Safety Study of Pandemic Candidate Influenza Vaccines in the Elderly Population

Study Overview
=================
Brief Summary
-----------------
Influenza pandemics are caused by viruses that possess an Hemagglutinin molecule to which most of the population lacks immunity. If such virus is pathogenic to human and demonstrates the ability to transmit from person to person, the result is a global outbreak of disease that affects a high percentage of individuals in a short period of time and is likely to cause substantially increased mortality and morbidity in all countries of the world. Recently, purely avian influenza viruses, including the H5N1, H9N2 and H7N7 subtypes, have been directly transmitted to humans, raising concern over the possibility of a new influenza pandemic among the world's immunologically naive populations. In order to face this kind of situation, a pandemic influenza vaccine has to be developed.

Official Title
-----------------
A Phase III, Open, Randomized, Multicenter, Comparative Vaccination Study to Evaluate the Immunogenicity and Reactogenicity of Various Formulations of a Monovalent Candidate Pandemic Influenza A Vaccine in Individuals Over 60 Years of Age

Conditions
-----------------
Influenza, Influenza Vaccines

Intervention / Treatment
-----------------
* Biological: SB218352_15
* Biological: SB218352_8
* Biological: SB218352_4
* Biological: SB218352_2
* Biological: SB218352_8AL
* Biological: SB218352_4AL
* Biological: SB218352_2AL


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Subjects who the investigator believes that they can and will comply with the requirements of the protocol A male or female aged over 60 years at the time of vaccination. Written informed consent obtained from the subject. Exclusion criteria: Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the administration of the study vaccine, or planned use during the study period. Participation in an earlier study with a candidate pandemic H9N2 vaccine. Acute disease at the time of enrolment. Acute clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. Drug and/or alcohol dependency.

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SB218352_15 Group<br>Male and female subjects over 60 years of age, healthy or with underlying disease, received 2 doses of SB218352 pandemic influenza A formulation 1 non-adjuvanted vaccine, administered in the deltoid region of the non-dominant arm, at Day 0 and Day 21. | Biological: SB218352_15<br>* Non-adjuvanted pandemic influenza A formulation 1 vaccine<br>|
| Experimental: SB218352_8 Group<br>Male and female subjects over 60 years of age, healthy or with underlying disease, received 2 doses of SB218352 pandemic influenza A formulation 2 non-adjuvanted vaccine, administered in the deltoid region of the non-dominant arm, at Day 0 and Day 21. | Biological: SB218352_8<br>* Non-adjuvanted pandemic influenza A formulation 2 vaccine<br>|
| Experimental: SB218352_4 Group<br>Male and female subjects over 60 years of age, healthy or with underlying disease, received 2 doses of SB218352 pandemic influenza A formulation 3 non-adjuvanted vaccine, administered in the deltoid region of the non-dominant arm, at Day 0 and Day 21. | Biological: SB218352_4<br>* Non-adjuvanted pandemic influenza A formulation 3 vaccine<br>|
| Experimental: SB218352_2 Group<br>Male and female subjects over 60 years of age, healthy or with underlying disease, received 2 doses of SB218352 pandemic influenza A formulation 4 non-adjuvanted vaccine, administered in the deltoid region of the non-dominant arm, at Day 0 and Day 21. | Biological: SB218352_2<br>* Non-adjuvanted pandemic influenza A formulation 4 vaccine<br>|
| Experimental: SB218352_8AL Group<br>Male and female subjects over 60 years of age, healthy or with underlying disease, received 2 doses of SB218352 pandemic influenza A formulation 2 aluminium-adjuvanted vaccine, administered in the deltoid region of the non-dominant arm, at Day 0 and Day 21. | Biological: SB218352_8AL<br>* Pandemic influenza A formulation 2 aluminium-adjuvanted vaccine<br>|
| Experimental: SB218352_4AL Group<br>Male and female subjects over 60 years of age, healthy or with underlying disease, received 2 doses of SB218352 pandemic influenza A formulation 3 aluminium-adjuvanted vaccine, administered in the deltoid region of the non-dominant arm, at Day 0 and Day 21. | Biological: SB218352_4AL<br>* Pandemic influenza A formulation 3 aluminium-adjuvanted vaccine<br>|
| Experimental: SB218352_2AL Group<br>Male and female subjects over 60 years of age, healthy or with underlying disease, received 2 doses of SB218352 pandemic influenza A formulation 4 aluminium-adjuvanted vaccine, administered in the deltoid region of the non-dominant arm, at Day 0 and Day 21. | Biological: SB218352_2AL<br>* Pandemic influenza A formulation 4 aluminium-adjuvanted vaccine<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Haemagglutination-inhibition (HI) Antibody Titers Against the Influenza A Virus Strain Subtype H9N2 (Anti-H9N2) | Anti-H9N2 antibody titers were expressed as Geometric Mean Titers (GMTs). | At Day 10 post Dose 1 | 
