Safety and Immunogenicity of MF59C.1 Adjuvanted Trivalent Subunit Influenza Vaccine in Elderly Subjects

• Sponsor: Novartis Vaccines (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01162122
• Collaborator: (none)
• Enrollment: 7,109
• Locations: 38
• Arms: 2
• Duration (Months): 15
• Patients Per Site: 187.1
• Patients Per Site Per Month: 12.5

Study Details

Study Description

Brief Summary

The present phase III study aims to evaluate the safety and immunogenicity of MF59-adjuvanted subunit seasonal influenza vaccine and to evaluate the consistency in the manufacturing process of three consecutive lots of MF59-adjuvanted subunit seasonal influenza vaccine with respect to immunogenicity in subjects aged 65 years and older. The active comparator non-adjuvanted seasonal influenza vaccine is approved for use in this age group in the United States and will be used to provide a comparative assessment for immunogenicity and safety.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Biological: MF59 adjuvanted trivalent subunit influenza vaccine (aTIV); Biological: Non-adjuvanted trivalent subunit influenza vaccine (TIV)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 7109 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Phase III, Randomized, Controlled, Observer-Blind, Multicenter Study to Evaluate the Safety and Immunogenicity and the Consistency of Three Consecutive Lots of a MF59C.1 Adjuvanted Trivalent Subunit Influenza Vaccine in Elderly Subjects Aged 65 Years and Older
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: aTIV Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Biological: MF59 adjuvanted trivalent subunit influenza vaccine (aTIV); one dose 0.5 mL administered IM in the deltoid muscle of (preferably) the non-dominant arm; Other Names: Fluad
Experimental: Licensed TIV Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).	Biological: Non-adjuvanted trivalent subunit influenza vaccine (TIV); one 0.5 mL dose administered IM in the deltoid muscle of (preferably) the non-dominant arm; Other Names: Agriflu

Outcome Measures

Primary Outcome Measures

1. Geometric Mean Titers in Subjects After Receiving One Dose of Lot 1 or Lot 2 or Lot 3 of aTIV [Day 22 post vaccination]

   Immunologic equivalence of 3 consecutive production lots of aTIV (Lot 1, Lot 2 and Lot 3), was assessed in terms of Hemagglutination Inhibition (HI) Geometric Mean Titers (GMTs) in subjects, at three weeks after vaccination, against each vaccine strain.

2. Comparison of aTIV Versus TIV in Terms of Geometric Mean Titers (GMTs) Against Homologous Strains - PPS [Day 22 post vaccination]

   The non-inferiority of HI antibody responses of aTIV compared to TIV assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.

3. Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-PPS [Day 22 post vaccination]

   The non-inferiority of HI antibody responses of aTIV compared to TIV assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the three homologous vaccine strains. Seroconversion defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.

4. Comparison of aTIV Versus TIV in Terms of GMTs Against Homologous Strains-Full Analysis Set (FAS) [Day 22 post vaccination]

   The superiority of HI antibody responses of aTIV compared to TIV assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.

5. Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-FAS [Day 22 post vaccination]

   The superiority of HI antibody responses of aTIV compared to TIV assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the three homologous vaccine strains. Seroconversion defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.

6. Percentage of Subjects With HI Titers ≥40 Against Homologous Strains [Day 22 post vaccination]

   The percentage of subjects demonstrating HI titers ≥40, in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV.

7. Percentage of Subjects Achieving Seroconversion in HI Titers, Against Homologous Strains [Day 22 post vaccination]

   The percentage of subjects achieving seroconversion in HI titers from baseline, in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.

8. Geometric Mean Ratio (GMR) of Post- Versus Pre-vaccination HI Titers Against Homologous Strains [Day 22 post vaccination]

   The GMR of post-vaccination versus pre-vaccination HI titers (day 22/day 1) in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV.

9. Percentage of Subjects With HI Titers ≥40 Against Heterologous Strains [Day 22 post vaccination]

   The percentage of subjects demonstrating HI titers ≥40, in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV.

10. Geometric Mean Ratio (GMR) of Post- Versus Pre-vaccination HI Titers, Against Heterologous Strains [Day 22 post vaccination]

    The GMR of post-vaccination versus pre-vaccination HI titers (day 22/day 1) in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV.

11. Percentage of Subjects Achieving Seroconversion in HI Titers, Against Heterologous Strains [Day 22 post vaccination]

    The percentage of subjects achieving seroconversion in HI titers from baseline, in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.

Secondary Outcome Measures

1. Comparison of aTIV Versus TIV in High Risk Group in Terms of GMTs Against Homologous Strains-PPS [Day 22 post vaccination]

   The non-inferiority of HI antibody responses of ATIV compared to TIV, in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.

2. Comparison of HI Antibody Responses of aTIV Versus TIV, in High Risk Group in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-PPS [Day 22 post vaccination]

   The non-inferiority of HI antibody responses of ATIV compared to TIV, in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the homologous vaccine strains. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.

3. Comparison of aTIV Versus TIV in High Risk Group in Terms of GMTs Against Homologous Strains-FAS [Day 22 post vaccination]

   The superiority of HI antibody responses of aTIV compared to TIV, in subjects with predefined co-morbidities (high risk group) assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.

4. Comparison of HI Antibody Responses of aTIV Versus TIV, in High Risk Group in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-FAS [Day 22 postvaccination]

   The superiority of HI antibody responses of aTIV compared to TIV, in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the homologous vaccine strains. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.

5. Comparison of aTIV Versus TIV in Terms of GMTs Against Heterologous Strains-PPS [Day 22 post vaccination]

   The non-inferiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination .

6. Comparison of aTIV Versus TIV in Terms of GMTs Against Heterologous Strains-FAS [Day 22 post vaccination]

   The superiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination.

7. Comparison of HI Antibody Responses of aTIV Versus TIV, in Terms of Percentage of Subjects Achieving Seroconversion Against Heterologous Strains-PPS [Day 22 postvaccination]

   The non-inferiority of HI antibody responses of aTIV compared to TIV against the heterologous strains, in overall group and in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.

8. Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Heterologous Strains-FAS [Day 22 post vaccination]

   The superiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of percentage of subjects achieving seroconversion, at three weeks after vaccination. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.

9. Persistence of GMTs Against Homologous and Heterologous Strains [Day 181, Day 366 post vaccination]

   The GMTs against homologous and heterologous strains, persisting in subjects at six months (day 181) and one year (day 366) after vaccination with either aTIV or TIV.

10. Percentage of Subjects With Seroconversion Upto One Year After Vaccination, Against Homologous and Heterologous Strains [Day 181, Day 366 post vaccination]

    The percentage of subjects demonstrating seroconversion in HI titers against homologous and heterologous strains, at six months (day 181) and one year (day 366) after vaccination with either aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.

11. Number of Subjects Reporting Influenza Like Illness (ILI) Across Vaccine Groups [Day 22 through Day 366 post vaccination]

    The number of subjects reporting ILI from three weeks after vaccination to up to one year in aTIV group compared to TIV group, by country.

12. Number of High Risk Subjects With Exacerbation of Preexisting Chronic Disease, Across Vaccine Groups [Day 1 through Day 366 post vaccination]

    The number of high risk subjects reporting exacerbation of preexisting chronic conditions (i.e.congestive heart failure, Chronic Obstructive Pulmonary disease (COPD), asthma, hepatic disease, renal insufficiency, and neurological/neuromuscular or metabolic disorders including diabetes mellitus) in aTIV group compared to TIV group.

13. Number of Subjects Reporting Healthcare Utilization Across Vaccine Groups [Day 1 through Day 366 post vaccination]

    The number of subjects with emergency room visits, unscheduled physician visits, and hospitalizations due to community acquired influenza or pneumonia, cardiopulmonary disease, cardiac disease, respiratory or pulmonary disease,in aTIV group compared to TIV group.

