Safety and Immunogenicity Among Healthy Children Receiving Fluzone® Quadrivalent Influenza Virus Vaccine

• ClinicalTrials.gov Identifier: NCT01946425
• Recruitment Status: Completed
• First Posted: September 19, 2013
• Results First Posted: September 25, 2014
• Last Update Posted: September 25, 2014
• 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
• Intervention: Biological: Fluzone® Quadrivalent Influenza Virus Vaccine, No Preservative
• Enrollment: 60

Participant Flow

Recruitment Details	The study participants were enrolled from 16 September 2013 to 10 October 2013 at 2 clinic centers in the United States.
Pre-assignment Details	A total of 60 participants who met all of the inclusion and none of the exclusion criteria were enrolled and vaccinated in this study.

Arm/Group Title	Age 6 Months to <36 Months Group	Age 3 Years to <9 Years Group
Arm/Group Description	Participants 6 months to <36 months of age who received a 0.25 mL dose of Fluzone® Quadrivalent, Influenza Virus Vaccine (2013-2014 formulation)	Participants 3 years to <9 years of age who received a 0.5 mL dose of Fluzone® Quadrivalent, Influenza Virus Vaccine (2013-2014 formulation)
Period Title: Overall Study
Started	30	30
Completed	28	30
Not Completed	2	0
Reason Not Completed
Protocol Violation	1	0
Withdrawal by Subject	1	0

Baseline Characteristics

Arm/Group Title		Age 6 to <36 Months Group	Age 3 to <9 Years Group	Total
Arm/Group Description		Participants 6 months to <36 months of age who received a 0.25 mL dose of Fluzone® Quadrivalent Influenza Virus Vaccine (2013-2014 formulation)	Participants 3 years to <9 years of age who received a 0.5 mL dose of Fluzone® Quadrivalent Influenza Virus Vaccine (2013-2014 formulation)	Total of all reporting groups
Overall Number of Baseline Participants		30	30	60
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants	30 participants	60 participants
	<=18 years	30 100.0%	30 100.0%	60 100.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
Age Continuous	Number Analyzed	30 participants	30 participants	60 participants
		1.9 (0.6)	5.4 (1.8)	3.7 (2.2)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants	30 participants	60 participants
	Female	16 53.3%	19 63.3%	35 58.3%
	Male	14 46.7%	11 36.7%	25 41.7%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	30 participants	30 participants	60 participants
		30	30	60

Outcome Measures

1. Primary Outcome

Title	Number of Participants Reporting Solicited Injection-Site or Systemic Reactions Following Vaccination With the 2013-2014 Formulation of Fluzone® Quadrivalent, Influenza Vaccine
Description	Solicited injection-site reactions (6 months to <36 months of age): Tenderness, Erythema, and Swelling. Systemic reactions: Fever (Temperature), Vomiting, Crying Abnormal, Drowsiness, Appetite loss, and Irritability. Grade 3: Tenderness, Cries if limb is moved; Erythema and Swelling, ≥50 mm; Fever, >103.1ºF; Vomiting, ≥6 episodes per 24 hours or requiring parenteral hydration; Crying abnormal, >3 hours; Drowsiness, Sleeping most of the time; Appetite lost, Refuses ≥3 feeds/meals or refuses most feeds/meals; Irritability, Inconsolable. Solicited injection-site reactions (3 years to < 9 years of age): Pain, Erythema, and Swelling. Systemic Reactions: Fever (Temperature), Headache, Malaise, and Myalgia. Grade 3: Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, ≥50 mm; Fever, ≥102.1ºF; Headache, Malaise, and Myalgia, Significant, prevents daily activity.
Time Frame	Day 0 up to Day 7 post-vaccination

Outcome Measure Data

Analysis Population Description

Solicited injection-site reactions and systemic reactions were assessed using the Safety Analysis Set, which includes all participants who received at least one dose of study vaccine.

Arm/Group Title	Age 6 Months to <36 Months Group	Age 3 Years to <9 Years Group
Arm/Group Description:	Participants 6 months to <36 months of age that received Fluzone® Quadrivalent, Influenza Vaccine (2013-2014 formulation)	Participants 3 years to <9 years of age that received Fluzone® Quadrivalent, Influenza Virus Vaccine (2013-2014 formulation)
Overall Number of Participants Analyzed	29	30
Measure Type: Number; Unit of Measure: Participants
Injection-site tenderness	20	NA [1]
Grade 3 Injection-site tenderness	5	NA [1]
Injection-site erythema	15	10
Grade 3 Injection-site erythema	0	1
Injection-site swelling	7	7
Grade 3 Injection-site swelling	0	1
Injection-site pain	NA [2]	21
Grade 3 Injection-site pain	NA [2]	1
Fever	6	2
Grade 3 Fever	0	0
Vomiting	4	NA [3]
Grade 3 Vomiting	0	NA [3]
Crying abnormal	10	NA [3]
Grade 3 Crying abnormal	3	NA [3]
Drowsiness	8	NA [3]
Grade 3 Drowsiness	1	NA [3]
Appetite lost	7	NA [3]
Grade 3 Appetite lost	2	NA [3]
Irritability	17	NA [3]
Grade 3 Irritability	3	NA [3]
Headache	NA [3]	4
Grade 3 Headache	NA [3]	1
Malaise	NA [3]	11
Grade 3 Malaise	NA [3]	0
Myalgia	NA [3]	13
Grade 3 Myalgia	NA [3]	1

[1]

This injection-site reaction was not solicited in this group

[2]

This injection-site reaction was not solicited in this group.

