Seasonal Trivalent Inactivated Split Virion Influenza Vaccine Clinical Trial (IVACFLU-S) - PHASE 2/3

Study Overview
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Brief Summary
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This Phase 2/3 study assessed whether a single dose of seasonal trivalent inactivated split virion influenza vaccine (IVACFLU-S) is safe and well-tolerated in adults 18 to 60 years of age; and whether it will induce immune responses to each of the 3 vaccine antigens to meet 1 or both age group-specific Vietnam Ministry of Health (MOH) licensure requirements.

Detailed Description
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Seasonal influenza viruses circulate widely and cause disease in humans every year. Seasonal influenza viruses evolve continuously, which means that people can get infected multiple times throughout their lives. Therefore the components of seasonal influenza vaccines are reviewed frequently (currently biannually) and updated periodically to ensure continued effectiveness of the vaccines. The World Health Organization (WHO) recommended that influenza vaccines for use in the 2016-2017 northern hemisphere influenza season contain the following viruses: NYMC BX-35 reassortant of B/Brisbane/60/2008 (B) NYMC X-179A reassortant of A/California/7/2009 (H1N1) NYMC X-263B reassortant of H3/A/Hong Kong/4801/2014 (H3N2) Among circulating influenza B viruses, there were 2 distinct lineages. The B/Brisbane/60/2008-like viruses were from the influenza B/Victoria lineage and represented the predominant circulating influenza B virus. The preclinical evaluation was conducted with all 3 lots of seasonal vaccine used in the Phase 1 study.The Phase 1 study of the IVACFLU-S that was completed in March 2016 identified no safety concerns and demonstrated the vaccine to be highly immunogenic. Given the promising findings, the current study proposed to expand on the safety data of the vaccine, to confirm the immunological findings, and by including individuals up to age 60 to seek regulatory approval for indication in nonelderly adults based on the Vietnam MOH Guidance on Clinical Trial of Influenza Vaccine serological criteria for assessing seasonal influenza. Phase 2 was conducted at 1 site (District Health Center of Ben Luc, Long An, Vietnam). Subjects were from two age groups: 18-45 years and 46-60 years. Vaccine safety was determined by the Protocol Safety Review Team (PSRT) and approved by Vietnam Ministry of Health (MOH) before starting Phase 3. Phase 3 was conducted at 2 sites: District Health Center (DHC) of Ben Luc, Long An, Vietnam; and DHC of Long Thanh, Dong Nai. Subjects were from two age groups: 18-45 years and 46-60 years. Both safety and immunogenicity were assessed.

Official Title
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A Phase 2/3 Double Blinded, Randomized, Placebo-Controlled Study in Healthy Adult Volunteers in Vietnam to Examine the Safety and Immunogenicity of a Seasonal Trivalent Inactivated Split Virion Influenza Vaccine (IVACFLU-S) Produced by IVAC