14. All Cause Mortality Rate, Across Vaccine Groups [Day 1 through Day 366 post vaccination]

    The all-cause mortality rate (excluding injury)reported in aTIV group compared to TIV group, by country.

15. Number of Subjects Reporting Solicited Adverse Events Following Vaccination [Day 1 through Day 7 post vaccination]

    The number of subjects reporting solicited local and systemic adverse events and other adverse events in aTIV group compared to TIV group.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Males and females subjects aged ≥65 years at day of vaccination who are willing and able to comply to study procedures.

Exclusion Criteria:

1. Individuals with behavioral or cognitive impairment or a psychiatric condition or with a history of any illness that,in the opinion of the investigator, would have interfered with the subject's ability to participate in the study.

2. Individuals who were not able to comprehend and/or follow all required study procedures for the whole period of the study.

3. Known or suspected impairment/alteration of immune function.

4. Individuals with a known bleeding diathesis.

5. History of Guillain-Barré syndrome.

6. Individuals with history of allergy to vaccine components and/or a history of any anaphylaxis, serious vaccine reactions or hypersensitivity to influenza viral proteins, egg proteins (including ovalbumin), polymyxin, neomycin, betapropiolactone, thimerosal/ sodium ethylmercurothiosalicylate/ mercury and nonylphenolethoxylate/ nonoxynol-9 (spermicide).

7. Receipt of another investigational agent within 30 days prior to enrollment in the study or before completion of the safety follow-up period in another study.

8. Individuals who had received any other vaccines within 2 weeks for inactivated vaccines or 4 weeks for live vaccines prior to enrollment in this study or who had planned to receive any vaccine within 3 weeks from the study vaccine.

9. Individuals who had received vaccination against seasonal influenza in the previous 6 months.

10. Individuals with oral temperature ≥38.0°C (≥100.4°F) on day of study vaccination.

11. Individuals with history of substance or alcohol abuse within the past 2 years.

12. Individuals providing consent who did not consent to the retention of their serum samples after study completion.

13. Elective surgery or hospitalization planned to occur during the treatment phase or during the follow-up phase that, according to the opinion of the investigator, might have poses additional risk to the subject.

14. Subjects from whom blood could not be drawn at visit 1.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	301, Tatum Highlands Medical Associates PLLC, 26224 N Tatum Blvd 15A	Phoenix	Arizona	United States	85253
2	318 Avail Clinical Research, 860 Peachwood Drive	Deland	Florida	United States	32720
3	306 Westside Center for Clinical Research, 810 Lane Avenue South	Jacksonville	Florida	United States	32205
4	328 Miami Research Associates, 6141 Sunset Drive	Miami	Florida	United States	33143
5	320 Johnson County Clin-Trials, 15602 College Blvd	Lenexa	Kansas	United States	66219
6	316 Heartland Research Associates LLC - Axtell Clinic - PA, 700 Medical Center Dr	Newton	Kansas	United States	67114
7	310 Heartland Research Associates LLC, 3730 N Ridge Road Suite 600	Wichita	Kansas	United States	67205
8	322 Heartland Research Associates Wichita, 1709 S. Rock Road	Wichita	Kansas	United States	67207
9	314 Saint Louis Univ Med Div of Infectious Diseases Immunology, 1100 S Grand Blvd DRC- Rm 827	Saint Louis	Missouri	United States	63104
10	330 Mercy Health Research, 12680 Olive Blvd Suite 200	Saint Louis	Missouri	United States	63141
11	313 Clinical Research Center of Nevada, 7425 W Azure Suite 150	Las Vegas	Nevada	United States	89130
12	311 Regional Clinical Research INC, 415 Hooper Road	Endwell	New York	United States	13760
13	326 Triangle Medical Research, 5816 Creedmoor Rd. Suite 104	Raleigh	North Carolina	United States	27612
14	332 Piedmont Medical Research, 1901 S. Hawthorne Rd. Suite 306	Winston-Salem	North Carolina	United States	27103
15	303 Prestige Clinical Research, 333 Conover Drive	Franklin	Ohio	United States	45005
16	325 Omega Medical Research, 400 Bald Hill Road	Warwick	Rhode Island	United States	02886
17	312 Spartanburg Regional Medical Center, 485 Simuel Road	Spartanburg	South Carolina	United States	29303
18	321 Jordan River Family Medicine, 1868 West 9800 South Ste 100	Jordan	Utah	United States
19	317 J. Lewis Research Inc., 2295 Foothill Drive	Salt Lake City	Utah	United States	84109
20	305 Foothill Family Clinic South, 6360 South 3000 East	Salt Lake City	Utah	United States	84121
21	323 PI Coor Clinical Research LCC, 10721 Main St Suite 1500	Fairfax	Virginia	United States	22030
22	209, Centro de Investigacion CAFAM	Avenida Carrera 68	Bogota	Colombia
23	206, Centro de Atencion e Investigacion Medica CAIMED	Carrera 42A	Bogota	Colombia	1750
24	213, Centro de Atencion e Investigacion Medica CAIMED	Carrera 42A	Bogota	Colombia	1750
25	207, Centro de Investigacion Cafesalud Medicina Prepagada	Cra 14 No Piso Sexto	Bogota	Colombia
26	203, Health Research International HRI	Clayton ciudad del Saber Edificio 118		Panama
27	205, Medical and Research Center Calle 53 Urbanizacion Marbella	Consultorios Royal Center 108		Panama
28	103, De La Salle Health Sciences Institute	DBB B Dasmarinas	Cavite	Philippines	4114
29	102, De La Salle Health Sciences Institute	Dbbb Dasmarinas	Cavite	Philippines	4114
30	105, Manila Doctors Hospital, 667 United Nations Avenue	Ermita	Manila	Philippines	1000
31	106, Our Lady of Lourdes Hospital, 46 P. Sanchez Street Sta.	Mesa	Manila	Philippines	1016
32	104 Jose Reyes Memorial Medical Center	Rizal Avenue Avenida Cruz	Manila	Philippines	1003
33	107 Philippine General Hospital	Taft Avenue	Manila	Philippines	1000
34	101, Asian Hospital and Medical Center 2205 Civic Drive Filinvest	Corporate City Alabang	Muntinlupa	Philippines	1781
35	109, Research Institute for Tropical Medicine Department of Health Compound FILINVEST	Corporate City Alabang	Muntinlupa	Philippines
36	108, City Health Office 1 Rosa City	City Health Office 1	Rosa City	Philippines	4026
37	110, San Juan de Dios Hospital, 2772 Roxas Blvd	Pasay City		Philippines	1300
38	111, St Lukes Medical Center, 279 E Rodriguez Sr Boulevard	Quezon City		Philippines	1102

Sponsors and Collaborators

• Novartis Vaccines

Investigators

• Study Chair: Novartis Vaccines, Novartis Vaccines

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Vaccines
• ClinicalTrials.gov Identifier: NCT01162122
• Other Study ID Numbers: V70_27
• First Posted: Jul 14, 2010
• Last Update Posted: Jun 26, 2014
• Last Verified: Jun 1, 2014

• Keywords provided by Novartis Vaccines: Elderly; Influenza; Immunogenicity; Safety; Adjuvant; Adjuvanted; Adjuvants; Vaccines
• Additional relevant MeSH terms: Influenza, Human; Vaccines

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled from 4 sites in Columbia, 2 sites in Panama, 11 sites in Philippines, 21 sites in USA.
Pre-assignment Detail	Five enrolled subjects were not randomized and did not receive study vaccination, hence were discontinued.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Period Title: Overall Study
STARTED	3552	3552
Vaccinated	3541	3541
COMPLETED	3361	3356
NOT COMPLETED	191	196

Baseline Characteristics

Arm/Group Title	aTIV (Pooled)	Licensed TIV	Total
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).	Total of all reporting groups
Overall Participants	3545	3537	7082
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.0 (5.3)	71.8 (5.3)	71.9 (5.3)
Sex: Female, Male (Count of Participants)
Female	2272 64.1%	2342 66.2%	4614 65.2%
Male	1273 35.9%	1195 33.8%	2468 34.8%

Outcome Measures

1. Primary Outcome

Title	Geometric Mean Titers in Subjects After Receiving One Dose of Lot 1 or Lot 2 or Lot 3 of aTIV
Description	Immunologic equivalence of 3 consecutive production lots of aTIV (Lot 1, Lot 2 and Lot 3), was assessed in terms of Hemagglutination Inhibition (HI) Geometric Mean Titers (GMTs) in subjects, at three weeks after vaccination, against each vaccine strain.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the per protocol set population (PPS) i.e all randomised subjects who received the correct vaccine, provided evaluable serum samples, and had no major protocol deviation prior to unblinding.

