Study to Evaluate the Effectiveness of a High-Dose Quadrivalent Influenza Vaccine (QIV-HD) Compared to a Standard-Dose Quadrivalent Influenza Vaccine (QIV-SD) in Adults 65 Years of Age and Older

Study Overview
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Brief Summary
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Primary Objective: To demonstrate the superior relative effectiveness of QIV-HD as compared to QIV-SD among persons 65 years of age and older for the prevention of cardiovascular and/or respiratory hospitalizations. Secondary Objective: To assess the clinical relative effectiveness of QIV-HD as compared to QIV-SD in prevention of: inpatient hospitalization for selected circulatory and respiratory causes death, either all-cause or cardiovascular or respiratory causes inpatient hospitalization (using primary and secondary discharge diagnoses) inpatient hospitalization (using admission diagnoses) hospital emergency room visits primary care visits to physician or major acute cardiovascular events (MACE) To assess the characteristics of inpatient hospitalization or hospital emergency room visits or primary care visits to physician by QIV-HD and QIV-SD groups. To describe the clinical relative effectiveness of QIV-HD as compared to QIV-SD: by age group and by group with specific comorbidities for different periods of observation To describe all serious adverse events (SAEs) (including adverse event of special interest [AESIs]) for all subjects in both QIV-HD and QIV-SD groups.

Detailed Description
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Study duration per participant was 1 day of screening and vaccination. The study was planned to be conducted over a period of 3 influenza seasons beginning in 2019-2020. The vaccination period was from October to December.

Official Title
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Relative Effectiveness of a High-Dose Quadrivalent Influenza Vaccine Versus a Standard-Dose Quadrivalent Influenza Vaccine in Subjects 65 Years of Age and Older

Conditions
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Influenza (Healthy Volunteers)

Intervention / Treatment
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* Biological: Quadrivalent Influenza Vaccine (split virion, inactivated) High-Dose (QIV-HD)
* Biological: Standard-Dose Inactivated Influenza Vaccine Quadrivalent, Northern Hemisphere strains (QIV-SD)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: - Aged 65 years or older on the day of inclusion (65 years means from the day of the 65th birthday). Exclusion criteria: Participation at the time of study enrollment (or in the 4 weeks [28 days] preceding the study vaccination) or planned participation during the present study period in another clinical study investigating a vaccine, drug, medical device, or medical procedure. Previous vaccination against influenza (in the preceding 6 months) with either the study vaccines or another vaccine. Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccines used in the study or to a vaccine containing any of the same substances. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 65 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: Group 1: QIV-HD<br>Participants received a single injection of 0.7 milliliters (mL) high dose quadrivalent influenza vaccine (QIV-HD), intramuscularly (IM) at Day 0. | Biological: Quadrivalent Influenza Vaccine (split virion, inactivated) High-Dose (QIV-HD)<br>* Pharmaceutical form: Suspension for injection in pre-filled syringe Route of administration: Intramuscular<br>* Other names: Efluelda®;|
| Active Comparator: Group 2: QIV-SD<br>Participants received a single injection of 0.5 mL standard-dose quadrivalent influenza vaccine (QIV-SD), IM at Day 0. | Biological: Standard-Dose Inactivated Influenza Vaccine Quadrivalent, Northern Hemisphere strains (QIV-SD)<br>* Pharmaceutical form: Suspension for injection in pre-filled syringe Route of administration: Intramuscular<br>* Other names: VaxigripTetra®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Hospitalizations Due to Cardiovascular or Respiratory Diseases | Number of participants with hospitalizations due to any cardiovascular or respiratory diseases on the basis of International Classification of Diseases, Tenth Revision (ICD-10) codes as per health care professional (HCP) assessment were collected using Finnish health registers and reported in this outcome measure (OM). ICD-10 codes for respiratory system diseases: J00-J06 (acute upper respiratory infections), J09-J18 (influenza & pneumonia), J20-J22 (other acute lower respiratory infections), J40-J47 (chronic lower respiratory diseases), J80-J81 (other respiratory diseases affecting interstitium), J85-J86 (suppurative & necrotic conditions of lower respiratory tract); codes for circulatory diseases: I11 (hypertensive diseases), I20-I25 (ischemic heart diseases), I26-I27 (pulmonary heart disease & diseases of pulmonary circulation), I30, I31, I33, I38-I42, I46-I50 (other forms of heart disease), I63-I67 (cerebrovascular diseases) & I74 (diseases of arteries, arterioles & capillaries). | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Primary Discharge Diagnoses For Any Respiratory and Circulatory Systems Diseases Hospitalizations | Number of participants with primary discharge diagnoses (final diagnosis given to participant before release from hospital) for any respiratory & circulatory diseases hospitalizations on the basis of ICD-10 codes per HCP assessment were collected using Finnish health registers and reported in this OM. ICD-10 codes for respiratory system diseases were: J00-J06 (acute upper respiratory infections), J09-J18 (influenza & pneumonia), J20-J22 (other acute lower respiratory infections), J40-J47 (chronic lower respiratory diseases), J80-J81 (respiratory diseases affecting interstitium), J85-J86 (suppurative & necrotic conditions of the lower respiratory tract); and codes for circulatory system diseases were: I11 (hypertensive diseases), I20-I25 (ischemic heart diseases), I26-I27 (pulmonary heart disease & diseases of pulmonary circulation), I30, I31, I33, I38-I42, I46-I50 (other heart disease), I63-I67 (cerebrovascular diseases) and I74 (diseases of arteries, arterioles and capillaries). | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Hospitalizations Due to Cardiovascular or Respiratory Diseases: By Age Groups | Number of participants with hospitalizations due to any diseases of the respiratory or circulatory system and separately for respiratory and circulatory diseases on the basis of ICD-10 codes as per HCP assessment were collected using Finnish health registers and presented by age groups (65 to 74 years, 75 years and above and 85 years and above) in this OM. The following codes were taken into account: ICD-10 codes for any respiratory system diseases were: J00-J06, J09-J18, J20-J22, J40-J47, J80-J81, J85 and J86; and codes for any circulatory system diseases were: I11, I20-I25, I26, I27, I30, I31, I33, I38-I42, I46-I50, I63-I67 and I74. | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Percentage of Observed Cardiorespiratory Events During the Assessment Period | Percentage of observed cardiorespiratory events during the different time durations over the assessment period were reported in this OM. The following codes were taken into account: ICD-10 codes for any respiratory system diseases were: J00-J06, J09-J18, J20-J22, J40-J47, J80-J81, J85 and J86; and codes for any circulatory system diseases were: I11, I20-I25, I26, I27, I30, I31, I33, I38-I42, I46-I50, I63-I67 and I74. International Classification of Primary Care Second Edition (ICPC-2) codes: R72, R74 to R81, R83, R95 and R96; K70, K74 to K80, K82, K84, K87 and K90 to K93. | 14 to 30 days, 31 to 60 days, 61 to 90 days, 91 to 120 days and 121 days or above | 
| Duration of Cardiorespiratory Hospitalization | Duration (in days) of cardiorespiratory hospitalization was defined as stop date of event (hospitalization) minus start date of event plus 1. The following codes were taken into account: ICD-10 codes for any respiratory system diseases were: J00-J06, J09-J18, J20-J22, J40-J47, J80-J81, J85 and J86; and codes for any circulatory system diseases were: I11, I20-I25, I26, I27, I30, I31, I33, I38-I42, I46-I50, I63-I67 and I74. | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Hospitalizations Due to Cardiovascular or Respiratory Diseases: Groups With Specific Comorbidities | Number of participants with hospitalizations due to any diseases of the respiratory or circulatory system and separately for respiratory