Conditions
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Influenza, Human

Intervention / Treatment
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* Biological: IVACFLU-S
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Aged 18 through 60 years on the day of screening/enrollment. Literate (by self-report) and willing to provide written informed consent. Able to attend all scheduled visits and to comply with all study procedures. Healthy or medically stable, as established by medical history and physical examination. For individuals with medical conditions, symptoms/signs, if present must be stable under controlled or unchanged for the past 3 months. If medication is used to treat the condition, the medication dose must have been stable for at least 1 month preceding vaccination. For female subjects: Not breastfeeding or pregnant (based on negative urine pregnancy test) or plan to become pregnant up to Day 22. Women who are not surgically sterile (hysterectomy or tubal ligation) or post-menopausal for more than 1 year must have negative pregnancy test and, be willing to utilize reliable birth control measures (intrauterine device, hormonal contraception, condom or diaphragm with spermicide) through the Day 22 visit. Exclusion criteria: Current or recent (within 2 weeks of enrollment) acute severe illness with or without fever. Participation in another clinical study involving any therapy within the previous 3 months or planned enrollment in such a study 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 22 visit. Received seasonal influenza vaccine in last 6 months 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 22 visit. Known or suspected congenital or acquired immunodeficiency. Chronic administration (defined as more than 14 consecutively-prescribed days) of immunosuppressants or other immune-modulating therapy within 6 months prior to study enrollment. (For corticosteroids, this means prednisone or equivalent, ≥ 0.5 mg/kg/day; topical steroids are allowed). Unstable illness by history or physical examination that in the opinion of the Investigator, might interfere with the conduct or results of the study or pose additional risk to the subject. Hypersensitivity after previous administration of any vaccine. Suspected or known hypersensitivity to any of the study vaccine components, including chicken or egg protein, and rubber (from the vaccine vial stoppers). Bleeding disorder or receipt of anticoagulants in the 3 weeks preceding inclusion. Known active tuberculosis or symptoms of active tuberculosis, regardless of cause (self-report). Current alcohol or drug addiction that in the opinion of the Investigator, might interfere with the ability to comply with study procedures. History of Guillain-Barré Syndrome Neoplastic disease or any hematologic malignancy. 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: 60 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccine<br>Received one dose of IVACFLU-S vaccine intramuscularly. | Biological: IVACFLU-S<br>* IVACFLU-S is seasonal inactivated, split virion, trivalent influenza vaccine (A/H3N2, A/H1N1, and B), produced in GCP facility by IVAC uses embryonated chicken eggs. This vaccine is purified by sucrose gradient ultracentrifugation (Alfa Wassermann, West Caldwell, NJ), and inactivated with formaldehyde. Each 0.5 mL dose of vaccine contains NYMC X-179A (A/California/7/2009) (H1N1) - 15μg hemagglutinin (HA) NYMC X-263B (A/HongKong/4801/2014) (H3N2) - 15μg HA NYMC BX-35 (B/Brisbane/60/2008) (B) - 15μg HA<br>|
| Placebo Comparator: Placebo<br>Received one dose of placebo intramuscularly. | Other: Placebo<br>* Phosphate buffered saline with pH 7.2; 0.5 ml/per dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects Experiencing Solicited Local Adverse Events (AE) | Solicited local AEs were assessed by study staff 30 minutes after vaccination. | Within 30 minutes of vaccination | 
| Number and Percentage of Subjects Experiencing Solicited Systemic Adverse Events (AE) | Solicited systemic AEs were assessed by study staff 30 minutes after vaccination. | Within 30 minutes of vaccination | 
| Number and Percentage of Subjects Experiencing Solicited Local Adverse Events (AE), by Severity | Solicited local AEs were assessed by study staff 30 minutes after vaccination then daily for 7 days by the subjects. Subjects were provided a thermometer, ruler and a diary to record the presence or absence of solicited AEs, severity of the solicited AE and use of concomitant medication. AEs were graded as follows: Mild: Mild symptoms causing no or minimal interference with usual social and functional activities with intervention not indicated. Moderate: Moderate symptoms causing greater than minimal interference with usual social and functional activities with intervention indicated. Severe: Severe symptoms causing inability to perform usual social and functional activities with intervention or hospitalization indicated. Life-threatening: Potentially life-threatening symptoms causing inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability, or death. | Day 1 to Day 7 | 
| Number and Percentage of Subjects Experiencing Solicited Systemic Adverse Events (AE), by Severity | Solicited systemic AEs were assessed by study staff 30 minutes after vaccination then daily for 7 days by the subjects. Subjects were provided a thermometer, ruler and a diary to record the presence or absence of solicited AEs, severity of the solicited AE and use of concomitant medication. AEs were graded as follows: Mild: Mild symptoms causing no or minimal interference with usual social and functional activities with intervention not indicated. Moderate: Moderate symptoms causing greater than minimal interference with usual social and functional activities with intervention indicated. Severe: Severe symptoms causing inability to perform usual social and functional activities with intervention or hospitalization indicated. Life-threatening: Potentially life-threatening symptoms causing inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability, or death. | Day 1 to Day 7 | 
| Number and Percentage of Subjects Experiencing Fever | Subjects reporting body temperature by maximum severity; Grade 0: <38°C, Grade 1: 38.0 - <38.6°C, Grade 2: 38.6 - <39.3°C, Grade 3: 39.3 - <40.0°C, Grade 4: >= 40.0°C | Day 1 to Day 7 | 