Arm/Group Title	aTIV_Lot 1	aTIV_Lot 2	aTIV_Lot 3
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from Lot 1	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from Lot 2	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from Lot 3
Measure Participants	1073	1078	1076
H1N1 strain (N=1072,1078,1075)	209	187	199
H3N2 strain (N=1072,1078,1075)	548	542	556
B strain	56	56	58

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 95% CIs of GMT ratios for the pairwise lot-to-lot group comparisons should fall within the equivalence range of 0.67 to 1.5.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H1N1 strain)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 1 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 3
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 95% CIs of GMT ratios for the pairwise lot-to-lot group comparisons should fall within the equivalence range of 0.67 to 1.5.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H1N1 strain)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.95 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 2, aTIV_Lot 3
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 95% CIs of GMT ratios for the pairwise lot-to-lot group comparisons should fall within the equivalence range of 0.67 to 1.5.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H1N1 strain)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 95% CIs of GMT ratios for the pairwise lot-to-lot group comparisons should fall within the equivalence range of 0.67 to 1.5.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H3N2 strain)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 3
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 95% CIs of GMT ratios for the pairwise lot-to-lot group comparisons should fall within the equivalence range of 0.67 to 1.5.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H3N2 strain)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.9 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 2, aTIV_Lot 3
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 95% CIs of GMT ratios for the pairwise lot-to-lot group comparisons should fall within the equivalence range of 0.67 to 1.5.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H3N2 strain)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 95% CIs of GMT ratios for the pairwise lot-to-lot group comparisons should fall within the equivalence range of 0.67 to 1.5.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (B strain)
	Estimated Value	1
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 3
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 95% CIs of GMT ratios for the pairwise lot-to-lot group comparisons should fall within the equivalence range of 0.67 to 1.5.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (B strain)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 2, aTIV_Lot 3
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 95% CIs of GMT ratios for the pairwise lot-to-lot group comparisons should fall within the equivalence range of 0.67 to 1.5.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (B strain)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Comparison of aTIV Versus TIV in Terms of Geometric Mean Titers (GMTs) Against Homologous Strains - PPS
Description	The non-inferiority of HI antibody responses of aTIV compared to TIV assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on PPS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3227	3259
H1N1 strain (N=3225,3257)	198	141
H3N2 strain (N=3225,3256)	544	337
B strain	55	48

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 homologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H1N1 strain)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 1.32 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 homologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H3N2 strain)
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 1.52 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 homologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (B strain)
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95%; 1.08 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-PPS
Description	The non-inferiority of HI antibody responses of aTIV compared to TIV assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the three homologous vaccine strains. Seroconversion defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on PPS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3227	3259
H1N1 strain (N=3225,3257)	77.4	67.6
H3N2 strain (N=3225,3256)	74.0	60.7
B strain	47.0	41.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 homologous strains was ≥-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (H1N1 strain)
	Estimated Value	9.2
	Confidence Interval	(2-Sided) 95%; 7.1 to 11.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 homologous strains was ≥-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (H3N2 strain)
	Estimated Value	12.7
	Confidence Interval	(2-Sided) 95%; 10.5 to 14.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 homologous strains was ≥-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (B strain)
	Estimated Value	5.2
	Confidence Interval	(2-Sided) 95%; 3.0 to 7.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Comparison of aTIV Versus TIV in Terms of GMTs Against Homologous Strains-Full Analysis Set (FAS)
Description	The superiority of HI antibody responses of aTIV compared to TIV assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on FAS i.e all randomized subjects who received a study vaccination and provided evaluable serum samples both at day 1 and at day 22

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3479	3482
H1N1 strain (N=3477,3480)	196	142
H3N2 strain (N=3477,3479)	534	334
B strain	54	48

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 homologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H1N1 strain)
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 1.29 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 homologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H3N2 strain)
	Estimated Value	1.60
	Confidence Interval	(2-Sided) 95%; 1.51 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 homologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (B strain)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 1.08 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-FAS
Description	The superiority of HI antibody responses of aTIV compared to TIV assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the three homologous vaccine strains. Seroconversion defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on FAS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3479	3482
H1N1 strain (N=3477, 3480)	77.3	67.8
H3N2 strain (N=3477,3479)	73.7	60.6
B strain	46.9	41.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 homologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (H1N1 strain)
	Estimated Value	8.9
	Confidence Interval	(2-Sided) 95%; 6.9 to 10.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 homologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (H3N2 strain)
	Estimated Value	12.7
	Confidence Interval	(2-Sided) 95%; 10.6 to 14.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 homologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (B strain)
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 95%; 2.9 to 7.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	Percentage of Subjects With HI Titers ≥40 Against Homologous Strains
Description	The percentage of subjects demonstrating HI titers ≥40, in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the FAS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3479	3482
H1N1 strain (N=3477,3480) overall	91.1	84.5
H3N2 strain (N=3477,3479) overall	99.0	97.0
B strain, overall	64.6	58.9
H1N1 strain (N=1299,1273), high risk group	91.9	85.8
H3N2 strain (N=1299,1273), high risk group	98.7	96.7
B strain (N=1300,1273), high risk group	66.3	61.4

7. Primary Outcome

Title	Percentage of Subjects Achieving Seroconversion in HI Titers, Against Homologous Strains
Description	The percentage of subjects achieving seroconversion in HI titers from baseline, in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the FAS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3479	3482
H1N1 strain ( N= 3477,3480), overall	77.3	67.8
H3N2 strain ( N= 3477,3479), overall	73.7	60.6
B strain, overall	46.9	41.5
H1N1 strain ( N= 1299,1273), high risk group	72.6	62.0
H3N2 strain ( N= 1299,1273), high risk group	68.9	55.2
B strain (N= 1299,1273), high risk group	40.0	34.3

8. Primary Outcome

Title	Geometric Mean Ratio (GMR) of Post- Versus Pre-vaccination HI Titers Against Homologous Strains
Description	The GMR of post-vaccination versus pre-vaccination HI titers (day 22/day 1) in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the FAS

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3479	3482
H1N1 strain (N=3477, 3480), overall	13	9.77
H3N2 strain (N=3477, 3479), overall	10	6.54
B strain , overall	4.85	4.27
H1N1 strain (N=1299, 1273), high risk group	12	9.17
H3N2 strain (N=1299, 1273), high risk group	9.26	6.24
B strain (N=1300, 1273), high risk group	4.48	3.99

9. Secondary Outcome

Title	Comparison of aTIV Versus TIV in High Risk Group in Terms of GMTs Against Homologous Strains-PPS
Description	The non-inferiority of HI antibody responses of ATIV compared to TIV, in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on PPS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	1195	1190
H1N1 strain (1194, 1190)	221	161
H3N2 strain (1194, 1190)	519	331
B strain	61	54