and circulatory diseases on the basis of ICD-10 codes as per HCP assessment were collected using Finnish health registers and presented by various comorbidities (diabetes, cardiovascular history and chronic lung disease) in this OM. The following codes were taken into account: ICD-10 codes for any respiratory system diseases were: J00-J06, J09-J18, J20-J22, J40-J47, J80-J81, J85 and J86; and codes for any circulatory system diseases were: I11, I20-I25, I26, I27, I30, I31, I33, I38-I42, I46-I50, I63-I67 and I74. | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Occurrences for Cardiorespiratory Diseases During Influenza Epidemic Period | The influenza epidemic period as per Finnish epidemic thresholds was defined as the period where the influenza incidence was high. The following codes were taken into account: ICD-10 codes for any respiratory system diseases were: J00-J06, J09-J18, J20-J22, J40-J47, J80-J81, J85-J86; and codes for any circulatory system diseases were: I11 and I16, I20-I25, I26-I27, I30, I31, I33, I38-I42, I46-I50, I63-I67 and I74. ICPC-2 codes: R72, R74 to R81, R83, R95 and R96; K70, K74 to K80, K82, K84, K87 and K90 to K93. | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Primary Discharge Diagnoses for Various Respiratory and Circulatory Diseases | Number of participants with primary discharge diagnoses (final diagnosis given to participant before release from hospital) due to each disease of respiratory and circulatory system on the basis of ICD-10 codes as per HCP assessment were collected using Finnish health registers and reported in this OM. The codes selected were pneumonia (J12-J18); heart failure (I50); acute myocardial infarction (I21); atrial fibrillation and flutter (I48); cerebral infarction (I63); influenza and pneumonia (J09-J18) and influenza (J09-J11). | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Deaths | Number of participants reporting death (all-cause) and due to any diseases of respiratory and circulatory system and separately due to each disease on the basis of ICD-10 codes as per HCP assessment were collected using Finnish health registers and reported in this OM. Based on ICD-10 codes, codes for any respiratory system diseases were: J00-J06, J09-J18, J20-J22, J40-J47, J80-J81, J85-J86; and codes for any circulatory system diseases were: I11, I20-I25, I26, I27, I30, I31, I33, I38-I42, I46-I50, I63-I67 and I74. Codes for pneumonia (J12-J18); heart failure (I50); acute myocardial infarction (I21); atrial fibrillation and flutter (I48); cerebral infarction (I63); influenza and pneumonia (J09-J18) and influenza (J09-J11). | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Primary and Secondary Admission Diagnoses for Respiratory and Circulatory Diseases | Number of participants with primary admission diagnosis (diagnosis given to the participant at the time of admission to hospital) and secondary admission diagnosis (diagnosis that coexist with the primary admission diagnosis at the time of admission) due to any diseases of respiratory and circulatory system and separately for each disease on the basis of ICD-10 codes as per HCP assessment were collected using Finnish health registers and reported in this OM. ICD-10 codes for any respiratory system diseases were: J00-J06, J09-J18, J20-J22, J40-J47, J80-J81, J85 and J86; and codes for any circulatory system diseases were: I11, I20-I25, I26, I27, I30, I31, I33, I38-I42, I46-I50, I63-I67 and I74. Codes for pneumonia (J12-J18); heart failure (I50); acute myocardial infarction (I21); atrial fibrillation and flutter (I48); cerebral infarction (I63); influenza and pneumonia (J09-J18) and influenza (J09-J11). | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Primary and Secondary Discharge Diagnoses for Respiratory and Circulatory Diseases | Number of participants with primary discharge diagnosis (final diagnosis given to a participant before release from the hospital) and secondary discharge diagnosis (diagnoses that coexist with the primary discharge diagnosis at the time of discharge) due to any diseases of respiratory and circulatory system and separately for each disease on the basis of ICD-10 codes as per HCP assessment were collected using Finnish health registers and reported in this OM. ICD-10 codes for any respiratory system