| Serum HI Antibody Titers Against the Influenza A Virus Strain Subtype H9N2 (Anti-H9N2) | Anti-H9N2 antibody titers were expressed as Geometric Mean Titers (GMTs). | At Day 21 post Dose 1 | 
| Number of Seroconverted Subjects Against Influenza A Subtype H9N2 | Seroconversion rate was defined as the percentage of vaccinees who had a pre-vaccination HI titer lower than (<) 1:10 and a post-vaccination titre higher than or equal to (≥) 1:40, or a pre-vaccination titer ≥ 1:10 and a minimum four-fold increase in post-vaccination titer | At Day 10 post Dose 1 | 
| Number of Seroconverted Subjects Against Influenza A Subtype H9N2 | Seroconversion rate was defined as the percentage of vaccinees who had a pre-vaccination HI titer < 1:10 and a post-vaccination titre ≥ 1:40, or a pre-vaccination titer ≥ 1:10 and a minimum four-fold increase in post-vaccination titer | At Day 21 post Dose 1 | 
| Seroconversion Factor for Influenza A Subtype H9N2 | Seroconversion factor was defined as the fold increase in serum HI GMTs on day 10 compared to day 0. | At Day 10 post Dose 1 | 
| Seroconversion Factor for Influenza A Subtype H9N2 | Seroconversion factor was defined as the fold increase in serum HI GMTs on day 21 compared to day 0. | At Day 21 post Dose 1 | 
| Number of Seroprotected Subjects Against H9N2 | Seroprotection rate was defined as the percentage of vaccinees with a serum HI titer ≥ 1:40 after vaccination (for each vaccine strain) that usually was accepted as indicating protection. | At Day 10 post Dose 1 | 
| Number of Seroprotected Subjects Against H9N2 | Seroprotection rate was defined as the percentage of vaccinees with a serum HI titer ≥ 1:40 after vaccination (for each vaccine strain) that usually was accepted as indicating protection. | At Day 21 post Dose 1 | 
| Number of Subjects With Seroprotection Power Against H9N2 | Seroprotection power was defined as the proportion of subjects who were unprotected prior to the vaccination (HI titer < 1:40 on day 0) and had a protective post-vaccination titer of ≥ 1:40. | At Day 10 post Dose 1 | 
| Number of Subjects With Seroprotection Power Against H9N2 | Seroprotection power was defined as the proportion of subjects who were unprotected prior to the vaccination (HI titer < 1:40 on day 0) and had a protective post-vaccination titer of ≥ 1:40. | At Day 21 post Dose 1 | 
| Serum HI Antibody Titers Against the Influenza A Virus Strain Subtype H9N2 (Anti-H9N2) | Anti-H9N2 antibody titers were expressed as Geometric Mean Titers (GMTs). | At Day 21 post Dose 2 (Day 42) | 
| Serum HI Antibody Titers Against the Influenza A Virus Strain Subtype H9N2 (Anti-H9N2) | Anti-H9N2 antibody titers were expressed as Geometric Mean Titers (GMTs). | At Day 21 post Dose 3 (Day 210 for Subset 1 groups and Day 386 for Subset 2 groups) | 
| Number of Seroconverted Subjects Against Influenza A Subtype H9N2 | Seroconversion rate was defined as the percentage of vaccinees who had a pre-vaccination HI titer < 1:10 and a post-vaccination titre ≥ 1:40, or a pre-vaccination titer ≥ 1:10 and a minimum four-fold increase in postvaccination titer | At Day 21 post Dose 2 (Day 42) | 
| Number of Seroconverted Subjects Against Influenza A Subtype H9N2 | Seroconversion rate was defined as the percentage of vaccinees who had a pre-vaccination HI titer < 1:10 and a post-vaccination titre ≥ 1:40, or a pre-vaccination titer ≥ 1:10 and a minimum four-fold increase in post-vaccination titer | At Day 21 post Dose 3 (Day 210 for Subset 1 groups and Day 386 for Subset 2 groups) | 
| Seroconversion Factor for Influenza A Subtype H9N2 | Seroconversion factor defined as the fold increase in serum HI GMTs on day 21 post Dose 3 (Day 42) compared to day 0. | At Day 21 post Dose 2 (Day 42) | 
| Seroconversion Factor for Influenza A Subtype H9N2 | Seroconversion factor was defined as the fold increase in serum HI GMTs on day 21 post Dose 3 (Day 210 for Subset 1 and Day 386 for Subset 2) compared to day 0. | At Day 21 post Dose 3 (Day 210 for Subset 1 groups and Day 386 for Subset 2 groups) | 
| Number of Seroprotected Subjects Against H9N2 | Seroprotection rate was defined as the percentage of vaccinees with a serum HI titer ≥ 1:40 after vaccination (for each vaccine strain) that usually was accepted as indicating protection. | At Day 21 post Dose 2 (Day 42) | 
| Number of Seroprotected Subjects Against H9N2 | Seroprotection rate was defined as the percentage of vaccinees with a serum HI titer ≥ 1:40 after vaccination (for each vaccine strain) that usually was accepted as indicating protection. | At Day 21 post Dose 3 (Day 210 for Subset 1 groups and Day 386 for Subset 2 groups) | 
