Safety and Immunogenicity of a Cell Culture-derived Influenza Vaccine in Healthy Adults and Elderly

• Sponsor: Novartis Vaccines (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00492063
• Collaborator: (none)
• Enrollment: 2,654
• Locations: 5
• Arms: 2
• Duration (Months): 8
• Patients Per Site: 530.8
• Patients Per Site Per Month: 66.8

Study Details

Study Description

Brief Summary

The present study aims to evaluate the safety and immunogenicity of the new influenza subunit vaccine produced in Madin Darby Canine Kidney (MDCK) cells in healthy adult and elderly subjects.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Biological: Cell culture-derived trivalent subunit influenza vaccine (cTIV); Biological: Egg-derived trivalent subunit influenza vaccine (TIV)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 2654 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Prevention
• Official Title: A Phase III, Observer-Blind, Randomized, Multi-Center Study to Evaluate Safety, Tolerability and Immunogenicity of a Single Intramuscular Dose of a Trivalent Subunit Influenza Vaccine Produced in Mammalian Cell Culture and of a Trivalent Subunit Influenza Vaccine Produced in Embryonated Hen Eggs, in Healthy Adult and Elderly Subjects
• Study Start Date: Sep 1, 2004
• Actual Primary Completion Date: Dec 1, 2004
• Actual Study Completion Date: May 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cell culture-derived influenza vaccine (cTIV)	Biological: Cell culture-derived trivalent subunit influenza vaccine (cTIV); One vaccination (0.5 mL) of cell culture-derived influenza vaccine (cTIV) was administered in the deltoid muscle
Active Comparator: Egg-derived influenza virus vaccine (TIV)	Biological: Egg-derived trivalent subunit influenza vaccine (TIV); One vaccination (0.5 mL) of egg-derived influenza virus vaccine (TIV) was administered in the deltoid muscle

Outcome Measures

Primary Outcome Measures

1. Percentages Of Subjects Who Achieved HI Titer ≥40 After One Vaccination of Cell Culture-derived (cTIV) or Egg-derived (TIV) Influenza Subunit Vaccines [Before vaccination (day 1) and three weeks after vaccination (day 22)]

   Immunogenicity was measured as the percentage of adults (≥18 to ≤60 years) and elderly (≥61 years) achieving HI titers ≥40 at baseline (day 1) and three weeks (day 22) after one vaccination of cTIV or TIV vaccine for each of three vaccine strains, evaluated using the hemagglutination inhibition (HI) egg-derived antigen assay. In compliance with the requirements of the EMEA recommendations (CPMP/BWP/2490/00, CPMP/BWP/214/96), this criterion is met if the percentage of subjects achieving HI titers ≥40 is >70% in the ≥18 to ≤60 years of age group or >60% in the ≥61 years of age group.

2. Percentages Of Subjects Who Achieved Seroconversion Or Significant Increase In HI Titer After One Vaccination of cTIV or TIV [Three weeks after vaccination (day 22)]

   Seroconversion or significant in HI titer is defined as the percentage of subjects with a prevaccination HI titer <10 (negative) to a postvaccination titer ≥40; or in subjects with prevaccination HI titer ≥10, at least a 4-fold increase in postvaccination HI titer. In compliance with the requirements of the EMEA recommendations (CPMP/BWP/2490/00, CPMP/BWP/214/96), the criterion is met if the percentage of subjects achieving seroconversion/significant increase is >40% in the ≥18 to ≤60 years of age group or >30% in the ≥61 years of age group.

3. Geometric Mean Ratio of Subjects After One Vaccination of cTIV or TIV [Three weeks after vaccination (day 22)]

   Immunogenicity was measured as the geometric mean ratio (GMR), calculated as the ratio of postvaccination to prevaccination HI Geometric Mean Titers (GMTs), three weeks after (day 22) one vaccination of cTIV or TIV. In compliance with the requirements of the EMEA recommendations (CPMP/BWP/2490/00, CPMP/BWP/214/96), this criterion is met if the GMR (day 22/day 1) in HI antibody titer is >2.5 in the ≥18 to ≤60 years of age group or >2.0 in the ≥61 years of age group.