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 homologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H1N1 strain)
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 95%; 1.25 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 homologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H3N2 strain)
	Estimated Value	1.57
	Confidence Interval	(2-Sided) 95%; 1.44 to 1.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 homologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (B strain)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 1.03 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Comparison of HI Antibody Responses of aTIV Versus TIV, in High Risk Group in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-PPS
Description	The non-inferiority of HI antibody responses of ATIV compared to TIV, in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the homologous vaccine strains. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on PPS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	1195	1190
H1N1 strain (N=1194, 1190)	73.6	61.7
H3N2 strain (N=1194, 1190)	69.1	54.8
B strain	40.0	34.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 homologous strains was ≥-10%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (H1N1 strain)
	Estimated Value	11.1
	Confidence Interval	(2-Sided) 95%; 7.5 to 14.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 homologous strains was ≥-10%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (H3N2 strain)
	Estimated Value	13.5
	Confidence Interval	(2-Sided) 95%; 9.8 to 17.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 homologous strains was ≥-10%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (B strain)
	Estimated Value	5.0
	Confidence Interval	(2-Sided) 95%; 1.4 to 8.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Comparison of aTIV Versus TIV in High Risk Group in Terms of GMTs Against Homologous Strains-FAS
Description	The superiority of HI antibody responses of aTIV compared to TIV, in subjects with predefined co-morbidities (high risk group) assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on FAS population.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	1300	1273
H1N1 strain (N=1299,1273)	212	160
H3N2 strain (N=1299,1273)	499	324
B strain	60	54

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 homologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H1N1 strain)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 1.2 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 homologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H3N2 strain)
	Estimated Value	1.54
	Confidence Interval	(2-Sided) 95%; 1.42 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 homologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (B strain)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 1.03 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Primary Outcome

Title	Percentage of Subjects With HI Titers ≥40 Against Heterologous Strains
Description	The percentage of subjects demonstrating HI titers ≥40, in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the FAS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	887	881
H3N2/Brisbane strain(N=887,880), overall	95.8	94.0
H3N2/Wisconsin strain, overall	99.6	98.4
B strain (N=887,880), overall	76.2	72.4
H3N2/Brisbane (N=330, 333), high risk group	94.9	94.0
H3N2/Wisconsin (N=330, 333), high risk group	99.7	98.5
B strain (N=330, 333), high risk group	83.3	78.4

13. Primary Outcome

Title	Geometric Mean Ratio (GMR) of Post- Versus Pre-vaccination HI Titers, Against Heterologous Strains
Description	The GMR of post-vaccination versus pre-vaccination HI titers (day 22/day 1) in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the FAS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	887	881
H3N2/Brisbane strain (N=887,880), overall	5.76	3.87
H3N2/Wisconsin strain, overall	4.95	3.54
B strain (N=887,880), overall	5.76	5.28
H3N2/Brisbane strain (N=330,333), high risk group	5.42	4.15
H3N2/Wisconsin strain (N=330,333), high risk group	4.67	3.73
B strain (N=330,333), high risk group	5.41	4.77

14. Primary Outcome

Title	Percentage of Subjects Achieving Seroconversion in HI Titers, Against Heterologous Strains
Description	The percentage of subjects achieving seroconversion in HI titers from baseline, in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the FAS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	887	881
H3N2/Brisbane, overall (N=887, 880)	60.4	48.4
H3N2/Wisconsin, overall	57.5	45.5
B strain, overall (N=887, 880)	53.3	49.8
H3N2/Brisbane (N= 330,333), high risk group	54.2	41.4
H3N2/Wisconsin ( N= 330,333), high risk group	52.1	38.7
B strain (N= 330, 333), high risk group	46.4	41.7

15. Secondary Outcome

Title	Comparison of HI Antibody Responses of aTIV Versus TIV, in High Risk Group in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-FAS
Description	The superiority of HI antibody responses of aTIV compared to TIV, in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the homologous vaccine strains. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.
Time Frame	Day 22 postvaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on FAS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	1300	1273
H1N1 strain (N=1299,1273)	72.6	62.0
H3N2 strain (N=1299,1273)	68.9	55.2
B strain	40.0	34.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 homologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (H1N1 strain)
	Estimated Value	9.9
	Confidence Interval	(2-Sided) 95%; 6.4 to 13.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 homologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (H3N2 strain)
	Estimated Value	13.0
	Confidence Interval	(2-Sided) 95%; 9.5 to 16.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 homologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (B strain)
	Estimated Value	4.9
	Confidence Interval	(2-Sided) 95%; 1.5 to 8.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Comparison of aTIV Versus TIV in Terms of GMTs Against Heterologous Strains-PPS
Description	The non-inferiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination .
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on PPS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	834	815
H3N2/Brisbane (overall) (N=834,814)	369	255
H3N2/Wisconsin (overall)	1037	764
B strain (overall) (N=834,814)	89	82
H3N2/Brisbane (high risk) (N=302,307)	377	279
H3N2/Wisconsin (high risk) (N=302,307)	965	751
B strain (high risk) (N=302,307)	117	105

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 heterologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT Ratio (H3N2/Brisbane-overall)
	Estimated Value	1.45
	Confidence Interval	(2-Sided) 95%; 1.29 to 1.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 heterologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT Ratio (H3N2/Wisconsin-overall)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 1.23 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 heterologous strains was ≥0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT Ratio (B strain-overall)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 heterologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT Ratio(H3N2/Brisbane-high risk group)
	Estimated Value	1.35
	Confidence Interval	() 95%; 1.13 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 heterologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT Ratio(H3N2/Wisconsin-high risk group
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 1.1 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for all 3 heterologous strains was >0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT Ratio (B strain-high risk group)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.95 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Comparison of aTIV Versus TIV in Terms of GMTs Against Heterologous Strains-FAS
Description	The superiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on FAS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	887	881
H3N2/Brisbane (overall) (N=887,880)	362	243
H3N2/Wisconsin (overall)	1016	738
B strain (overall) (N=887,880)	87	80
H3N2/Brisbane (high risk) (N=302,307)	364	267
H3N2/Wisconsin (high risk) (N=302,307)	927	724
B strain (high risk) (N=302,307)	112	99

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 heterologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H3N2/Brisbane-overall)
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 1.33 to 1.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 heterologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio(H3N2/Wisconsin-overall)
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 95%; 1.25 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 heterologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (B strain-overall)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 0.99 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 heterologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (H3N2/Brisbane-high risk)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 1.15 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 heterologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio(H3N2/Wisconsin-high risk)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; 1.1 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 vaccine group GMT ratios for at least 2 heterologous strains was >1.5.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMT ratio (B strain-high risk)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.97 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Comparison of HI Antibody Responses of aTIV Versus TIV, in Terms of Percentage of Subjects Achieving Seroconversion Against Heterologous Strains-PPS
Description	The non-inferiority of HI antibody responses of aTIV compared to TIV against the heterologous strains, in overall group and in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.
Time Frame	Day 22 postvaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on PPS.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	834	815
H3N2/Brisbane (overall) (N=834,814)	60.0	49.1
H3N2/Wisconsin (overall)	57.0	45.9
B strain (overall) (N=834,814)	52.8	49.3
H3N2/Brisbane (high risk) (N=302,307)	54.3	41.7
H3N2/Wisconsin (high risk) (N=302,307)	51.7	38.8
B strain (high risk) (N=302,307)	45.7	41.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 heterologous strains was ≥-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (H3N2/Brisbane-overall)
	Estimated Value	11.3
	Confidence Interval	(2-Sided) 95%; 6.7 to 15.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 heterologous strains was ≥-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference(H3N2/Wisconsin-overall)
	Estimated Value	11.9
	Confidence Interval	(2-Sided) 95%; 7.3 to 16.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 homologous strains was ≥-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	4.0
	Confidence Interval	(2-Sided) 95%; -0.4 to 8.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 heterologous strains was ≥-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference(H3N2/Brisbane-high risk
	Estimated Value	12.3
	Confidence Interval	(2-Sided) 95%; 4.8 to 19.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 homologous strains was ≥-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference(H3N2Wisconsin-high risk
	Estimated Value	12.6
	Confidence Interval	(2-Sided) 95%; 5.0 to 20.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for all 3 heterologous strains was ≥-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (B strain-high risk)
	Estimated Value	4.8
	Confidence Interval	(2-Sided) 95%; -2.1 to 11.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Heterologous Strains-FAS
Description	The superiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of percentage of subjects achieving seroconversion, at three weeks after vaccination. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.
Time Frame	Day 22 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on FAS