| Number of Subjects With Seroprotection Power Against H9N2 | Seroprotection power was defined as the proportion of subjects who were unprotected prior to the vaccination (HI titer < 1:40 on day 0) and had a protective post-vaccination titer of ≥ 1:40. | At Day 21 post Dose 2 (Day 42) | 
| Number of Subjects With Seroprotection Power Against H9N2 | Seroprotection power was defined as the proportion of subjects who were unprotected prior to the vaccination (HI titer < 1:40 on day 0) and had a protective post-vaccination titer of ≥ 1:40. | At Day 21 post Dose 3 (Day 210 for Subset 1 groups and Day 386 for Subset 2 groups) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | During the 30-days (Day 0-30) post vaccination | 
| Number of Subjects With Serious Adverse Events (SAEs) | A SAE was any untoward medical occurrence which resulted in death, was life-threatening, resulted in hospitalization or prolongation of hospitalization, resulted in permanent of serious physical disability or incapacity, caused a congenital anomaly or birth defect in the offspring of a subject or might have put the subject at risk based on medical or scientific judgment or necessitated intervention to prevent such an event (e.q. invasive or malignant cancers, intensive treatment in an emergency room or at home for bronchospasm, blood dyscrasias, or convulsion that do not resulted in hospitalization). | From Day 0 to Day 51 | 
| Frequency of Antigen-specific Cluster of Differentiation 4 (CD4) T-cells | Among expressed immune markers were interferon-gamma (IFN-γ) and cluster of differentiation 40 - ligand (CD40-L). | At Days 0, 10, 21 and 42 post vaccination | 
| Frequency of Antigen-specific CD4 T-cells | Among expressed immune markers were interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α). | At Days 0, 10, 21 and 42 post-vaccination | 
| Cytokine-positive CD4 T-cells Frequency | Among expressed immune markers were interleukin-2 (IL-2), interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and cluster of differentiation 40 - ligand (CD40-L). Descriptive comparison of the CMI response after Dose 1 and Dose 2 of the monovalent candidate pandemic influenza A vaccine. CMI response was determined in terms of the proportion of lymphocytes (CD4+ and CD8+ per million T cells) activated in vitro by the vaccine antigen on Days 10 and 21 after the Dose 1 and on Day 21 after Dose 2 as compared to Day 0 (pre-vaccination). The results were calculated based on the individual difference between each post-vaccination timepoint (Day 10, Day 21, Day 42) and Day 0. | At Days 10, 21 and 42 post-vaccination | 
| Frequency of Antigen-specific Cluster of Differentiation 8 (CD8) T-cells | Among expressed immune markers were interferon-gamma (IFN-γ) and cluster of differentiation 40 - ligand (CD40-L). | At Days 0, 10, 21 and 42 post-vaccination | 
| Frequency of Antigen-specific CD8 T-cells | Among expressed immune markers were interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α). | At Days 0, 10, 21 and 42 post-vaccination | 
| Cytokine-positive CD8 T-cells Frequency | Among expressed immune markers were interleukin-2 (IL-2), interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and cluster of differentiation 40 - ligand (CD40-L). Descriptive comparison of the CMI response after Dose 1 and Dose 2 of the monovalent candidate pandemic influenza A vaccine. CMI response was determined in terms of the proportion of lymphocytes (CD4+ and CD8+ per million T cells) activated in vitro by the vaccine antigen on Days 10 and 21 after the Dose 1 and on Day 21 after Dose 2 as compared to Day 0 (pre-vaccination). The results were calculated based on the individual difference between each post-vaccination timepoint (Day 10, Day 21, Day 42) and Day 0. | At Days 10, 21 and 42 post-vaccination | 
| Number of Subjects With Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness, swelling. Any = occurrence of any local symptom regardless of intensity grade. Grade 3 pain = pain which prevents normal everyday activities. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm). | During the 4-days post Dose 1 (Days 0-3), post Dose 2 (Days 21-24) and across these doses | 
| Number of Subjects With Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness, swelling. Any = occurrence of any local symptom regardless of intensity grade. Grade 3 pain = pain which prevents normal everyday activities. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm). | During the 4 Days post Dose 3 (Days 189-192 for Subset 1 groups and Days 365-368 for Subset 2 groups) | 