Secondary Outcome Measures

1. Number of Subjects Who Reported Solicited Local and Systemic Reactions up to 7 Days After Vaccination [Up to 7 days postvaccination]

   The solicited local and systemic reactions were collected from day 1 up to and including day 7 after vaccination for both the vaccine groups.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. 18 to 60 years of age (first age group) OR over 60 years of age (second age group)

2. mentally competent to understand the nature, the scope and the consequences of the study

3. able and willing to give written informed consent prior to study entry

4. available for all the visits scheduled in the study

5. residence in the study area

6. in good health as determined by:

7. medical history,

8. physical examination,

9. clinical judgment of the investigator.

Exclusion Criteria:

1. unable or unwilling to give written informed consent to participate in the study

2. suffering from an acute infectious disease

3. any serious disease such as:

4. cancer (except for benign or localized skin cancer and non metastatic prostate cancer not currently treated with chemotherapy),_

5. autoimmune disease (including rheumatoid arthritis),

6. advanced arteriosclerotic disease or complicated diabetes mellitus,

7. chronic obstructive pulmonary disease (COPD) requiring oxygen therapy,

8. acute or progressive hepatic disease,

9. acute or progressive renal disease,

10. congestive heart failure

11. surgery planned during the study period

12. bleeding diathesis

13. history of hypersensitivity to any component of the study medication or chemically related substances, such as allergy to eggs or egg products

14. known or suspected impairment/alteration of immune function resulting from:

15. receipt of immunosuppressive therapy (any cortical steroid or cancer chemotherapy),

16. receipt of immunostimulants,

17. receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within the past 3 months and for the full length of the study,

18. high risk for developing an immunocompromising disease within the past 6 months

19. history of drug or alcohol abuse

20. laboratory confirmed influenza disease in the past 6 months

21. received influenza vaccine within the past 6 months

22. received another vaccine or any investigational agent within the past 60 days, or planned vaccination within 3 weeks following the study vaccination

23. any acute respiratory disease or infections requiring systemic antibiotic or antiviral therapy (chronic antibiotic therapy for urinary tract prophylaxis was acceptable) or experienced fever ≥ 38°C within the past 3 days

24. pregnant women or women who refused to use a reliable contraceptive method throughout the study (180 days)

25. any condition which, in the opinion of the investigator, might have interfered with the evaluation of the study objectives.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wojewódzki Szpital Dzieciecy	ul. Langiewicza 2	Kielce	Poland	25-381
2	N ZOZ Jagiellonskie, Centrum Medyczne Sp. z o.o.	os. Jagiellonskie 1	Kraków	Poland	31-832
3	Praktyka Grupowa Lekarzy POZ "Familia"	Pl. Sikorskiego 6a	Kraków	Poland	31-115
4	Szpital Jana Pawła II	ul. Pradnicka 80	Kraków	Poland	31-202
5	Centrum Farmakologii Klinicznej	Krakow		Poland	30-969

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: NCT00492063
• Other Study ID Numbers: V58P4
• First Posted: Jun 27, 2007
• Last Update Posted: Jan 1, 2016
• Last Verified: Dec 1, 2015

• Keywords provided by Novartis Vaccines: safety; immunogenicity; non-inferiority; MDCK; cell culture-derived; subunit influenza vaccine; influenza prevention
• Additional relevant MeSH terms: Influenza, Human; Vaccines

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled at 5 sites in Poland.
Pre-assignment Detail	All enrolled subjects were included in the trial.

