Safety and Immunogenicity of Fluzone® Quadrivalent and Fluzone® High-Dose, Influenza Vaccines, 2016-2017 Formulations

• Sponsor: Sanofi Pasteur, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Sanofi Pasteur, a Sanofi Company )

Study Type	Interventional
Study Design	Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
Condition	Influenza
Interventions	Biological: Fluzone Quadrivalent vaccine, 2016-2017 formulation, No Preservative; Biological: Fluzone High-Dose, vaccine, 2016-2017 formulation
Enrollment	180

Participant Flow

Recruitment Details	Study participants were enrolled in 2 centers in the United States from 15 September 2016 to 28 September 2016.
Pre-assignment Details	A total of 180 participants (60 for each group) were enrolled and vaccinated in the study.

Arm/Group Title	Fluzone Quadrivalent Vaccine Group 1: 3 to < 9 Years	Fluzone Quadrivalent Vaccine Group 2: 18 to < 65 Years	Fluzone High-Dose Vaccine Group 3: ≥ 65 Years
Arm/Group Description	Participants aged 3 to < 9 years received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per Advisory Committee on Immunization Practices (ACIP) guidance, a second dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Participants aged 18 to < 65 years received one 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0.	Participants aged ≥ 65 years received one 0.5-mL dose of Fluzone High-Dose vaccine, intramuscularly, at Day 0.
Period Title: Overall Study
Started	60	60	60
Completed	60	60	60
Not Completed	0	0	0

Baseline Characteristics

Arm/Group Title		Fluzone Quadrivalent Vaccine Group 1: 3 to < 9 Years	Fluzone Quadrivalent Vaccine Group 2: 18 to < 65 Years	Fluzone High-Dose Vaccine Group 3: ≥ 65 Years	Total
Arm/Group Description		Participants aged 3 to < 9 years received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Participants aged 18 to < 65 years received one 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0.	Participants aged ≥ 65 years received one 0.5-mL dose of Fluzone High-Dose vaccine, intramuscularly, at Day 0.	Total of all reporting groups
Overall Number of Baseline Participants		60	60	60	180
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	60 participants	60 participants	60 participants	180 participants
		6.03 (1.61)	42.2 (12.9)	72.6 (6.19)	40.3 (28.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	60 participants	60 participants	60 participants	180 participants
	Female	26	42	45	113
	Male	34	18	15	67
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	60 participants	60 participants	60 participants	180 participants
		60	60	60	180

Outcome Measures

1. Primary Outcome

Title	Number of Participants Reporting Solicited Injection Site Reactions (Pain, Erythema, and Swelling) and Systemic Reactions (Fever, Headache, Malaise, Myalgia): Group 1 (3 to < 9 Years of Age)
Description	Solicited injection site reactions: Pain (Grade 1: easily tolerated, Grade 2: sufficiently discomforting to interfere with normal behavior or activities, Grade 3: incapacitating, unable to perform usual activities), erythema & swelling (Grade 1: >0 to <25 mm;Grade 2: ≥ 25 to < 50 mm; Grade 3: ≥ 50 mm). Solicited systemic reactions: Fever (Grade 1: ≥ 38.0 degrees Celsius to ≤ 38.4 degrees Celsius, Grade 2: ≥ 38.5 degrees Celsius to ≤ 38.9 degrees Celsius, Grade 3: ≥ 39.0 degrees Celsius), headache, malaise & myalgia (Grade 1: no interference with activity, Grade 2: some interference, Grade 3: significant interference). Number of participants with any solicited injection-site & systemic reactions are reported; number of participants with Grade 3 solicited injection-site & systemic reactions are also reported.
Time Frame	Within 7 days after any vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Safety Analysis Set, which included all participants who received the study vaccine. Number of participants analyzed corresponds to participants with available data for the listed solicited reaction.

