A/H5N1/LT Dose Ranging Study

Study Overview
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Brief Summary
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This is a Phase 2, randomized, blinded, clinical trial. Up to 500 eligible subjects will be enrolled and randomized in a 1:2:2:1:2:2 ratio into one of six groups, and vaccinated in this study. Subjects will receive an intramuscular injection of the influenza A/H5N1 (low or high dose) on Day 0 with or without a patch (low or high dose).

Official Title
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A Randomized Blinded, LT Dose-ranging Study to Assess the Immunogenicity and Safety of Different Doses of LT Adjuvant Patch Administered in Conjunction With Different Doses of Inactivated Influenza A/H5N1 Vaccine in Healthy Adults

Conditions
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Pandemic Influenza

Intervention / Treatment
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* Biological: A/H5N1
* Biological: A/H5N1
* Biological: LT Adjuvant Patch
* Biological: LT Adjuvant Patch


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult male or females 18 to 49 years of age (inclusive) Signed Informed Consent Women who are not post-menopausal or surgically sterile must have a negative serum or urine pregnancy test at screening and within 24 hours of vaccination with understanding (through informed Consent process) to not become pregnant over the duration of the study, and must agree to employ an effective form of birth control for the duration of the study. Acceptable forms of birth control are: abstinence, hormonal contraceptives (oral, injectable, implant, patch, ring), double-barrier contraceptives (condom or diaphragm, with spermicide) and IUD Exclusion Criteria: Clinically significant laboratory abnormalities at screening Abnormalities at physical examination [as determined by the Toxicity Grading Scale (grade 1-4)] Known allergies to any component of the vaccine Known egg protein allergy Known allergies to adhesives Known disturbance of coagulation Participated in research involving investigational product within 45 days before planned date of vaccination Donated or received blood or blood products such as plasma within the past 45 days Received any licensed vaccines within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) prior to planned date of vaccination Ever received investigational enterotoxigenic E. coli, or LT (R192G) or NasalFlu, Berna Biotech Ltd Ever received cholera toxin or vaccine (e.g. Orochol, Dukoral) History of abdominal surgery (excluding C-Section, hysterectomy, cosmetic surgery, liposuction, appendectomy, cholecystectomy, ventral hernia repair, and other surgeries not pertaining to gastrointestinal problems) or history of, or recent acute gastrointestinal (GI) illness Previous vaccination with a pandemic vaccine or previous proven contact with A/H5N1 wild type virus (contact with an individual with laboratory-confirmed A/H5N1 infection or contact with an animal which died as a result of A/H5N1 infection) Recent or regular use of oral, topical or injected steroid medications within 45 days prior to vaccination Use of immunosuppressive systemic steroid medications including inhaled steroids within three months prior to vaccination Comorbid conditions or treatments that are immunosuppressive, including cancer, diabetes, and end-stage renal disease, as determined by the Investigator Positive serology for HIV-1, HIV-2, HBsAg, or HCV History of severe atopy Medical history of acute or chronic skin disease at vaccination area Active skin allergy Signs of acute skin infection, sunburn or skin abnormalities at the vaccination area including fungal infections, severe acne, active contact dermatitis, or a history of keloid formation Hirsute (significant amount of hair) at vaccination area Artificial tanning (UV radiation) over the duration of the study including the screening period Visible tattoos or marks (tattoos/scars) at the vaccination area that would prevent appropriate dermatologic monitoring of the vaccination site Fever greater than or equal to 38.0°C (100.4°F) at the time of planned vaccination Suspicion of or recent history (within one year of planned vaccination) of alcohol or substance abuse Women who are pregnant or breastfeeding Acute illness at screening or at baseline Ever had a serious reaction to prior influenza vaccination Developed a neurological disorder (such as Guillian Barré syndrome) in the six weeks following a previous influenza vaccination Medical history of achlorhydria Employee of the investigational site or sponsor History of employment in bird or poultry industries or considerable exposure to birds (e.g. poultry or avian veterinarians, bird breeders, poultry butchers and/or culler, etc.)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 30 µg HA, no LT patch<br>A/H5N1 Vaccine 30 µg HA i.m. on Day 0 | Biological: A/H5N1<br>* A/H5N1 Low Dose<br>|
| Experimental: Group 2: 30 µg HA + 50 µg LT patch<br>A/H5N1 Vaccine 30 µg HA i.m. + LT adjuvant patch containing 50 µg of LT on Day 0 | Biological: A/H5N1<br>* A/H5N1 Low Dose<br>Biological: LT Adjuvant Patch<br>* LT Adjuvant Patch Low Dose<br>|
| Experimental: Group 3: 30 µg HA + 100 µg LT patch<br>A/H5N1 Vaccine 30 µg HA i.m. + LT adjuvant patch containing 100 µg of LT on Day 0 | Biological: A/H5N1<br>* A/H5N1 Low Dose<br>Biological: LT Adjuvant Patch<br>* LT Adjuvant Patch High Dose<br>|
| Experimental: Group 4: 45 µg HA, no LT patch<br>A/H5N1 Vaccine 45 µg HA i.m. on Day 0 | Biological: A/H5N1<br>* A/H5N1 High Dose<br>|
| Experimental: Group 5: 45 µg HA + 50 µg LT patch<br>A/H5N1 Vaccine 45 µg HA i.m. + LT adjuvant patch containing 50 µg of LT on Day 0 | Biological: A/H5N1<br>* A/H5N1 High Dose<br>Biological: LT Adjuvant Patch<br>* LT Adjuvant Patch Low Dose<br>|
| Experimental: Group 6: 45 µg HA + 100 µg LT patch<br>A/H5N1 Vaccine 45 µg HA i.m. + LT adjuvant patch containing 100 µg of LT on Day 0 | Biological: A/H5N1<br>* A/H5N1 High Dose<br>Biological: LT Adjuvant Patch<br>* LT Adjuvant Patch High Dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the Proportion of Subjects in Each Dose Group Achieving Seroconversion and Seroprotection for HI Antibody Titer Through Day 28. | Seroconversion is defined as either 1) baseline HI titer < 1:10 and a post-vaccination HI titer ≥ 1:40, or 2) baseline HI titer ≥ 1:10 and a minimum four-fold rise. Seroprotection is defined as a post-vaccination HI antibody titer ≥ 1:40. FDA/EMEA criterion for seroconversion was to meet or exceed 40%. FDA/EMEA criterion for seroprotection was to meet or exceed 70%. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of A/H5N1 Vaccine IM Injection With and Without an LT Adjuvant Patch |  | 6 months | 
| Evaluate Treatment Group HI Responses Against US FDA Guidance for Industry: Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines (May 2007) and EMA CPMP/BWP/214/96 Criteria for Immunogenicity |  | Day 28 |