| Number of Subjects With Solicited General Symptoms | Assessed solicited general symptoms were arthralgia, fatigue, fever [defined as axillary temperature higher than (≥) 37.5 degrees Celsius (°C)], headache, myalgia, shivering and sweating. Any = occurrence of any solicited general symptom regardless of intensity grade or relationship to the study vaccination. Grade 3 symptom = symptoms that prevented normal activity. Grade 3 fever = axillary temperature higher than (>) 39°C. Related symptom = symptom assessed by the investigator as being casually related to the study vaccination. | During the 4-days (Day 0-3) post Dose 1 | 
| Number of Subjects With Solicited General Symptoms | Assessed solicited general symptoms were arthralgia, fatigue, fever [defined as axillary temperature higher than (≥) 37.5 degrees Celsius (°C)], headache, myalgia, shivering and sweating. Any = occurrence of any solicited general symptom regardless of intensity grade or relationship to the study vaccination. Grade 3 symptom = symptoms that prevented normal activity. Grade 3 fever = axillary temperature higher than (>) 39°C. Related symptom = symptom assessed by the investigator as being casually related to the study vaccination. | During the 4-days post Dose 2 (Days 21-24) | 
| Number of Subjects With Solicited General Symptoms | Assessed solicited general symptoms were arthralgia, fatigue, fever [defined as axillary temperature higher than (≥) 37.5 degrees Celsius (°C)], headache, myalgia, shivering and sweating. Any = occurrence of any solicited general symptom regardless of intensity grade or relationship to the study vaccination. Grade 3 symptom = symptoms that prevented normal activity. Grade 3 fever = axillary temperature higher than (>) 39°C. Related symptom = symptom assessed by the investigator as being casually related to the study vaccination. | During the 4-Days (Day 0-3) across doses 1 and 2 | 
| Number of Subjects With Solicited General Symptoms | Assessed solicited general symptoms were arthralgia, fatigue, fever [defined as axilar temperature higher than (≥) 37.5 degrees Celsius (°C)], headache, myalgia, shivering and sweating. Any = occurrence of any solicited general symptom regardless of intensity grade or relationship to the study vaccination. Grade 3 symptom = symptoms that prevented normal activity. Grade 3 fever = fever higher than (>) 39°C. Related symptom = symptom assessed by the investigator as being casually related to the study vaccination. | During the 4 Days post Dose 3 (Days 189-192 for Subset 1 groups and Days 365-368 for Subset 2 groups) | 
| Number of Subjects With Unsolicited AEs | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | During the 30-days post Dose 3 (Days 189-219 for Subset 1 groups and Days 365-395 for Subset 2 groups) | 
| Number of Subjects With SAEs | A SAE was any untoward medical occurrence which resulted in death, was life-threatening, resulted in hospitalization or prolongation of hospitalization, resulted in permanent of serious physical disability or incapacity, caused a congenital anomaly or birth defect in the offspring of a subject or might have put the subject at risk based on medical or scientific judgment or necessitated intervention to prevent such an event (e.q. invasive or malignant cancers, intensive treatment in an emergency room or at home for bronchospasm, blood dyscrasias, or convulsion that do not resulted in hospitalization). | Within the 365-day post-vaccination period (Days 0-364 for Subset 1 groups) and within the 395-day post-vaccination period (Days 0-394 for Subset 2 groups) | 
| Number of Subjects With Any SAEs | A SAE was any untoward medical occurrence which resulted in death, was life-threatening, resulted in hospitalization or prolongation of hospitalization, resulted in permanent of serious physical disability or incapacity, caused a congenital anomaly or birth defect in the offspring of a subject or might have put the subject at risk based on medical or scientific judgment or necessitated intervention to prevent such an event (e.q. invasive or malignant cancers, intensive treatment in an emergency room or at home for bronchospasm, blood dyscrasias, or convulsion that do not resulted in hospitalization). Only Subset 2 groups had available data for the specified time frame. | Up to 30-day post Dose 3 (Days 365-394) | 
| Number of Subjects With Antibody Persistence | Antibody persistence was evaluated in terms of seroprotection rate (SPR) against influenza A subtype H9N2 and seroconversion rate (SCR) against influenza A subtype H9N2. | At Days 189 and 365 | 
| Seroconversion Factor (SCF) for Influenza A Subtype H9N2. | SCF was defined as the fold increase in serum HI GMTs at the post-vaccination time points compared to Day 0, for each vaccine strain. | At Days 189 and 365 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
prophylaxis of pandemic influenza