Arm/Group Title	cTIV (Adults)	TIV (Adults)	cTIV (Elderly)	TIV (Elderly)
Arm/Group Description	Subjects ≥18 to ≤60 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥18 to ≤60 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)	Subjects ≥61 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥61 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)
Period Title: Overall Study
STARTED	652	648	678	676
COMPLETED	642	634	667	666
NOT COMPLETED	10	14	11	10

Baseline Characteristics

Arm/Group Title	cTIV (Adults)	TIV (Adults)	cTIV (Elderly)	TIV (Elderly)	Total
Arm/Group Description	Subjects ≥18 to ≤60 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥18 to ≤60 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)	Subjects ≥61 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥61 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)	Total of all reporting groups
Overall Participants	652	648	678	676	2654
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	38.7 (12.7)	38.3 (13.3)	69.1 (5.7)	68.8 (5.6)	54.0 (18.2)
Sex: Female, Male (Count of Participants)
Female	376 57.7%	371 57.3%	389 57.4%	375 55.5%	1511 56.9%
Male	276 42.3%	277 42.7%	289 42.6%	301 44.5%	1143 43.1%

Outcome Measures

1. Primary Outcome

Title	Percentages Of Subjects Who Achieved HI Titer ≥40 After One Vaccination of Cell Culture-derived (cTIV) or Egg-derived (TIV) Influenza Subunit Vaccines
Description	Immunogenicity was measured as the percentage of adults (≥18 to ≤60 years) and elderly (≥61 years) achieving HI titers ≥40 at baseline (day 1) and three weeks (day 22) after one vaccination of cTIV or TIV vaccine for each of three vaccine strains, evaluated using the hemagglutination inhibition (HI) egg-derived antigen assay. In compliance with the requirements of the EMEA recommendations (CPMP/BWP/2490/00, CPMP/BWP/214/96), this criterion is met if the percentage of subjects achieving HI titers ≥40 is >70% in the ≥18 to ≤60 years of age group or >60% in the ≥61 years of age group.
Time Frame	Before vaccination (day 1) and three weeks after vaccination (day 22)

Outcome Measure Data

Analysis Population Description

Analysis was done on the per-protocol (PP) set, i.e. the subjects who received the vaccination correctly; provided evaluable data before and after vaccination; and with no major protocol violations, as defined before unblinding.

Arm/Group Title	cTIV (Adults)	TIV (Adults)	cTIV (Elderly)	TIV (Elderly)
Arm/Group Description	Subjects ≥18 to ≤60 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥18 to ≤60 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)	Subjects ≥61 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥61 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)
Measure Participants	650	644	672	674
A/H1N1 (Day 1)	29	33	30	31
A/H1N1 (Day 22)	92	92	85	85
A/H3N2 (Day 1)	65	63	66	59
A/H3N2 (Day 22)	99	99	97	98
B (Day 1)	16	18	23	20
B (Day 22)	90	91	90	89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	cTIV (Adults), TIV (Adults)
	Comments	Non-inferiority testing in immune response (HI titer ≥40) of cTIV to that of TIV vaccine for strain A/H1N1 after one vaccination in adults.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with HI titer ≥40 in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with HI titer ≥40 in the cTIV group is non-inferior to that of TIV group if, for strain A/H1N1, the lower limit of the 95% CI of the difference in the percentages is greater than -10%)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -3 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	cTIV (Adults), TIV (Adults)
	Comments	Non-inferiority testing in immune response (HI titer ≥40) of cTIV to that of TIV vaccine for strain A/H3N2 after one vaccination in adults.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with HI titer ≥40 in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with HI titer ≥40 in the cTIV group is non-inferior to that of TIV group if, for strain A/H3N2, the lower limit of the 95% CI of the difference in the percentages is greater than -10%)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -1 to 2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	cTIV (Adults), TIV (Adults)
	Comments	Non-inferiority testing in immune response (HI titer ≥40) of cTIV to that of TIV vaccine for strain B after one vaccination in adults.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with HI titer ≥40 in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with HI titer ≥40 in the cTIV group is non-inferior to that of TIV group if, for strain B, the lower limit of the 95% CI of the difference in the percentages is greater than -10%)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -3 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	cTIV (Elderly), TIV (Elderly)
	Comments	Non-inferiority testing in immune response (HI titer ≥40) of cTIV to that of TIV vaccine for strain A/H1N1 after one vaccination in the elderly population.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with HI titer ≥40 in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with HI titer ≥40 in the cTIV group is non-inferior to that of TIV group if, for strain A/H1N1, the lower limit of the 95% CI of the difference in the percentages is greater than -10%)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -4 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	cTIV (Elderly), TIV (Elderly)
	Comments	Non-inferiority testing in immune response (HI titer ≥40) of cTIV to that of TIV vaccine for strain A/H3N2 after one vaccination in the elderly population.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with HI titer ≥40 in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with HI titer ≥40 in the cTIV group is non-inferior to that of TIV group if, for strain A/H3N2, the lower limit of the 95% CI of the difference in the percentages is greater than -10%)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -2 to 1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	cTIV (Elderly), TIV (Elderly)
	Comments	Non-inferiority testing in immune response (HI titer ≥40) of cTIV to that of TIV vaccine for strain B after one vaccination in the elderly population.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with HI titer ≥40 in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with HI titer ≥40 in the cTIV group is non-inferior to that of TIV group if, for strain B, the lower limit of the 95% CI of the difference in the percentages is greater than -10%)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	1
	Confidence Interval	(2-Sided) 95%; -2 to 4
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Percentages Of Subjects Who Achieved Seroconversion Or Significant Increase In HI Titer After One Vaccination of cTIV or TIV
Description	Seroconversion or significant in HI titer is defined as the percentage of subjects with a prevaccination HI titer <10 (negative) to a postvaccination titer ≥40; or in subjects with prevaccination HI titer ≥10, at least a 4-fold increase in postvaccination HI titer. In compliance with the requirements of the EMEA recommendations (CPMP/BWP/2490/00, CPMP/BWP/214/96), the criterion is met if the percentage of subjects achieving seroconversion/significant increase is >40% in the ≥18 to ≤60 years of age group or >30% in the ≥61 years of age group.
Time Frame	Three weeks after vaccination (day 22)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the PP set.