Arm/Group Title		Fluzone Quadrivalent Vaccine Group 1: 3 to < 9 Years
Arm/Group Description:		Participants aged 3 to < 9 years received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second dose of Fluzone Quadrivalent vaccine was administered at Day 28.
Overall Number of Participants Analyzed		60
Measure Type: Count of Participants; Unit of Measure: Participants
Any Injection site pain	Number Analyzed	58 participants
		18 31.0%
Grade 3 Injection site pain	Number Analyzed	58 participants
		1 1.7%
Any Injection site erythema	Number Analyzed	58 participants
		6 10.3%
Grade3 Injection site erythema	Number Analyzed	58 participants
		0 0.0%
Any Injection site swelling	Number Analyzed	58 participants
		7 12.1%
Grade3 Injection site swelling	Number Analyzed	58 participants
		0 0.0%
Any Fever	Number Analyzed	57 participants
		3 5.3%
Grade 3 Fever	Number Analyzed	57 participants
		1 1.8%
Any Headache	Number Analyzed	57 participants
		9 15.8%
Grade 3 Headache	Number Analyzed	57 participants
		0 0.0%
Any Malaise	Number Analyzed	57 participants
		15 26.3%
Grade 3 Malaise	Number Analyzed	57 participants
		1 1.8%
Any Myalgia	Number Analyzed	57 participants
		12 21.1%
Grade 3 Myalgia	Number Analyzed	57 participants
		0 0.0%

2. Primary Outcome

Title	Number of Participants Reporting Solicited Injection Site Reactions (Pain, Erythema, and Swelling) and Systemic Reactions (Fever, Headache, Malaise, Myalgia): Group 2 (18 to < 65 Years) and Group 3 (≥ 65 Years)
Description	Solicited injection site reactions: Pain (Grade 1: no interference with activity, Grade 2: some interference, Grade 3: significant; prevents daily activity), erythema & swelling (Grade 1: ≥ 25 to ≤ 50 mm; Grade 2: ≥ 51 to ≤ 100 mm; Grade 3: >100 mm). Solicited systemic reactions: Fever (Grade 1: ≥ 38.0 degrees Celsius to ≤ 38.4 degrees Celsius, Grade 2: ≥ 38.5 degrees Celsius to ≤ 38.9 degrees Celsius, Grade 3: ≥ 39.0 degrees Celsius), headache, malaise & myalgia (Grade 1: no interference with activity, Grade 2: some interference, Grade 3: significant interference). Number of participants with any solicited injection-site & systemic reactions are reported; number of participants with Grade 3 solicited injection-site & systemic reactions are also reported.
Time Frame	Within 7 days after any vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety analysis set.

Arm/Group Title	Fluzone Quadrivalent Vaccine Group 2: 18 to < 65 Years	Fluzone High-Dose Vaccine Group 3: ≥ 65 Years
Arm/Group Description:	Participants aged 18 to < 65 years received one 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0.	Participants aged ≥ 65 years received one 0.5-mL dose of Fluzone High-Dose vaccine, intramuscularly, at Day 0.
Overall Number of Participants Analyzed	60	60
Measure Type: Count of Participants; Unit of Measure: Participants
Any Injection site pain	28 46.7%	12 20.0%
Grade 3 Injection site pain	0 0.0%	0 0.0%
Any Injection site erythema	0 0.0%	3 5.0%
Grade3 Injection site erythema	0 0.0%	0 0.0%
Any Injection site swelling	0 0.0%	1 1.7%
Grade3 Injection site swelling	0 0.0%	0 0.0%
Any Fever	0 0.0%	1 1.7%
Grade 3 Fever	0 0.0%	0 0.0%
Any Headache	11 18.3%	8 13.3%
Grade 3 Headache	0 0.0%	0 0.0%
Any Malaise	10 16.7%	4 6.7%
Grade 3 Malaise	0 0.0%	0 0.0%
Any Myalgia	15 25.0%	11 18.3%
Grade 3 Myalgia	0 0.0%	0 0.0%

3. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Influenza Vaccine Antibodies (Group 1: 3 to < 9 Years)
Description	Anti-influenza antibodies were measured using hemagglutination inhibition (HAI) assay for 4 strains: H1N1, H3N2, Victoria lineage, Yamagata lineage.
Time Frame	Day 0 (pre-vaccination) and 28 days post-final vaccination (post-vaccination)

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Per-protocol Analysis Set (PPAS), which included all participants who received study vaccine and had a valid post-vaccination serology result for at least 1 strain.