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	887	881
H3N2/Brisbane (overall) (N=887,880)	60.4	48.4
H3N2/Wisconsin (overall)	57.5	45.5
B strain (overall) (N=887,880)	53.3	49.8
H3N2/Brisbane (high risk) (N=330, 333)	54.2	41.4
H3N2/Wisconsin (high risk) (N=330,333)	52.1	38.7
B strain (high risk) (N=330, 333)	46.4	41.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 heterologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (H3N2/Brisbane-overall)
	Estimated Value	12.5
	Confidence Interval	(2-Sided) 95%; 8.1 to 16.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 heterologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference(H3N2/Wisconsin-overall)
	Estimated Value	12.6
	Confidence Interval	(2-Sided) 95%; 8.1 to 17.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 heterologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (B strain-overall)
	Estimated Value	4.6
	Confidence Interval	(2-Sided) 95%; 0.4 to 8.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 heterologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference(H3N2/Brisbane-high risk
	Estimated Value	12.4
	Confidence Interval	(2-Sided) 95%; 5.2 to 19.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 heterologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference(H3N2/Wisconsin-highrisk
	Estimated Value	13.0
	Confidence Interval	(2-Sided) 95%; 5.8 to 20.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	aTIV_Lot 1, aTIV_Lot 2
	Comments	Superiority was established if the lower bound of the 95% CI for the day 22 differences in seroconversion rates for at least 2 heterologous strains was >10%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference (B strain-high risk)
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 95%; -1.6 to 11.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Persistence of GMTs Against Homologous and Heterologous Strains
Description	The GMTs against homologous and heterologous strains, persisting in subjects at six months (day 181) and one year (day 366) after vaccination with either aTIV or TIV.
Time Frame	Day 181, Day 366 post vaccination

Outcome Measure Data

Analysis Population Description

The analysis was done on the FAS (persistence) subset population i.e all randomized population only from US sites who received a study vaccination, provided evaluable blood samples at day 1, day 22, day 181, and day 366.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	189	191
H1N1 (homologous) Day 181	71	68
H1N1 (homologous) Day 366	49	52
H3N2 (homologous) Day 181	123	91
H3N2 (homologous) Day 366	70	54
B (homologous) Day 181	25	22
B (homologous) Day 366	21	20
B (heterologous) Day 181	39	38
B (heterologous) Day 366	38	40
H3N2/Brisbane (heterologous) Day 181	100	81
H3N2/Brisbane(heterologous) Day 366	75	72
H3N2/Wisconsin (heterologous) Day 181	228	194
H3N2/Wisconsin (heterologous) Day 366	190	182

21. Secondary Outcome

Title	Percentage of Subjects With Seroconversion Upto One Year After Vaccination, Against Homologous and Heterologous Strains
Description	The percentage of subjects demonstrating seroconversion in HI titers against homologous and heterologous strains, at six months (day 181) and one year (day 366) after vaccination with either aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.
Time Frame	Day 181, Day 366 post vaccination

Outcome Measure Data

Analysis Population Description

The analysis was done on the FAS (persistence) subset.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	189	191
H1N1 (homologous) Day 181	28.6	26.2
H1N1 (homologous) Day 366	18.5	19.4
H3N2 (homologous) Day 181	36.0	24.6
H3N2 (homologous) Day 366	16.9	12.6
B (homologous) Day 181	3.7	2.6
B (homologous) Day 366	2.1	3.1
B (heterologous) Day 181	2.65	3.14
B (heterologous) Day 366	4.23	3.14
H3N2/Brisbane (heterologous) Day 181	15.34	8.38
H3N2/Brisbane(heterologous) Day 366	7.94	5.24
H3N2/Wisconsin (heterologous) Day 181	12.17	8.90
H3N2/Wisconsin (heterologous) Day 366	8.99	6.28

22. Secondary Outcome

Title	Number of Subjects Reporting Influenza Like Illness (ILI) Across Vaccine Groups
Description	The number of subjects reporting ILI from three weeks after vaccination to up to one year in aTIV group compared to TIV group, by country.
Time Frame	Day 22 through Day 366 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the modified full analysis set (mFAS; effectiveness) population i.e all subjects in the randomized population who received a study vaccination but excluding those who received a non-study vaccine during the follow-up phase.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3497	3498
Columbia (N=516, 506)	119 3.4%	97 2.7%
Panama (N=108, 102)	20 0.6%	21 0.6%
Philippines (N=1836,1835)	102 2.9%	113 3.2%
United states (N=1037,1055)	72 2%	76 2.1%

23. Secondary Outcome

Title	Number of High Risk Subjects With Exacerbation of Preexisting Chronic Disease, Across Vaccine Groups
Description	The number of high risk subjects reporting exacerbation of preexisting chronic conditions (i.e.congestive heart failure, Chronic Obstructive Pulmonary disease (COPD), asthma, hepatic disease, renal insufficiency, and neurological/neuromuscular or metabolic disorders including diabetes mellitus) in aTIV group compared to TIV group.
Time Frame	Day 1 through Day 366 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the mFAS (effectiveness) population.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	1307	1281
Number [participants]	55 1.6%	48 1.4%

24. Secondary Outcome

Title	Number of Subjects Reporting Healthcare Utilization Across Vaccine Groups
Description	The number of subjects with emergency room visits, unscheduled physician visits, and hospitalizations due to community acquired influenza or pneumonia, cardiopulmonary disease, cardiac disease, respiratory or pulmonary disease,in aTIV group compared to TIV group.
Time Frame	Day 1 through Day 366 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the mFAS (effectiveness).

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3499	3502
Number [participants]	275 7.8%	289 8.2%

25. Secondary Outcome

Title	All Cause Mortality Rate, Across Vaccine Groups
Description	The all-cause mortality rate (excluding injury)reported in aTIV group compared to TIV group, by country.
Time Frame	Day 1 through Day 366 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the mFAS (effectiveness).

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3540	3541
Columbia (N=519, 509)	7 0.2%	7 0.2%
Panama (N=109, 105)	0 0%	0 0%
Philippines (N=1873,1867)	39 1.1%	34 1%
United states (N=1039,1060)	6 0.2%	5 0.1%

26. Secondary Outcome

Title	Number of Subjects Reporting Solicited Adverse Events Following Vaccination
Description	The number of subjects reporting solicited local and systemic adverse events and other adverse events in aTIV group compared to TIV group.
Time Frame	Day 1 through Day 7 post vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the safety set i.e all randomized subjects who received a study vaccination and provided postvaccination safety data.