Arm/Group Title	cTIV (Adults)	TIV (Adults)	cTIV (Elderly)	TIV (Elderly)
Arm/Group Description	Subjects ≥18 to ≤60 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥18 to ≤60 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)	Subjects ≥61 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥61 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)
Measure Participants	650	644	672	674
A/H1N1	69	67	55	55
A/H3N2	63	64	68	65
B	85	81	80	73

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	cTIV (Adults), TIV (Adults)
	Comments	Non-inferiority testing in immune response (seroconversion or significant increase in HI titer) after one vaccination of cTIV to that of TIV vaccine for strain A/H1N1 in adults.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with seroconversion or significant increase in HI titer in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with seroconversion or significant in HI titer of cTIV group is non-inferior to that of the TIV group if, for strain A/H1N1, the lower limit of the 95% CI of the difference in the percentages is greater than -10%).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	2
	Confidence Interval	(2-Sided) 95%; -3 to 7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	cTIV (Adults), TIV (Adults)
	Comments	Non-inferiority testing in immune response (seroconversion or significant increase in HI titer) after one vaccination of cTIV to that of TIV vaccine for strain A/H3N2 in adults.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with seroconversion or significant increase in HI titer in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with seroconversion or significant in HI titer of cTIV group is non-inferior to that of the TIV group if, for strain A/H3N2, the lower limit of the 95% CI of the difference in the percentages is greater than -10%).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -6 to 4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	cTIV (Adults), TIV (Adults)
	Comments	Non-inferiority testing in immune response (seroconversion or significant increase in HI titer) after one vaccination of cTIV to that of TIV vaccine for strain B in adults.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with seroconversion or significant increase in HI titer in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with seroconversion or significant in HI titer of cTIV group is non-inferior to that of the TIV group if, for strain B, the lower limit of the 95% CI of the difference in the percentages is greater than -10%).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	4
	Confidence Interval	(2-Sided) 95%; 0 to 8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	cTIV (Elderly), TIV (Elderly)
	Comments	Non-inferiority testing in immune response (seroconversion or significant increase in HI titer) after one vaccination of cTIV to that of TIV vaccine for strain A/H1N1 in the elderly population.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with seroconversion or significant increase in HI titer in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with seroconversion or significant in HI titer of cTIV group is non-inferior to that of the TIV group if, for strain A/H1N1, the lower limit of the 95% CI of the difference in the percentages is greater than -10%).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -6 to 5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	cTIV (Elderly), TIV (Elderly)
	Comments	Non-inferiority testing in immune response (seroconversion or significant increase in HI titer) after one vaccination of cTIV to that of TIV vaccine for strain A/H3N2 in the elderly population.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with seroconversion or significant increase in HI titer in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with seroconversion or significant in HI titer of cTIV group is non-inferior to that of the TIV group if, for strain A/H3N2, the lower limit of the 95% CI of the difference in the percentages is greater than -10%).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	3
	Confidence Interval	(2-Sided) 95%; -2 to 8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	cTIV (Elderly), TIV (Elderly)
	Comments	Non-inferiority testing in immune response (seroconversion or significant increase in HI titer) after one vaccination of cTIV to that of TIV vaccine for strain B in the elderly population.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The percentage of subjects with seroconversion or significant increase in HI titer in the cTIV group is >10% lower than in the TIV group (i.e., the percentage of subjects with seroconversion or significant in HI titer of cTIV group is non-inferior to that of the TIV group if, for strain B, the lower limit of the 95% CI of the difference in the percentages is greater than -10%).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Group difference
	Estimated Value	6
	Confidence Interval	(2-Sided) 95%; 2 to 11
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Geometric Mean Ratio of Subjects After One Vaccination of cTIV or TIV