[3]

This systemic reaction was not solicited in this group.

2. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Influenza Antibodies Before and Following Vaccination With the 2013-2014 Formulation of Fluzone® Quadrivalent, Influenza Vaccine
Description	Influenza virus antibodies were measured using a hemagglutination inhibition (HAI) assay.
Time Frame	Day 0 (pre-vaccination) and Day 28 after final vaccination

Outcome Measure Data

Analysis Population Description

Geometric mean titers of antibodies against the hemagglutinin antigens were assessed in the Per-Protocol Analysis Set.

Arm/Group Title	Age 6 Months to <36 Months Group	Age 3 Years to <9 Years Group
Arm/Group Description:	Participants 6 months to <36 months of age that received Fluzone® Quadrivalent, Influenza Vaccine (2013-2014 formulation)	Participants 3 years to <9 years of age that received Fluzone® Quadrivalent, Influenza Vaccine (2013-2014 formulation)
Overall Number of Participants Analyzed	26	28
Geometric Mean (95% Confidence Interval); Unit of Measure: Titers
A/H1N1 (pre-vaccination; N = 25, 28)	14.1; (7.76 to 25.8)	136; (68.4 to 271)
A/H1N1 (post-vaccination; N = 26, 28)	245; (132 to 455)	1264; (930 to 1719)
A/H3N2 (pre-vaccination; N = 25, 28)	23.6; (12.5 to 44.8)	215; (109 to 427)
A/H3N2 (post-vaccination; N = 26, 28)	484; (287 to 817)	1103; (788 to 1544)
B Yamagata (pre-vaccination; N = 25, 28)	6.24; (4.94 to 7.88)	29.0; (18.3 to 45.8)
B Yamagata (post-vaccination; N = 26, 28)	48.2; (26.7 to 87.1)	162; (114 to 231)
B Victoria (pre-vaccination; N = 25, 28)	5.99; (4.76 to 7.54)	13.1; (8.61 to 20.0)
B Victoria (post-vaccination; N = 26, 28)	24.8; (12.7 to 48.1)	113; (72.8 to 176)

3. Secondary Outcome

Title	Number of Participants With Seroprotection Before and Following Vaccination With the 2013-2014 Formulation of Fluzone® Quadrivalent, Influenza Vaccine
Description	Influenza virus antibodies were measured using an HAI assay. Seroprotection was defined as a titer ≥40 (1/dilution).
Time Frame	Day 0 (pre-vaccination) and Day 28 after final vaccination

Outcome Measure Data

Analysis Population Description

Seroprotection against the hemagglutinin antigens were assessed in the Per-Protocol Analysis Set.

Arm/Group Title	Age 6 Months to <36 Months Group	Age 3 Years to <9 Years Group
Arm/Group Description:	Participants 6 months to <36 months of age that received Fluzone® Quadrivalent, Influenza Vaccine (2013-2014 formulation)	Participants 3 years to <9 years of age that received Fluzone® Quadrivalent, Influenza Vaccine (2013-2014 formulation)
Overall Number of Participants Analyzed	26	28
Measure Type: Number; Unit of Measure: Participants
A/H1N1 (pre-vaccination; N = 25, 28)	5	19
A/H1N1 (post-vaccination; N = 26, 28)	22	28
A/H3N2 (pre-vaccination; N = 25, 28)	8	24
A/H3N2 (post-vaccination; N = 26, 28)	24	28
B Yamagata (pre-vaccination; N = 25, 28)	1	16
B Yamagata (post-vaccination; N = 26, 28)	18	27
B Victoria (pre-vaccination; N = 25, 28)	1	6
B Victoria (post-vaccination; N = 26, 28)	8	22

4. Secondary Outcome

Title	Number of Participants Achieving Seroconversion Following Vaccination With the 2013-2014 Formulation of Fluzone® Quadrivalent, Influenza Vaccine
Description	Influenza virus antibodies were measured using an HAI assay. Seroconversion was defined as either a pre-vaccination HAI titer < 1:10 and a post-vaccination titer ≥ 1:40 or a pre-vaccination titer ≥ 1:10 and a ≥ 4-fold increase in post-vaccination titer.
Time Frame	Day 0 (pre-vaccination) and Day 28 after final vaccination

Outcome Measure Data

Analysis Population Description

Seroconversion against the hemagglutinin antigens were assessed in the Per-Protocol Analysis Set.