Arm/Group Title		Fluzone Quadrivalent Vaccine Group 1: 3 to < 9 Years
Arm/Group Description:		Participants aged 3 to < 9 years received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second dose of Fluzone Quadrivalent vaccine was administered at Day 28.
Overall Number of Participants Analyzed		54
Geometric Mean (95% Confidence Interval); Unit of Measure: Titers (1/dilutions)
Pre-Vaccination: A/H1N1	Number Analyzed	54 participants
		273; (177 to 419)
Pre-Vaccination: A/H3N2	Number Analyzed	54 participants
		167; (106 to 265)
Pre-Vaccination: B Victoria	Number Analyzed	53 participants
		111; (63.1 to 195)
Pre-Vaccination: B Yamagata	Number Analyzed	54 participants
		170; (103 to 279)
Post-Vaccination: A/H1N1	Number Analyzed	54 participants
		1232; (961 to 1579)
Post-Vaccination: A/H3N2	Number Analyzed	54 participants
		2495; (1893 to 3289)
Post-Vaccination: B Victoria	Number Analyzed	54 participants
		1208; (807 to 1809)
Post-Vaccination: B Yamagata	Number Analyzed	54 participants
		1731; (1230 to 2435)

4. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Influenza Vaccine Antibodies (Group 2: 18 to < 65 Years)
Description	Anti-influenza antibodies were measured using hemagglutination inhibition (HAI) assay for 4 strains: H1N1, H3N2, Victoria lineage, Yamagata lineage.
Time Frame	Day 0 (pre-vaccination) and 21 days post-final vaccination (post-vaccination)

Outcome Measure Data

Analysis Population Description

Analysis was performed on PPAS.

Arm/Group Title	Fluzone Quadrivalent Vaccine Group 2: 18 to < 65 Years
Arm/Group Description:	Participants aged 18 to < 65 years received one 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0.
Overall Number of Participants Analyzed	60
Geometric Mean (95% Confidence Interval); Unit of Measure: Titers (1/dilutions)
Pre-Vaccination: A/H1N1	225; (151 to 335)
Pre-Vaccination: A/H3N2	66.1; (45.7 to 95.6)
Pre-Vaccination: B Victoria	195; (136 to 278)
Pre-Vaccination: B Yamagata	264; (181 to 386)
Post-Vaccination: A/H1N1	779; (584 to 1039)
Post-Vaccination: A/H3N2	752; (562 to 1006)
Post-Vaccination: B Victoria	998; (787 to 1267)
Post-Vaccination: B Yamagata	1470; (1114 to 1941)

5. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Influenza Vaccine Antibodies (Group 3: ≥ 65 Years)
Description	Anti-influenza antibodies were measured using hemagglutination inhibition (HAI) assay for 3 strains: H1N1, H3N2, Victoria lineage.
Time Frame	Day 0 (pre-vaccination) and 21 days post-final vaccination (post-vaccination)

Outcome Measure Data

Analysis Population Description

Analysis was performed on PPAS.

Arm/Group Title	Fluzone High-Dose Vaccine Group 3: ≥ 65 Years
Arm/Group Description:	Participants aged ≥ 65 years received one 0.5-mL dose of Fluzone High-Dose vaccine, intramuscularly, at Day 0.
Overall Number of Participants Analyzed	60
Median (95% Confidence Interval); Unit of Measure: Titers (1/dilutions)
Pre-Vaccination: A/H1N1	77.3; (51.8 to 115)
Pre-Vaccination: A/H3N2	59.6; (39.6 to 89.6)
Pre-Vaccination: B Victoria	106; (77.4 to 146)
Post-Vaccination: A/H1N1	347; (249 to 484)
Post-Vaccination: A/H3N2	590; (406 to 858)
Post-Vaccination: B Victoria	816; (607 to 1097)

6. Secondary Outcome

Title	Number of Participants With Seroprotection to Influenza Vaccine Antigens (Group 1: 3 to < 9 Years)
Description	Anti-influenza antibodies were measured using HAI assay for 4 strains: H1N1, H3N2, Victoria lineage, Yamagata lineage. Seroprotection was defined as an antibody titer ≥40 (1/dilution [dil]) at pre-vaccination and at post-final vaccination.
Time Frame	Day 0 (pre-vaccination) and 28 days post-final vaccination (post-vaccination)

Outcome Measure Data

Analysis Population Description

Analysis was performed on PPAS.