Arm/Group Title	aTIV (Pooled)	Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).	Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
Measure Participants	3505	3495
Any Local	1137 32.1%	593 16.8%
Injection site erythema (N=3492, 3485)	43 1.2%	18 0.5%
Injection site induration (N=3494, 3488)	45 1.3%	17 0.5%
Injection site tenderness (N=3495,3483)	739 20.8%	391 11.1%
Injection site swelling (N=3495,3488)	43 1.2%	15 0.4%
Injection site pain (N=3495,3485)	875 24.7%	425 12%
Any sytemic	1120 31.6%	902 25.5%
Chills (N=3495,3485)	235 6.6%	163 4.6%
Myalgia (N=3496,3487)	515 14.5%	339 9.6%
Arthralgia (N=3492,3486)	296 8.3%	272 7.7%
Headache (N= 3495,3486)	463 13.1%	391 11.1%
Fatigue (N= 3494, 3484)	466 13.1%	361 10.2%
Nausea (N=3492,3482)	101 2.8%	98 2.8%
Vomiting (N=3494,3483)	48 1.4%	59 1.7%
Diarrhea (N=3494,3485)	168 4.7%	158 4.5%
Fever (≥ 38°C)	122 3.4%	116 3.3%
Any other	210 5.9%	165 4.7%
Oral Temperature (≥ 40°C)	3 0.1%	0 0%
Analgesic/Antipyretic used	158 4.5%	122 3.4%