Arm/Group Title	Age 6 Months to <36 Months Group	Age 3 Years to <9 Years Group
Arm/Group Description:	Participants 6 months to <36 months of age that received Fluzone® Quadrivalent, Influenza Vaccine (2013-2014 formulation)	Participants 3 years to <9 years of age that received Fluzone® Quadrivalent, Influenza Vaccine (2013-2014 formulation)
Overall Number of Participants Analyzed	26	28
Measure Type: Number; Unit of Measure: Participants
A/H1N1 (N = 25, 28)	20	19
A/H3N2 (N = 25, 28)	22	14
B Yamagata (N = 25, 28)	17	17
B Victoria (N = 25, 28)	8	17

5. Secondary Outcome

Title	Geometric Mean Titer Ratios (GMTRs) of Influenza Antibodies Following Vaccination With the 2013-2014 Formulation of Fluzone® Quadrivalent, Influenza Vaccine
Description	Influenza virus antibodies were measured using an HAI assay. Geometric mean titer ratios are the geometric means of the individual post-vaccination/pre-vaccination titer ratios for each hemagglutinin antigen contained in the vaccine.
Time Frame	Day 0 (pre-vaccination) and Day 28 after final vaccination

Outcome Measure Data

Analysis Population Description

Geometric mean titer ratios against the hemagglutinin antigens were assessed in the Per-Protocol Analysis Set.

Arm/Group Title	Age 6 Months to <36 Months Group	Age 3 Years to <9 Years Group
Arm/Group Description:	Participants 6 months to <36 months of age that received Fluzone® Quadrivalent, Influenza Vaccine (2013-2014 formulation)	Participants 3 years to <9 years of age that received Fluzone® Quadrivalent, Influenza Vaccine (2013-2014 formulation)
Overall Number of Participants Analyzed	26	28
Geometric Mean (95% Confidence Interval); Unit of Measure: Titer Ratio
A/H1N1 (N = 25, 28)	13.9; (8.33 to 23.3)	8.83; (4.95 to 15.7)
A/H3N2 (N = 25, 28)	15.8; (9.43 to 26.4)	4.82; (2.99 to 7.75)
B Yamagata (N = 25, 28)	5.13; (3.06 to 8.61)	4.70; (3.20 to 6.90)
B Victoria (N = 25, 28)	2.87; (1.72 to 4.79)	6.17; (4.17 to 9.13)

Adverse Events

Time Frame	Adverse event data were collected from Day 0 (post-vaccination) up to Day 28 after final vaccination.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Age 6 Months to <36 Months Group		Age 3 Years to <9 Years Group
Arm/Group Description	Participants 6 months to < 36 months of age that received Fluzone® Quadrivalent Influenza Vaccine (2013-2014 formulation)		Participants age 3 years to < 9 years of age that received Fluzone® Quadrivalent Influenza Vaccine (2013-2014 formulation)
All-Cause Mortality
	Age 6 Months to <36 Months Group		Age 3 Years to <9 Years Group
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Age 6 Months to <36 Months Group		Age 3 Years to <9 Years Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0.00%)		0/30 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5.00%
	Age 6 Months to <36 Months Group		Age 3 Years to <9 Years Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/30 (70.00%)		21/30 (70.00%)
Gastrointestinal disorders
Diarrhoea * 1	2/30 (6.67%)	2	1/30 (3.33%)	1
Vomiting † 1	4/29 (13.79%)	4	0/0	0
General disorders
Injection-site tenderness † 1	20/29 (68.97%)	20	0/0	0
Injection-site erythema † 1	15/29 (51.72%)	15	10/30 (33.33%)	10
Injection-site swelling † 1	7/29 (24.14%)	7	7/30 (23.33%)	7
Fever † 1	6/29 (20.69%)	6	2/30 (6.67%)	2
Injection-site pain † 1	0/0	0	21/30 (70.00%)	21
Malaise † 1	0/0	0	11/30 (36.67%)	11
Infections and infestations
Croup infectious * 1	1/30 (3.33%)	1	2/30 (6.67%)	2
Sinusitis * 1	0/30 (0.00%)	0	2/30 (6.67%)	2
Upper respiratory tract infection * 1	7/30 (23.33%)	8	2/30 (6.67%)	3
Metabolism and nutrition disorders
Appetite lost † 1	7/29 (24.14%)	7	0/0	0
Musculoskeletal and connective tissue disorders
Myalgia † 1	0/0	0	13/30 (43.33%)	13
Nervous system disorders
Drowsiness † 1	8/29 (27.59%)	8	0/0	0
Headache † 1	0/0	0	4/30 (13.33%)	4
Psychiatric disorders
Crying abnormal † 1	10/29 (34.48%)	10	0/0	0
Irritability † 1	17/29 (58.62%)	17	0/0	0
Respiratory, thoracic and mediastinal disorders
Cough * 1	3/30 (10.00%)	3	1/30 (3.33%)	1
Rhinorrhoea * 1	2/30 (6.67%)	2	3/30 (10.00%)	3
† Indicates events were collected by systematic assessment; * Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA version 16.0

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: NCT01946425
• Other Study ID Numbers: GRC51; U1111-1120-1262 ( Other Identifier: WHO )
• First Submitted: September 16, 2013
• First Posted: September 19, 2013
• Results First Submitted: September 17, 2014
• Results First Posted: September 25, 2014
• Last Update Posted: September 25, 2014