Description	Immunogenicity was measured as the geometric mean ratio (GMR), calculated as the ratio of postvaccination to prevaccination HI Geometric Mean Titers (GMTs), three weeks after (day 22) one vaccination of cTIV or TIV. In compliance with the requirements of the EMEA recommendations (CPMP/BWP/2490/00, CPMP/BWP/214/96), this criterion is met if the GMR (day 22/day 1) in HI antibody titer is >2.5 in the ≥18 to ≤60 years of age group or >2.0 in the ≥61 years of age group.
Time Frame	Three weeks after vaccination (day 22)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the PP set.

Arm/Group Title	cTIV (Adults)	TIV (Adults)	cTIV (Elderly)	TIV (Elderly)
Arm/Group Description	Subjects ≥18 to ≤60 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥18 to ≤60 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)	Subjects ≥61 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥61 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)
Measure Participants	650	644	672	674
A/H1N1	11	11	5.74	5.96
A/H3N2	5.99	7.08	7.25	8.36
B	13	12	12	9.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	cTIV (Adults), TIV (Adults)
	Comments	Non-inferiority testing in immune response (GMR) after one vaccination of cTIV to that of TIV vaccine for strain A/H1N1 in adults.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The value of GMR ratio of cTIV to TIV is >0.5 (i.e., the GMR of the cTIV group is non-inferior to that of the TIV group if, for strain A/H1N1, the lower limit of the 95% CI for ratio of GMRs at day 22 is greater than 0.5).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMRs
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.9 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	cTIV (Adults), TIV (Adults)
	Comments	Non-inferiority testing in immune response (GMR) after one vaccination of cTIV to that of TIV vaccine for strain A/H3N2 in adults.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The value of GMR ratio of cTIV to TIV is >0.5 (i.e., the GMR of the cTIV group is non-inferior to that of the TIV group if, for strain A/H3N2, the lower limit of the 95% CI for ratio of GMRs at day 22 is greater than 0.5).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMRs
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.72 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	cTIV (Adults), TIV (Adults)
	Comments	Non-inferiority testing in immune response (GMR) after one vaccination of cTIV to that of TIV vaccine for strain B in adults.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The value of GMR ratio of cTIV to TIV is >0.5 (i.e., the GMR of the cTIV group is non-inferior to that of the TIV group if, for strain B, the lower limit of the 95% CI for ratio of GMRs at day 22 is greater than 0.5).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMRs
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.99 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	cTIV (Elderly), TIV (Elderly)
	Comments	Non-inferiority testing in immune response (GMR) after one vaccination of cTIV to that of TIV vaccine for strain A/H1N1 in the elderly population.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The value of GMR ratio of cTIV to TIV is >0.5 (i.e., the GMR of the cTIV group is non-inferior to that of the TIV group if, for strain A/H1N1, the lower limit of the 95% CI for ratio of GMRs at day 22 is greater than 0.5).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMRs
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	cTIV (Elderly), TIV (Elderly)
	Comments	Non-inferiority testing in immune response (GMR) after one vaccination of cTIV to that of TIV vaccine for strain A/H3N2 in the elderly population.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The value of GMR ratio of cTIV to TIV is >0.5 (i.e., the GMR of the cTIV group is non-inferior to that of the TIV group if, for strain A/H3N2, the lower limit of the 95% CI for ratio of GMRs at day 22 is greater than 0.5).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMRs
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	cTIV (Elderly), TIV (Elderly)
	Comments	Non-inferiority testing in immune response (GMR) after one vaccination of cTIV to that of TIV vaccine for strain B in the elderly population.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The value of GMR ratio of cTIV to TIV is >0.5 (i.e., the GMR of the cTIV group is non-inferior to that of the TIV group if, for strain B, the lower limit of the 95% CI for ratio of GMRs at day 22 is greater than 0.5).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMRs
	Estimated Value	1.27
	Confidence Interval	(2-Sided) 95%; 1.11 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Subjects Who Reported Solicited Local and Systemic Reactions up to 7 Days After Vaccination
Description	The solicited local and systemic reactions were collected from day 1 up to and including day 7 after vaccination for both the vaccine groups.
Time Frame	Up to 7 days postvaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on Safety population i.e., all subjects with vaccination and with some post-baseline safety data.