diseases were: J00-J06, J09-J18, J20-J22, J40-J47, J80-J81, J85 and J86; and codes for any circulatory system diseases were: I11, I20-I25, I26, I27, I30, I31, I33, I38-I42, I46-I50, I63-I67 and I74. Codes for pneumonia (J12-J18); heart failure (I50); acute myocardial infarction (I21); atrial fibrillation and flutter (I48); cerebral infarction (I63); influenza and pneumonia (J09-J18) and influenza (J09-J11). | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Hospital Emergency Room Visits | Number of participants reporting hospital emergency room visits due to any diseases of respiratory and circulatory system and separately due to each disease, on the basis of ICD-10 codes as per HCP assessment were collected using Finnish health registers and reported in this OM. ICD-10 codes for any respiratory system diseases were: J00-J06, J09-J18, J20-J22, J40-J47, J80-J81, J85 and J86; and codes for any circulatory system diseases were: I11, I20-I25, I26, I27, I30, I31, I33, I38-I42, I46-I50, I63-I67 and I74. Codes for pneumonia (J12-J18); heart failure (I50); acute myocardial infarction (I21); atrial fibrillation and flutter (I48); cerebral infarction (I63); influenza and pneumonia (J09-J18) and influenza (J09-J11). | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Acute Primary Care Visits to Physician | Number of participants reporting acute primary care visits to physician due to any diseases of the respiratory and circulatory system and separately for each disease, on the basis of ICD-10 codes as per HCP assessment were collected using Finnish health registers and reported in this OM. ICD-10 codes for any respiratory system diseases were: J00-J06, J09-J18, J20-J22, J40-J47, J80-J81, J85 and J86; and codes for any circulatory system diseases were: I11, I20-I25, I26, I27, I30, I31, I33, I38-I42, I46-I50, I63-I67 and I74. Codes for pneumonia (J12-J18); heart failure (I50); acute myocardial infarction (I21); atrial fibrillation and flutter (I48); cerebral infarction (I63); influenza and pneumonia (J09-J18) and influenza (J09-J11). | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Major Acute Cardiovascular Events (MACE) | Major acute cardiovascular events (MACE) were defined by all of the following outcomes: ischemic heart diseases based on codes I20-I25, non-fatal myocardial infarction based on codes I21-I23, unstable angina based on codes I20 and I25 and fatal or non-fatal cerebral infarction based on code I63. Number of participants with MACE events on the basis of ICD-10 codes as per HCP assessment were collected using Finnish health registers and reported in this OM. | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Serious Adverse Events (SAEs), Serious Adverse Reactions (SARs), and Adverse Event of Special Interest (AESIs) | SAE: any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization/ prolongation of existing hospitalization, resulted in persistent/ significant disability/ incapacity, was congenital anomaly/ birth defect or was an important medical event. SAR: all noxious and unintended responses to study vaccine related to any dose administered that resulted in death, was life-threatening, required hospitalization/ prolongation of existing hospitalization, resulted in persistent/ significant disability/ incapacity, or was congenital anomaly or birth defect. SAR referred to potential causal relationship between study vaccine & SAE, based on assessment of healthcare professional. AESI was defined as one of scientific & medical concern specific to study for which ongoing monitoring and rapid communication by the Investigator to the Sponsor was considered appropriate. Relatedness to study vaccine was based on Investigator's discretion. | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) | 
| Number of Participants With Non-fatal SAEs | SAEs were defined as any untoward medical occurrence that at any dose was life-threatening, required inpatient hospitalization/ prolongation of existing hospitalization, resulted in persistent/ significant disability/ incapacity, was congenital anomaly/ birth defect or was an important medical event. Information on non-fatal SAEs was collected from the health registers. | From 14 days post-vaccination up to 31 May 2020 post-vaccination (i.e., up to a duration of 6 months post-vaccination) |