A Study of a Seasonal Trivalent Split, Inactivated Influenza Vaccine

Study Overview
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Brief Summary
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This is a phase I, double-blind, randomized, placebo-controlled trial with two groups of participants to receive seasonal trivalent split, inactivated influenza vaccine (A/H1N1; A/H3N2 and B) or placebo (phosphate buffered saline). A total of 60 healthy male and female adults 18 through 45 years of age will be randomized to receive vaccine (30) or placebo (30).

Detailed Description
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This is a phase 1, double blinded, randomized, placebo-controlled study. The study will be conducted at 1 site in Serbia. Sixty (60) healthy male and female adults, 18 to 45 years of age, will be enrolled into the trial. Subjects will be randomized 1:1 to one of two treatment allocations: 30 to vaccine, 30 to placebo. The study will utilize a randomized block design to assure a balance of 1:1 vaccine and placebo when all subjects are enrolled. The study will be double blinded, meaning the study subjects, investigators, and the sponsor will be unaware of the treatment allocated to each subject until the clinical trial database is declared final and locked. The study should take about 5 months to complete, with each subject involved for 3 months from the day of injection. The justification for the 3 month follow up, rather than 6 month follow up is that this is an inactivated vaccine that follows very standard manufacturing practices with standard antigens. The safety of inactivated influenza vaccines is well-established. Adding length to the follow up results in delays in future testing of the vaccine for licensure.

Official Title
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A Phase 1 Double Blinded, Randomized, Placebo-Controlled Study to Examine the Safety and Immunogenicity of a Seasonal Trivalent Split, Inactivated Influenza Vaccine Produced by Torlak in Healthy Adult Volunteers in Serbia

Conditions
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Influenza, Human

Intervention / Treatment
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* Biological: Influenza vaccine, split inactivated
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female adult 18 through 45 years of age at the enrollment visit. Literate (by self-report) and willing to provide written informed consent. Healthy, as established by the medical history, physical examination, and screening laboratory evaluations. Capable and willing to complete Memory Aids and willing to return for all follow-up visits. For females, willing to utilize reliable birth control measures (e.g., intrauterine device, hormonal contraception, condoms) from Day 0 through the Day 21 visit. Exclusion Criteria: Participation in another clinical trial involving any therapy within the previous three months or planned enrollment in such a trial during the period of this study. Receipt of any non-study vaccine within 4 weeks prior to enrollment or refusal to postpone receipt of such vaccines until after the Day 21 visit. Current or recent (within 2 weeks of vaccination) acute illness with or without fever. Receipt of immune globulin or other blood products within 3 months prior to study enrollment or planned receipt of such products prior to the Day 21 visit. Chronic administration (defined as more than 14 consecutively-prescribed days) of immunosuppressants or other immune-modulating therapy within six months prior to study vaccination. (For corticosteroids, this means prednisone or equivalent, equal or more than 0.5 mg per kg per day; topical steroids are allowed.) History of asthma. Hypersensitivity after previous administration of any vaccine. Suspected or known hypersensitivity to any of the study vaccine components, including chicken or egg protein. Acute or chronic clinically significant pulmonary, cardiovascular, hepatobiliary, metabolic, neurologic, psychiatric or renal functional abnormality, as determined by medical history, physical examination or clinical laboratory screening tests, which in the opinion of the investigator, might interfere with the study objectives. History of any blood or solid organ cancer. History of thrombocytopenic purpura or known bleeding disorder. History of seizures. Known or suspected immunosuppressed or immunodeficient condition of any kind. Confirmed hepatitis B virus (HBV) or hepatitis C virus (HCV) infection Known HIV infection (self-report). Known active tuberculosis or symptoms of active tuberculosis, regardless of cause (self-report). History of chronic alcohol abuse and/or illegal drug use. Pregnancy or lactation. (A negative pregnancy test will be required before administration of study product for all women of childbearing potential.) History of Guillain-Barré Syndrome Any condition that, in the opinion of the investigator, would increase the health risk to the subject if he/she participates in the study or would interfere with the evaluation of the study objectives.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccine<br>0.5 mL of influenza vaccine, split, inactivated with 15 mcg of haemagglutination (HA) of each of 3 strains: NYMC BX-51B reassortant of B/Massachusetts/2/2012 X-181 reassortant of H1/A/California/7/2009 X-223A reassortant of H3/A/Texas/50/2012. | Biological: Influenza vaccine, split inactivated<br>* Seasonal trivalent inactivated influenza vaccine (TIV), inactivated split virion, purified by sucrose gradient ultracentrifugation. The vaccine is produced in hen's eggs, and inactivated with beta-propiolactone.<br>|
| Placebo Comparator: Placebo<br>0.5 mL of phosphate buffered saline | Other: Placebo<br>* 0.5 mL of phosphate buffered saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Immediate Adverse Events | Number of subjects with observed immediate adverse events, including allergic reaction or anaphylaxis, following administration of the study product. | 30-minute post-vaccination period. | 
| Number and Percentage of Subjects With Solicited Local Reactogenicity | Number of subjects reporting solicited local reactions (redness, swelling, induration, pain and tenderness) at the injection site post-vaccination with study vaccine or placebo | 7-day period (Days 0-6) post-vaccination. | 
| Number and Percentage of Subjects With Solicited Systemic Reactogenicity | Number of subjects reporting solicited systemic reactions (fever, fatigue/malaise, muscle aches, joint aches, chills, nausea, vomiting, and headache) post-vaccination with study vaccine or Placebo | 7-day period (Days 0-6) post-vaccination. | 
| Number and Percentage of Subjects With Occurrence of Unsolicited Adverse Events | These data are presented broadly as number per group for the study. Please see AE reporting section for more specific details on AEs. | Within 21 days post vaccination | 
| Number and Percentage of Subjects With Occurrence of Serious Adverse Events (SAE) |  | Over the entire study period (Day 90). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Seroconverted Subjects Against 3 Strains of Influenza Vaccine. | Seroconversion is defined as a serum HAI titer meeting the following criteria: pre-vaccination titer <1:10 and a post-vaccination titer ≥ 1:40 or pre-vaccination titer ≥ 1:10 and at least a four-fold increase in post-vaccination measured on Day 21. The 3 influenza strains assessed were B/Massachusetts, H1/A/California and H3/A/Texas | Day 21 | 
| Number and Percentage of Seroprotected Subjects Against 3 Strains of Influenza Vaccine | A seroprotected subject was defined as a vaccinated subject who had a serum Hemagluttination Inhibition (HAI) titer ≥ 1:40. The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas | Day 0 and Day 21 post vaccination | 
| Geometric Mean Titers (GMTs) of Serum Hemagglutination Inhibition (HAI) Antibodies Pre- (Day 0) and Post-vaccination (Day 21) for Each of the 3 Antigens | The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas | Pre- (Day 0) and post-vaccination (Day 21) | 
| Geometric Mean Fold Rises (GMFRs) of Serum (HAI) Antibodies (Post-vaccination / Pre-vaccination) for Each of the 3 Antigens. | The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas | Pre- (Day 0) and post-vaccination (Day 21) | 
| Geometric Mean Neutralization Titers of Neutralizing Antibodies (MNT) Pre- (Day 0) and Post-vaccination (Day 21) for Each of the 3 Antigens. |  | Pre- (Day 0) and post-vaccination (Day 21) | 
| Geometric Mean Fold Rises (GMFRs) of MNT (Post-vaccination / Pre-vaccination) for Each of the 3 Antigens. | The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas | Pre- (Day 0) and post-vaccination (Day 21) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Grippe, Human Flu, Human influenza