Arm/Group Title	cTIV (Adults)	TIV (Adults)	cTIV (Elderly)	TIV (Elderly)
Arm/Group Description	Subjects ≥18 to ≤60 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥18 to ≤60 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)	Subjects ≥61 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)	Subjects ≥61 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)
Measure Participants	652	648	678	676
Ecchymosis	18	22	26	25
Erythema	92	106	72	72
Induration	38	42	37	29
Swelling	25	27	23	17
Pain	141	111	64	32
Chills	25	29	23	26
Malaise	74	74	70	75
Myalgia	45	49	46	57
Arthralgia	31	27	41	44
Headache	81	79	69	70
Sweating	28	27	44	48
Fatigue	73	73	73	84
Fever (≥38°C)	2	5	5	5
Stayed home due to reaction	14	16	19	14
Analgesic/antipyretic medication used	44	40	34	29

Adverse Events

Time Frame	Throughout the study (day 1 to day 180)
Adverse Event Reporting Description	All serious adverse events (AEs) were collected throughout the study (day 1 to day 180).
Arm/Group Title	cTIV (Adults)		TIV (Adults)		cTIV (Elderly)		TIV (Elderly)
Arm/Group Description	Subjects ≥18 to ≤60 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)		Subjects ≥18 to ≤60 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)		Subjects ≥61 years of age who received one vaccination of cell culture-derived influenza virus vaccine (cTIV)		Subjects ≥61 years of age who received one vaccination of egg-derived influenza virus vaccine (TIV)
All Cause Mortality
	cTIV (Adults)		TIV (Adults)		cTIV (Elderly)		TIV (Elderly)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	cTIV (Adults)		TIV (Adults)		cTIV (Elderly)		TIV (Elderly)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/652 (1.1%)		5/648 (0.8%)		19/678 (2.8%)		18/676 (2.7%)
Cardiac disorders
Acute myocardial infarction	0/652 (0%)	0	1/648 (0.2%)	1	2/678 (0.3%)	2	0/676 (0%)	0
Atrial fibrillation	1/652 (0.2%)	1	0/648 (0%)	0	3/678 (0.4%)	3	2/676 (0.3%)	2
Angina pectoris	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Angina unstable	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	2/676 (0.3%)	2
Coronary artery disease	0/652 (0%)	0	0/648 (0%)	0	2/678 (0.3%)	2	0/676 (0%)	0
Myocardial ischaemia	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Ear and labyrinth disorders
Hypoacusis	2/652 (0.3%)	2	1/648 (0.2%)	1	0/678 (0%)	0	0/676 (0%)	0
Inner ear disorder	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Eye disorders
Angle closure glaucoma	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Retinal detachment	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Gastrointestinal disorders
Inguinal hernia	1/652 (0.2%)	1	0/648 (0%)	0	0/678 (0%)	0	0/676 (0%)	0
Colitis	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Diverticulum intestinal	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Dyspepsia	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Food poisoning	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Gastric haemorrhage	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Pancreatitis acute	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Hepatobiliary disorders