| Number and Percentage of Subjects Experiencing Unsolicited Adverse Events (AE) | Unsolicited AEs were observed by study staff while the subject is at a clinic for a study visit or reported by the subject at any time. Any sign or symptom that would normally be considered a solicited AE (for example, fever, nausea, injection site pain) starting after 7 days post-vaccination was to be recorded as an unsolicited AE. The clinician determined whether there was a reasonable possibility that the investigational product(s) caused or contributed to an AE. The following guidelines were used: Related: There is a reasonable possibility that the study vaccine caused the AE. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the AE. Not Related: There is not a reasonable possibility that the administration of the study product caused the event. | Day 1 to Day 21 | 
| Number and Percentage of Subjects Experiencing Unsolicited Serious Adverse Events (SAE) | Unsolicited AEs were observed by study staff while the subject is at a clinic for a study visit or reported by the subject at any time. Any sign or symptom that would normally be considered a solicited AE (for example, fever, nausea, injection site pain) starting after 7 days post-vaccination was to be recorded as an unsolicited AE. The clinician determined whether there was a reasonable possibility that the investigational product(s) caused or contributed to an AE. The following guidelines were used: Related: There is a reasonable possibility that the study vaccine caused the AE. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the AE. Not Related: There is not a reasonable possibility that the administration of the study product caused the event. | Day 1 to Day 91 | 
| Number and Percentage of Subjects With Seroconversion of Hemagglutination Inhibition (HAI) Antibodies for Vaccine Antigens, Overall and by Age Group | Serum specimens during Phase 3 were tested for the presence and titer of HAI antibodies to each one of the influenza strains represented in the vaccine (A/H1N1, B, and A/H3N2). This testing was performed by VisMederi SRL laboratory (Siena, Italy), by using a validated assay. Sample collection on Day 1 was prior to administration of study product. Seroconversion is defined as a serum HAI antibody titer meeting the following criteria: pre-vaccination titer < 1:10 and a post-vaccination titer measured on Day 22 of ≥ 1:40, or pre-vaccination titer ≥ 1:10 and at least a 4-fold increase in post-vaccination measured on Day 22 | Day 1, Day 22 | 
| Geometric Mean Titer (GMT) of Hemagglutination Inhibition (HAI) Antibodies for Vaccine Antigens at Baseline and Day 22, Overall and by Age Group | Serum specimens during Phase 3 were tested for the presence and titer of HAI antibodies to each one of the influenza strains represented in the vaccine (A/H1N1, B, and A/H3N2). This testing was performed by VisMederi SRL laboratory (Siena, Italy), by using a validated assay. Sample collection on Day 1 was prior to administration of study product. | Day 1, Day 22 | 
| Geometric Mean Fold Change of Serum Hemagglutination Inhibition (HAI) Antibody Titer, Overall and by Age Group | Fold change in titer between Day 1 and Day 22. Serum specimens during Phase 3 were tested for the presence and titer of HAI antibodies to each one of the influenza strains represented in the vaccine (A/H1N1, B, and A/H3N2). This testing was performed by VisMederi SRL laboratory (Siena, Italy), by using a validated assay. Sample collection on Day 1 was prior to administration of study product. | Day 1, Day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects With at Least a 4-fold Increase in HAI Antibody Titer, by Strain, Age Group, and Baseline Titer | Serum specimens during Phase 3 were tested for the presence and titer of HAI antibodies to each one of the influenza strains represented in the vaccine (A/H1N1, B, and A/H3N2). This testing was performed by VisMederi SRL laboratory (Siena, Italy), by using a validated assay. Sample collection on Day 1 was prior to administration of study product. | Day 22 | 
| Geometric Mean Titer (GMT) of Hemagglutination Inhibition (HAI) Antibodies for Vaccine Antigens at Baseline and Day 22: All Subjects | Serum specimens during Phase 3 were tested for the presence and titer of HAI antibodies to each one of the influenza strains represented in the vaccine (A/H1N1, B, and A/H1N1). This testing was performed by VisMederi SRL laboratory (Siena, Italy), by using a validated assay. Sample collection on Day 1 was prior to administration of study product. | Day 1, Day 22 | 
| Geometric Mean Titer (GMT) of Hemagglutination Inhibition (HAI) Antibodies for Vaccine Antigens at Baseline and Day 22: Subjects Aged 18-45 | Serum specimens during Phase 3 were tested for the presence and titer of HAI antibodies to each one of the influenza strains represented in the vaccine (A/H1N1, B, and A/H3N2). This testing was performed by VisMederi SRL laboratory (Siena, Italy), by using a validated assay. Sample collection on Day 1 was prior to administration of study product. | Day 1, Day 22 | 
| Geometric Mean Titer (GMT) of Hemagglutination Inhibition (HAI) Antibodies for Vaccine Antigens at Baseline and Day 22: Subjects Aged 46-60 | Serum specimens during Phase 3 were tested for the presence and titer of HAI antibodies to each one of the influenza strains represented in the vaccine (A/H1N1, B, and A/H3N2). This testing was performed by VisMederi SRL laboratory (Siena, Italy), by using a validated assay. Sample collection on Day 1 was prior to administration of study product. | Day 1, Day 22 | 
| Geometric Mean Fold Change in HAI Antibody Titer, by Strain, Age Group, and Baseline Titer | Serum specimens during Phase 3 were tested for the presence and titer of HAI antibodies to each one of the influenza strains represented in the vaccine (A/H1N1, B, and A/H3N2). This testing was performed by VisMederi SRL laboratory (Siena, Italy), by using a validated assay. Sample collection on Day 1 was prior to administration of study product. | Day 1, Day 22 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza, Vaccine