Treatment
-----------------
* Biological: Inactivated Influenza A/H5N1 Vaccine (sanofi pasteur)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The subject must be male or female, aged 2 through 10 years at enrollment, and must have participated in protocol 04-077 as a placebo recipient or a subject at the UCLA site. The subject must be in good health (and not on any chronic medications), as determined by medical history and a history-directed targeted physical examination. Parents or guardians of the subject must be able to understand and comply with planned study procedures and be available for all study visits. Parents or guardians of the subject must provide written consent prior to initiation of any study procedures, and subject may provide written assent as appropriate. Exclusion Criteria: The subject must not have a known allergy to eggs or other components of the vaccine or sensitivity or allergy to latex. The subject must not have a history of asthma or recurrent wheezing. The subject must not be undergoing immunosuppression as a result of an underlying illness or treatment. The subject must not have an active neoplastic disease or a history of any hematologic malignancy. The subject must not be using oral or parenteral steroids, inhaled steroids, or other immunosuppressive or cytotoxic drugs. Note: Subjects on nasal or topical steroids will be allowed to enroll in this study. The subject must not have a history of receiving immunoglobulin or other blood product within the 3 months prior to enrollment in this study. The subject must not receive any other inactivated vaccines within 2 weeks before or after any study vaccine or any other live vaccines within 4 weeks before or after any study vaccine in this study. The subject must not 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 (these conditions include, but are not limited to, known chronic liver disease, significant renal disease, unstable or progressive neurological disorders, diabetes mellitus, and transplant recipients). The subject must not have a history of severe reactions following immunization with contemporary influenza virus vaccines. The subject must not have an acute illness, including an axillary temperature greater than or equal to 100 degrees F or an oral temperature greater than or equal to 101 degrees F within 3 days prior to vaccination. The subject must not have received an experimental vaccine or medication within 1 month prior to enrollment in this study, or expect to receive an experimental vaccine, medication, or blood product during the 13-month study period. The subject must not have any condition that would, in the opinion of the investigator, place them at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol. The subject must not have a history of Guillain-Barré syndrome. The subject must not be participating concurrently in another clinical trial aside from DMID 04-077 (either in active phase or in follow-up phase).

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 10 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>All subjects will receive at least 2 and up to 3 doses of the vaccine approximately 28 days apart. | Biological: Inactivated Influenza A/H5N1 Vaccine (sanofi pasteur)<br>* Inactivated influenza A/H5N1 vaccine administered via intramuscular (IM) injection; dosage 45-mcg.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Solicited Adverse Events Among All Subjects | Number of subjects reporting solicited Adverse Events collected on Memory Aid for Days 0-7 post each vaccination for all subjects (systematic assessment), for any and severe severities. | Days 0-7 post each vaccination | 
| Occurrence of the Solicited Adverse Event of Body Aches, Solicited Only From Children Age 6-10 | Number of subjects reporting solicited Adverse Event of Body Aches, collected on Memory Aid for Days 0-7 post each vaccination for children age 6-10 only (systematic assessment), of any and severe severities. | Days 0-7 post each vaccination | 
| Occurrence of Unsolicited Adverse Events | Number of subjects with spontaneous reports of Adverse Events of any and severe severities. Events reported by more than 5.6% of subjects in any group are reported by MedDRA Preferred Term. | Through Day 28 after second vaccination | 
| Occurrence of Serious Adverse Events | Number of subjects with Serious Adverse Events during the 6 months after the first vaccination. | 6 months after the first vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serum Hemagglutination Inhibition (HAI) Antibody Titers of 1:40 or Greater | Number of subjects achieving serum hemagglutination inhibition antibody titer of 1:40 or greater against the influenza A/H5N1 virus after receipt of two doses of vaccine. | Day 28 after second vaccination | 
| Geometric Mean Titer of Hemagglutination Inhibition Antibody Titers | Geometric mean titer of hemagglutination inhibition antibody titers after receipt of two doses of vaccine. | Day 28 after second vaccination | 
| Number of Participants With a Four-fold or Greater Increase in Hemagglutination Inhibition Antibody Titers | Number of subjects with a 4-fold or greater increase, relative to baseline, in hemagglutination inhibition antibody titers after receipt of two doses of vaccine. | Day 28 after second vaccination | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
influenza, A/H5N1, avian influenza, vaccine