Arm/Group Title		Fluzone Quadrivalent Vaccine Group 1: 3 to < 9 Years
Arm/Group Description:		Participants aged 3 to < 9 years received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second dose of Fluzone Quadrivalent vaccine was administered at Day 28.
Overall Number of Participants Analyzed		54
Measure Type: Count of Participants; Unit of Measure: Participants
Pre-Vaccination: A/H1N1	Number Analyzed	54 participants
		46 85.2%
Pre-Vaccination: A/H3N2	Number Analyzed	54 participants
		47 87.0%
Pre-Vaccination: B Victoria	Number Analyzed	53 participants
		35 66.0%
Pre-Vaccination: B Yamagata	Number Analyzed	54 participants
		41 75.9%
Post-Vaccination: A/H1N1	Number Analyzed	54 participants
		54 100.0%
Post-Vaccination: A/H3N2	Number Analyzed	54 participants
		54 100.0%
Post-Vaccination: B Victoria	Number Analyzed	54 participants
		52 96.3%
Post-Vaccination: B Yamagata	Number Analyzed	54 participants
		53 98.1%

7. Secondary Outcome

Title	Number of Participants With Seroprotection to Influenza Vaccine Antigens (Group 2: 18 to < 65 Years)
Description	Anti-influenza antibodies were measured using HAI assay for 4 strains: H1N1, H3N2, Victoria lineage, Yamagata lineage. Seroprotection was defined as an antibody titer ≥ 40 (1/dilution [dil]) at pre-vaccination and at post-final vaccination.
Time Frame	Day 0 (pre-vaccination) and 21 days post-final vaccination (post-vaccination)

Outcome Measure Data

Analysis Population Description

Analysis was performed on PPAS.

Arm/Group Title	Fluzone Quadrivalent Vaccine Group 2: 18 to < 65 Years
Arm/Group Description:	Participants aged 18 to < 65 years received one 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0.
Overall Number of Participants Analyzed	60
Measure Type: Count of Participants; Unit of Measure: Participants
Pre-Vaccination: A/H1N1	53 88.3%
Pre-Vaccination: A/H3N2	40 66.7%
Pre-Vaccination: B Victoria	52 86.7%
Pre-Vaccination: B Yamagata	56 93.3%
Post-Vaccination: A/H1N1	60 100.0%
Post-Vaccination: A/H3N2	60 100.0%
Post-Vaccination: B Victoria	60 100.0%
Post-Vaccination: B Yamagata	60 100.0%

8. Secondary Outcome

Title	Number of Participants With Seroprotection to Influenza Vaccine Antigens (Group 3: ≥ 65 Years)
Description	Anti-influenza antibodies were measured using HAI assay for 3 strains: H1N1, H3N2, Victoria lineage. Seroprotection was defined as an antibody titer ≥ 40 (1/dilution [dil]) at pre-vaccination and at post-final vaccination.
Time Frame	Day 0 (pre-vaccination) and 21 days post-final vaccination (post-vaccination)

Outcome Measure Data

Analysis Population Description

Analysis was performed on PPAS.

Arm/Group Title	Fluzone High-Dose Vaccine Group 3: ≥ 65 Years
Arm/Group Description:	Participants aged ≥ 65 years received one 0.5-mL dose of Fluzone High-Dose vaccine, intramuscularly, at Day 0.
Overall Number of Participants Analyzed	60
Measure Type: Count of Participants; Unit of Measure: Participants
Pre-Vaccination: A/H1N1	41 68.3%
Pre-Vaccination: A/H3N2	39 65.0%
Pre-Vaccination: B Victoria	51 85.0%
Post-Vaccination: A/H1N1	56 93.3%
Post-Vaccination: A/H3N2	58 96.7%
Post-Vaccination: B Victoria	60 100.0%