Adverse Events

Time Frame	Solicited adverse events (AEs) were collected from Day 1 to 7 postvaccination; unsolicited AEs from Day 1 to Day 22; Serious AEs from Day 1 to Day 366.
Arm/Group Title	aTIV (Pooled)		Licensed TIV
Arm/Group Description	Subjects received one dose of MF59-adjuvanted trivalent subunit influenza vaccine (aTIV) from one of three consecutive lots (Lot 1, Lot 2 or Lot 3).		Subjects received one dose of non-adjuvanted trivalent subunit influenza vaccine (TIV).
All Cause Mortality
	aTIV (Pooled)		Licensed TIV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	aTIV (Pooled)		Licensed TIV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	264/3545 (7.4%)		243/3537 (6.9%)
Blood and lymphatic system disorders
Anemia	2/3545 (0.1%)		5/3537 (0.1%)
Disseminated intravascular coagulation	1/3545 (0%)		0/3537 (0%)
Idiopathic Thrombocytopenic coagulation	1/3545 (0%)		0/3537 (0%)
Leukocytosis	0/3545 (0%)		1/3537 (0%)
Sideroblastic anaemia	1/3545 (0%)		0/3537 (0%)
Cardiac disorders
Acute coronary syndrome	2/3545 (0.1%)		0/3537 (0%)
Acute myocardial infarction	11/3545 (0.3%)		7/3537 (0.2%)
Angina pectoris	1/3545 (0%)		2/3537 (0.1%)
Angina unstable	3/3545 (0.1%)		1/3537 (0%)
Arrhythmia	0/3545 (0%)		2/3537 (0.1%)
Arteriosclerosis coronary artery	2/3545 (0.1%)		0/3537 (0%)
Atrial Fibrillation	4/3545 (0.1%)		8/3537 (0.2%)
Atrial tachycardia	1/3545 (0%)		0/3537 (0%)
Bradycardia	2/3545 (0.1%)		0/3537 (0%)
Cardiac arrest	0/3545 (0%)		2/3537 (0.1%)
Cardiac disorder	2/3545 (0.1%)		0/3537 (0%)
Cardiac failure	3/3545 (0.1%)		4/3537 (0.1%)
Cardiac failure congestive	8/3545 (0.2%)		16/3537 (0.5%)
Cardio-respiratory arrest	3/3545 (0.1%)		1/3537 (0%)
Cardiogenic shock	0/3545 (0%)		1/3537 (0%)
Coronary artery disease	7/3545 (0.2%)		6/3537 (0.2%)
Dressler's syndrome	1/3545 (0%)		0/3537 (0%)
Hypertensive heart disease	2/3545 (0.1%)		1/3537 (0%)
Hypertrophic cardiomyopathy	0/3545 (0%)		1/3537 (0%)
Myocardial infarction	10/3545 (0.3%)		9/3537 (0.3%)
Myocardial Ischemia	3/3545 (0.1%)		2/3537 (0.1%)
Nodal arrythmia	1/3545 (0%)		0/3537 (0%)
Pericarditis	1/3545 (0%)		0/3537 (0%)
Sinus Tachycardia	1/3545 (0%)		0/3537 (0%)
Ventricular extrasystoles	2/3545 (0.1%)		0/3537 (0%)
Ventricular tachycardia	1/3545 (0%)		1/3537 (0%)
Congenital, familial and genetic disorders
Hydrocele	1/3545 (0%)		1/3537 (0%)
Ear and labyrinth disorders
Vertigo	1/3545 (0%)		1/3537 (0%)
Vertigo positional	2/3545 (0.1%)		1/3537 (0%)
Eye disorders
Blindness unilateral	0/3545 (0%)		1/3537 (0%)
Corneal degeneration	0/3545 (0%)		1/3537 (0%)
Retinal neovascularisation	0/3545 (0%)		1/3537 (0%)
Viterous hemorrhage	0/3545 (0%)		1/3537 (0%)
Gastrointestinal disorders
Abdominal hernia	1/3545 (0%)		0/3537 (0%)
Abdominal pain	0/3545 (0%)		1/3537 (0%)
Abdominal pain upper	0/3545 (0%)		1/3537 (0%)
Abdominal wall hematoma	0/3545 (0%)		1/3537 (0%)
Ascites	1/3545 (0%)		0/3537 (0%)
Colitis	0/3545 (0%)		1/3537 (0%)
Diverticular perforation	0/3545 (0%)		1/3537 (0%)
Diverticulum	1/3545 (0%)		2/3537 (0.1%)
Duodenal ulcer perforation	0/3545 (0%)		1/3537 (0%)
Dyspepsia	0/3545 (0%)		1/3537 (0%)
Erosive oesophagitis	1/3545 (0%)		0/3537 (0%)
Femoral hernia,obstructive	1/3545 (0%)		0/3537 (0%)
Gastric ulcer perforation	0/3545 (0%)		1/3537 (0%)
Gastritis	1/3545 (0%)		1/3537 (0%)
Gastrointestinal haemorrhage	2/3545 (0.1%)		1/3537 (0%)
Hiatus hernia	1/3545 (0%)		1/3537 (0%)
Ileus	0/3545 (0%)		1/3537 (0%)
Ileus paralytic	0/3545 (0%)		1/3537 (0%)
Inguinal hernia, obstructive	0/3545 (0%)		1/3537 (0%)
Intestinal perforation	1/3545 (0%)		0/3537 (0%)
Irritable bowel syndrome	1/3545 (0%)		0/3537 (0%)
Large intestine perforation	1/3545 (0%)		0/3537 (0%)
Lower gastrointestinal haemorrhage	1/3545 (0%)		1/3537 (0%)
Oesophagitis	1/3545 (0%)		0/3537 (0%)
Pancreatic mass	1/3545 (0%)		0/3537 (0%)
Pancreatitis	4/3545 (0.1%)		0/3537 (0%)
Pancreatitis acute	1/3545 (0%)		1/3537 (0%)
Peptic ulcer	0/3545 (0%)		4/3537 (0.1%)
Peptic ulcer perforation	1/3545 (0%)		0/3537 (0%)
Pneumoperitonium	0/3545 (0%)		1/3537 (0%)
Rectal haemorrhage	1/3545 (0%)		1/3537 (0%)
Small intestinal obstruction	0/3545 (0%)		4/3537 (0.1%)
Upper gastrointestinal haemorrhage	4/3545 (0.1%)		7/3537 (0.2%)
Volvulus	1/3545 (0%)		0/3537 (0%)
General disorders
Chest pain	7/3545 (0.2%)		3/3537 (0.1%)
Hernia obstructive	0/3545 (0%)		1/3537 (0%)
Multi-organ failure	3/3545 (0.1%)		1/3537 (0%)
Non-cardiac chest pain	1/3545 (0%)		1/3537 (0%)
Pyrexia	1/3545 (0%)		2/3537 (0.1%)
Hepatobiliary disorders
Bile duct stone	1/3545 (0%)		0/3537 (0%)
Cholecystitis	7/3545 (0.2%)		2/3537 (0.1%)
Cholecystitis chronic	1/3545 (0%)		0/3537 (0%)
Cholelithiasis	4/3545 (0.1%)		4/3537 (0.1%)
Chronic hepatic failure	1/3545 (0%)		0/3537 (0%)
Hepatic cirrhosis	1/3545 (0%)		0/3537 (0%)
Jaundice	0/3545 (0%)		1/3537 (0%)
Immune system disorders
Drug hypersensitivity	1/3545 (0%)		0/3537 (0%)
Infections and infestations
Appendicitis	1/3545 (0%)		2/3537 (0.1%)
Arthritis bacterial	0/3545 (0%)		1/3537 (0%)
Arthritis infective	0/3545 (0%)		1/3537 (0%)
Bronchitis	5/3545 (0.1%)		1/3537 (0%)
Cellulitis	2/3545 (0.1%)		3/3537 (0.1%)
Cellulitis staphylococcal	1/3545 (0%)		0/3537 (0%)
Cystitis	0/3545 (0%)		1/3537 (0%)
Diverticulitis	1/3545 (0%)		2/3537 (0.1%)
Escherichia sepsis	1/3545 (0%)		0/3537 (0%)
Gastroenteritis	5/3545 (0.1%)		6/3537 (0.2%)
Gastroenteritis viral	0/3545 (0%)		1/3537 (0%)
Herpes zoster	0/3545 (0%)		1/3537 (0%)
Incision site infection	0/3545 (0%)		1/3537 (0%)
Infected skin ulcer	1/3545 (0%)		0/3537 (0%)
Infectious peritonitis	1/3545 (0%)		1/3537 (0%)
Laryngitis	1/3545 (0%)		0/3537 (0%)
Leptospirosis	1/3545 (0%)		0/3537 (0%)
Lobar pneumonia	2/3545 (0.1%)		1/3537 (0%)
Lower respiratory tract infection	0/3545 (0%)		1/3537 (0%)
Meningitis aseptic	0/3545 (0%)		1/3537 (0%)
Peritonsillar abscess	0/3545 (0%)		1/3537 (0%)
Pneumonia	32/3545 (0.9%)		35/3537 (1%)
Pneumonia viral	1/3545 (0%)		0/3537 (0%)
Pulmonary Tuberculosis	2/3545 (0.1%)		2/3537 (0.1%)
Pyelonephritis acute	0/3545 (0%)		1/3537 (0%)
Sepsis	3/3545 (0.1%)		2/3537 (0.1%)
Septic shock	3/3545 (0.1%)		3/3537 (0.1%)
Staphylococcal infection	0/3545 (0%)		1/3537 (0%)
Streptococcal sepsis	1/3545 (0%)		1/3537 (0%)
Tetanus	0/3545 (0%)		1/3537 (0%)
Tracheobronchitis	1/3545 (0%)		0/3537 (0%)
Tuberculosis	1/3545 (0%)		0/3537 (0%)
Upper respiratory tract infection	1/3545 (0%)		0/3537 (0%)
Urinary tract infection	8/3545 (0.2%)		6/3537 (0.2%)
Urosepsis	0/3545 (0%)		1/3537 (0%)
Wound abscess	0/3545 (0%)		1/3537 (0%)
Injury, poisoning and procedural complications
Back injury	1/3545 (0%)		0/3537 (0%)
Brain herniation	0/3545 (0%)		1/3537 (0%)
Clavicle fracture	0/3545 (0%)		1/3537 (0%)
Concussion	1/3545 (0%)		0/3537 (0%)
Craniocerebral injury	0/3545 (0%)		1/3537 (0%)
Facial bones fracture	0/3545 (0%)		1/3537 (0%)
Fall	1/3545 (0%)		0/3537 (0%)
Femoral neck fracture	2/3545 (0.1%)		1/3537 (0%)
Femur fracture	3/3545 (0.1%)		4/3537 (0.1%)
Foot fracture	0/3545 (0%)		1/3537 (0%)
Forearm Fracture	0/3545 (0%)		1/3537 (0%)
Hip fracture	1/3545 (0%)		3/3537 (0.1%)
Humerus Fracture	0/3545 (0%)		1/3537 (0%)
Incisional hernia	0/3545 (0%)		1/3537 (0%)
Jaw fracture	0/3545 (0%)		1/3537 (0%)
Laceration	0/3545 (0%)		1/3537 (0%)
Lower limb fracture	1/3545 (0%)		0/3537 (0%)
Multiple injuries	1/3545 (0%)		0/3537 (0%)
Nerve injury	1/3545 (0%)		0/3537 (0%)
Pelvic fracture	0/3545 (0%)		1/3537 (0%)
Perirenal haematoma	0/3545 (0%)		1/3537 (0%)
Post procedural haemorrhage	1/3545 (0%)		0/3537 (0%)
Postoperative adhesion	0/3545 (0%)		1/3537 (0%)