Cholecystitis acute	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Infections and infestations
Bronchopneumonia	1/652 (0.2%)	1	1/648 (0.2%)	1	0/678 (0%)	0	1/676 (0.1%)	1
Pneumonia	0/652 (0%)	0	0/648 (0%)	0	2/678 (0.3%)	2	1/676 (0.1%)	1
Injury, poisoning and procedural complications
Alcohol poisoning	1/652 (0.2%)	1	0/648 (0%)	0	0/678 (0%)	0	0/676 (0%)	0
Postoperative hernia	0/652 (0%)	0	1/648 (0.2%)	1	0/678 (0%)	0	0/676 (0%)	0
Carbon monoxide poisoning	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Procedural complication	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Tibia fracture	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign oesophageal neoplasm	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Gallbladder cancer	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Lung adenocarcinoma	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Lung neoplasm	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Lung squamous cell carcinoma	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Nervous system disorders
Carpal tunnel syndrome	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Cerebrovascular accident	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Sleep apnoea syndrome	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Syncope Vasovagal	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Renal and urinary disorders
Nephrolithiasis	1/652 (0.2%)	1	0/648 (0%)	0	0/678 (0%)	0	0/676 (0%)	0
Reproductive system and breast disorders
Uterine polyp	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive airways disease	0/652 (0%)	0	1/648 (0.2%)	1	0/678 (0%)	0	0/676 (0%)	0
Pulmonary embolism	0/652 (0%)	0	0/648 (0%)	0	1/678 (0.1%)	1	0/676 (0%)	0
Vascular disorders
Atherosclerosis obliterans	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Hypertension	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Hypertensive crisis	0/652 (0%)	0	0/648 (0%)	0	0/678 (0%)	0	1/676 (0.1%)	1
Other (Not Including Serious) Adverse Events
	cTIV (Adults)		TIV (Adults)		cTIV (Elderly)		TIV (Elderly)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	261/652 (40%)		257/648 (39.7%)		224/678 (33%)		207/676 (30.6%)
General disorders
Injection site erythema	92/652 (14.1%)	92	106/648 (16.4%)	106	72/678 (10.6%)	72	72/676 (10.7%)	72
Injection site induration	38/652 (5.8%)	38	42/648 (6.5%)	42	37/678 (5.5%)	37	29/676 (4.3%)	29
Injection site pain	141/652 (21.6%)	141	111/648 (17.1%)	111	64/678 (9.4%)	64	32/676 (4.7%)	32
Malaise	76/652 (11.7%)	76	75/648 (11.6%)	75	74/678 (10.9%)	74	76/676 (11.2%)	76
Fatigue	73/652 (11.2%)	73	73/648 (11.3%)	73	74/678 (10.9%)	74	85/676 (12.6%)	85
Musculoskeletal and connective tissue disorders
Arthralgia	37/652 (5.7%)	37	36/648 (5.6%)	36	48/678 (7.1%)	48	48/676 (7.1%)	48
Myalgia	46/652 (7.1%)	46	51/648 (7.9%)	51	47/678 (6.9%)	47	58/676 (8.6%)	58
Nervous system disorders
Headache	87/652 (13.3%)	87	88/648 (13.6%)	88	75/678 (11.1%)	75	75/676 (11.1%)	75
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/652 (0%)	0	0/648 (0%)	0	45/678 (6.6%)	45	48/676 (7.1%)	48

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.