Adverse Events

Time Frame	Adverse event (AE) data were collected from Day 0 (post-vaccination) up to Day 56 for Group 1; up to Day 21 for Groups 2 and 3.
Adverse Event Reporting Description	A solicited reaction is an AE that is prelisted in the electronic Case Report Form (eCRF) and considered to be related to vaccination. A solicited reaction is therefore an adverse drug reaction (ADR) observed and reported under the conditions (nature and time to onset) prelisted (i.e., solicited) in the eCRF. An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the eCRF in terms of symptom and/or time to onset post-vaccination.
Arm/Group Title	Fluzone Quadrivalent Vaccine Group 1: 3 to < 9 Years	Fluzone Quadrivalent Vaccine Group 2: 18 to < 65 Years	Fluzone High-Dose Vaccine Group 3: ≥ 65 Years
Arm/Group Description	Participants aged 3 to < 9 years received a 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0. For participants for whom 2 doses of influenza vaccine were recommended per ACIP guidance, a second dose of Fluzone Quadrivalent vaccine was administered at Day 28.	Participants aged 18 to < 65 years received one 0.5-mL dose of Fluzone Quadrivalent vaccine, intramuscularly, at Day 0.	Participants aged ≥ 65 years received one 0.5-mL dose of Fluzone High-Dose vaccine, intramuscularly, at Day 0.
All-Cause Mortality
	Fluzone Quadrivalent Vaccine Group 1: 3 to < 9 Years	Fluzone Quadrivalent Vaccine Group 2: 18 to < 65 Years	Fluzone High-Dose Vaccine Group 3: ≥ 65 Years
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/60 (0.00%)	0/60 (0.00%)	0/60 (0.00%)
Serious Adverse Events
	Fluzone Quadrivalent Vaccine Group 1: 3 to < 9 Years	Fluzone Quadrivalent Vaccine Group 2: 18 to < 65 Years	Fluzone High-Dose Vaccine Group 3: ≥ 65 Years
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/60 (1.67%)	0/60 (0.00%)	2/60 (3.33%)
Cardiac disorders
Atrial fibrillation † 1	0/60 (0.00%)	0/60 (0.00%)	1/60 (1.67%)
Infections and infestations
Pneumonia † 1	0/60 (0.00%)	0/60 (0.00%)	1/60 (1.67%)
Sepsis † 1	0/60 (0.00%)	0/60 (0.00%)	1/60 (1.67%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain † 1	0/60 (0.00%)	0/60 (0.00%)	1/60 (1.67%)
Renal and urinary disorders
Acute kidney injury † 1	0/60 (0.00%)	0/60 (0.00%)	1/60 (1.67%)
Respiratory, thoracic and mediastinal disorders
Asthma † 1	1/60 (1.67%)	0/60 (0.00%)	0/60 (0.00%)
1 Term from vocabulary, MedDra 19.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Fluzone Quadrivalent Vaccine Group 1: 3 to < 9 Years	Fluzone Quadrivalent Vaccine Group 2: 18 to < 65 Years	Fluzone High-Dose Vaccine Group 3: ≥ 65 Years
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	35/60 (58.33%)	33/60 (55.00%)	25/60 (41.67%)
General disorders
Injection site erythema † 1	6/60 (10.00%)	0/60 (0.00%)	3/60 (5.00%)
Injection site pain † 1	18/60 (30.00%)	28/60 (46.67%)	12/60 (20.00%)
Injection site swelling † 1	7/60 (11.67%)	0/60 (0.00%)	1/60 (1.67%)
Malaise † 1	15/60 (25.00%)	10/60 (16.67%)	4/60 (6.67%)
Pyrexia † 1	5/60 (8.33%)	0/60 (0.00%)	1/60 (1.67%)
Infections and infestations
Bronchiolitis † 1	3/60 (5.00%)	0/60 (0.00%)	0/60 (0.00%)
Pharyngitis streptococcal † 1	4/60 (6.67%)	0/60 (0.00%)	0/60 (0.00%)
Musculoskeletal and connective tissue disorders
Myalgia † 1	12/60 (20.00%)	15/60 (25.00%)	12/60 (20.00%)
Nervous system disorders
Headache † 1	9/60 (15.00%)	11/60 (18.33%)	8/60 (13.33%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	6/60 (10.00%)	0/60 (0.00%)	0/60 (0.00%)
Oropharyngeal pain † 1	3/60 (5.00%)	0/60 (0.00%)	0/60 (0.00%)
1 Term from vocabulary, MedDra 19.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Sponsor must have the opportunity to review at least 60 days prior to submission for publication or presentation. If review indicates that potentially patentable subject matter would be disclosed, publication or public disclosure may be delayed for a maximum of an additional 60 days to allow for filing the necessary patent applications.

Results Point of Contact

Name/Title: Medical Director

Organization: Sanofi Pasteur Inc.

EMail: RegistryContactUs@sanofipasteur.com

Responsible Party:	Sanofi ( Sanofi Pasteur, a Sanofi Company )
ClinicalTrials.gov Identifier:	NCT02908269 History of Changes
Other Study ID Numbers:	GRC71; U1111-1174-4738 ( Other Identifier: WHO )
First Submitted:	September 16, 2016
First Posted:	September 20, 2016
Results First Submitted:	December 8, 2017
Results First Posted:	January 8, 2018
Last Update Posted:	February 2, 2018