Radius fracture	0/3545 (0%)		1/3537 (0%)
Seroma	0/3545 (0%)		1/3537 (0%)
Spinal compression fracture	1/3545 (0%)		0/3537 (0%)
Spinal cord injury	0/3545 (0%)		1/3537 (0%)
Subdural haematoma	1/3545 (0%)		0/3537 (0%)
Thoracic vertebral fracture	0/3545 (0%)		1/3537 (0%)
Tibia fracture	1/3545 (0%)		0/3537 (0%)
Traumatic liver injury	0/3545 (0%)		1/3537 (0%)
Wound dehiscence	0/3545 (0%)		1/3537 (0%)
Wrist fracture	2/3545 (0.1%)		0/3537 (0%)
Metabolism and nutrition disorders
Dehydration	1/3545 (0%)		1/3537 (0%)
Diabetes Mellitus	5/3545 (0.1%)		2/3537 (0.1%)
Diabetes mellitus inadequate control	2/3545 (0.1%)		2/3537 (0.1%)
Diabetic foot	2/3545 (0.1%)		1/3537 (0%)
Diabetic ketoacidosis	0/3545 (0%)		1/3537 (0%)
Electrolyte imbalance	1/3545 (0%)		0/3537 (0%)
Hyperglycaemia	2/3545 (0.1%)		1/3537 (0%)
Hypocalcaemia	0/3545 (0%)		1/3537 (0%)
Hypoglycaemia	2/3545 (0.1%)		0/3537 (0%)
Hypokalaemia	0/3545 (0%)		1/3537 (0%)
Hypomagnesaemia	0/3545 (0%)		1/3537 (0%)
Hyponatraemia	0/3545 (0%)		1/3537 (0%)
Malnutrition	0/3545 (0%)		1/3537 (0%)
Type 2 diabetes mellitus	3/3545 (0.1%)		0/3537 (0%)
Arthropathy	1/3545 (0%)		0/3537 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/3545 (0.1%)		3/3537 (0.1%)
Arthritis	3/3545 (0.1%)		0/3537 (0%)
Costochondritis	1/3545 (0%)		0/3537 (0%)
Gouty arthritis	1/3545 (0%)		0/3537 (0%)
Intervertebral disc degeneration	0/3545 (0%)		1/3537 (0%)
Intervertebral disc protrusion	0/3545 (0%)		3/3537 (0.1%)
Lumbar spinal stenosis	1/3545 (0%)		1/3537 (0%)
Osteoarthritis	7/3545 (0.2%)		12/3537 (0.3%)
Rhabdomyolysis	0/3545 (0%)		1/3537 (0%)
Spinal column stenosis	1/3545 (0%)		0/3537 (0%)
Spondylolisthesis	1/3545 (0%)		0/3537 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia	1/3545 (0%)		0/3537 (0%)
Acute myeloid leukaemia	1/3545 (0%)		1/3537 (0%)
Adenocarcinoma	0/3545 (0%)		1/3537 (0%)
B-cell lymphoma	0/3545 (0%)		1/3537 (0%)
Basal cell carcinoma	1/3545 (0%)		0/3537 (0%)
Bladder adenocarcinoma stage unspecified	0/3545 (0%)		1/3537 (0%)
Bladder cancer	1/3545 (0%)		0/3537 (0%)
Bladder transitional cell carcinoma	2/3545 (0.1%)		0/3537 (0%)
Brain neoplasm malignant	1/3545 (0%)		0/3537 (0%)
Breast cancer	1/3545 (0%)		3/3537 (0.1%)
Breast cancer stage II	1/3545 (0%)		0/3537 (0%)
Chronic myeloid leukaemia	1/3545 (0%)		0/3537 (0%)
Colon adenoma	0/3545 (0%)		1/3537 (0%)
Colon cancer	2/3545 (0.1%)		1/3537 (0%)
Gastric cancer	0/3545 (0%)		1/3537 (0%)
Gastrointestinal stromal tumor	0/3545 (0%)		1/3537 (0%)
Lung adenocarcinoma	1/3545 (0%)		1/3537 (0%)
Lung cancer metastatic	1/3545 (0%)		0/3537 (0%)
Lung carcinoma cell type unspecified stage IV	1/3545 (0%)		0/3537 (0%)
Lung neoplasm malignant	0/3545 (0%)		1/3537 (0%)
Lung squamous cell carcinoma stage unspecified	0/3545 (0%)		1/3537 (0%)
Malignant melanoma	1/3545 (0%)		0/3537 (0%)
Meningioma	1/3545 (0%)		0/3537 (0%)
Metastases to lung	0/3545 (0%)		1/3537 (0%)
Metastatic neoplasm	1/3545 (0%)		0/3537 (0%)
Neoplasm malignant	0/3545 (0%)		1/3537 (0%)
Non-small cell lung cancer	1/3545 (0%)		0/3537 (0%)
Oesophageal carcinoma	0/3545 (0%)		1/3537 (0%)
Ovarian adenoma	0/3545 (0%)		1/3537 (0%)
Pancreatic neoplasm	0/3545 (0%)		2/3537 (0.1%)
Prolymphocytic leukaemia	0/3545 (0%)		1/3537 (0%)
Prostrate cancer	2/3545 (0.1%)		4/3537 (0.1%)
Rectal cancer	1/3545 (0%)		0/3537 (0%)
Sarcoma	1/3545 (0%)		0/3537 (0%)
Squamous cell carcinoma of the cervix	0/3545 (0%)		1/3537 (0%)
Transitional cell carcinoma	2/3545 (0.1%)		0/3537 (0%)
Nervous system disorders
Ovarian cancer	0/3545 (0%)		1/3537 (0%)
Pancreatic carcinoma	0/3545 (0%)		1/3537 (0%)
Carotid artery disease	0/3545 (0%)		1/3537 (0%)
Carotid artery stenosis	1/3545 (0%)		1/3537 (0%)
Cerebellar infraction	1/3545 (0%)		1/3537 (0%)
Cerebral haemorrhage	3/3545 (0.1%)		2/3537 (0.1%)
Cerebral infraction	3/3545 (0.1%)		2/3537 (0.1%)
Cerebral ischaemia	0/3545 (0%)		1/3537 (0%)
Cerebrovascular accident	4/3545 (0.1%)		10/3537 (0.3%)
Cerebrovascular disorder	8/3545 (0.2%)		3/3537 (0.1%)
Cervical myelopathy	0/3545 (0%)		1/3537 (0%)
Cervicobrachial syndrome	0/3545 (0%)		1/3537 (0%)
Convulsion	2/3545 (0.1%)		0/3537 (0%)
Dementia alzheimer's type	1/3545 (0%)		1/3537 (0%)
Dementia with lewy bodies	1/3545 (0%)		0/3537 (0%)
Embolic stroke	0/3545 (0%)		1/3537 (0%)
Guillain-barre syndrome	0/3545 (0%)		1/3537 (0%)
Haemorrhage intracranial	1/3545 (0%)		1/3537 (0%)
Headcahe	0/3545 (0%)		1/3537 (0%)
Hemiplegia	1/3545 (0%)		0/3537 (0%)
Ishaemic stroke	0/3545 (0%)		3/3537 (0.1%)
Metabolic encephalopathy	0/3545 (0%)		1/3537 (0%)
Radiculopathy	1/3545 (0%)		0/3537 (0%)
Ruptured cerebral aneurysm	1/3545 (0%)		0/3537 (0%)
Stroke in evolution	0/3545 (0%)		1/3537 (0%)
Subarachnoid hemorrhage	1/3545 (0%)		1/3537 (0%)
Syncope	4/3545 (0.1%)		4/3537 (0.1%)
Transient ischemic attack	3/3545 (0.1%)		2/3537 (0.1%)
Vertebrobasilar insufficiency	0/3545 (0%)		1/3537 (0%)
VIIth nerve paralysis	1/3545 (0%)		0/3537 (0%)
Confusional state	0/3545 (0%)		1/3537 (0%)
Psychiatric disorders
Mental status change	1/3545 (0%)		0/3537 (0%)
Renal and urinary disorders
Azotemia	1/3545 (0%)		0/3537 (0%)
Calculus ureteric	1/3545 (0%)		0/3537 (0%)
Nephropathy	1/3545 (0%)		0/3537 (0%)
Obstructive uropathy	1/3545 (0%)		0/3537 (0%)
Renal Failure	2/3545 (0.1%)		0/3537 (0%)
Renal Failure acute	3/3545 (0.1%)		2/3537 (0.1%)
Renal failure chronic	2/3545 (0.1%)		2/3537 (0.1%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/3545 (0%)		1/3537 (0%)
Endometriosis	1/3545 (0%)		0/3537 (0%)
Prostatomegaly	0/3545 (0%)		1/3537 (0%)
Uterovaginal prolapse	0/3545 (0%)		1/3537 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/3545 (0%)		1/3537 (0%)
Asthma	1/3545 (0%)		0/3537 (0%)
Asthmatic crisis	0/3545 (0%)		1/3537 (0%)
Chronic obstructive pulmonary disease	10/3545 (0.3%)		14/3537 (0.4%)
Dyspnea	2/3545 (0.1%)		2/3537 (0.1%)
Hypoxia	1/3545 (0%)		0/3537 (0%)
Interstitial lung disease	1/3545 (0%)		0/3537 (0%)
Pleural effusion	1/3545 (0%)		2/3537 (0.1%)
Pneumonia aspiration	2/3545 (0.1%)		0/3537 (0%)
Pulmonary embolism	3/3545 (0.1%)		0/3537 (0%)
Pulmonary hypertension	1/3545 (0%)		0/3537 (0%)
Pulmonary mass	1/3545 (0%)		0/3537 (0%)
Pulmonary edema	1/3545 (0%)		1/3537 (0%)
Respiratory arrest	1/3545 (0%)		0/3537 (0%)
Respiratory failure	2/3545 (0.1%)		3/3537 (0.1%)
Upper airway obstruction	1/3545 (0%)		0/3537 (0%)
Angioedema	1/3545 (0%)		0/3537 (0%)
Vascular disorders
Aneurysm ruptured	0/3545 (0%)		1/3537 (0%)
Aortic aneurysm	3/3545 (0.1%)		1/3537 (0%)
Aortic dissection	0/3545 (0%)		1/3537 (0%)
Aortic stenosis	0/3545 (0%)		1/3537 (0%)
Arteriosclerosis	1/3545 (0%)		1/3537 (0%)
Hypertension	8/3545 (0.2%)		8/3537 (0.2%)
Hypertensive crisis	4/3545 (0.1%)		2/3537 (0.1%)
Hypotension	2/3545 (0.1%)		1/3537 (0%)
Peripheral artery aneurysm	1/3545 (0%)		1/3537 (0%)
Varicose ulceration	1/3545 (0%)		0/3537 (0%)
Other (Not Including Serious) Adverse Events
	aTIV (Pooled)		Licensed TIV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1678/3545 (47.3%)		1257/3537 (35.5%)
Gastrointestinal disorders
Diarrhoea	186/3545 (5.2%)		172/3537 (4.9%)
General disorders
Chills	258/3545 (7.3%)		176/3537 (5%)
Fatigue	480/3545 (13.5%)		379/3537 (10.7%)
Injection site erythema	292/3545 (8.2%)		255/3537 (7.2%)
Injection site pain	1172/3545 (33.1%)		643/3537 (18.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	315/3545 (8.9%)		293/3537 (8.3%)
Myalgia	536/3545 (15.1%)		360/3537 (10.2%)
Nervous system disorders
Headache	492/3545 (13.9%)		426/3537 (12%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.