Immunogenicity, Safety and Tolerability of a Trivalent Su... | NCT01867021

Status Module

Name	Class
Novartis Vaccines	INDUSTRY

Label	Type	Description	Intervention Names
Agriflu	Experimental	A single 0.5 mL dose of Investigational vaccine TIV (Agriflu) at visit 1, administered intramuscularly	Biological: Agriflu (TIV)
Fluvirin	Active Comparator	A single 0.5 mL dose of control vaccine TIVf (Fluvirin) at visit 1, administered intramuscularly	Biological: Fluvirin(TIVf)

Name	Type	Description	Arm Group Labels	Other Names
Fluvirin(TIVf)	Biological		Fluvirin	Trivalent Influenza Virus Vaccine (purified surface antigen, inactivated, egg-derived)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Hemagglutination Inhibition (HI) Geometric Mean Titers (GMTs) of TIV Group and TIVf Group for All Three Strains, in Healthy Adults Aged ≥50 Years	Non-inferiority of Postvaccination Hemagglutination Inhibition (HI) Geometric Mean Titers (GMTs) of TIV (Trivalent Subunit Inactivated Influenza Vaccine) Group Over the Corresponding TIVf Group for All Three Strains, three weeks after vaccination (day 22). The upper limit of the two-sided 95% confidence interval (CI) on the ratio of GMTs (GMT TIVf/GMT TIV) should not exceed the non-inferiority margin of 1.5.	Day 22
Percentages of Subjects Achieving Seroconversion (SC) in Antibody Titers in the TIV Group Compared With the Corresponding Percentages of Subjects in the TIVf Group for All Three Strains At Day 22, in Healthy Adults Aged ≥50 Years	Non-Inferiority was measured as the percentages of subjects who achieved seroconversion in HI titers three weeks (day 22) after vaccination of TIV compared with TIVf, against each of three vaccine strains. Seroconversion is defined as a prevaccination titer <10 and postvaccination HI ≥40 or as a prevaccination titer ≥10 and at minimum four-fold rise in postvaccination antibody titer. The upper limit of the two-sided 95% CI on the difference between the seroconversion rates (Seroconversion TIVf - SeroconversionTIV) should not exceed 10%.	Day 22

Secondary Outcomes

Measure	Description	Time Frame
Evaluation of Percentages of Subjects Who Achieved HI Seroconversion and HI Titer ≥1:40 Against Each of Three Strains After One Vaccination of TIV and TIVf Vaccine	Percentage of subjects achieving HI seroconversion against each of three vaccine strains was measured three weeks after vaccination of TIV and TIVf vaccine (day 22). Percentage of subjects who achieved HI titer ≥1:40 against each of three vaccine strains was measured three weeks after one vaccination of TIV and TIVf vaccine. According to Center for Biologics Evaluation and Research recommendations (CBER 2007), the criterion for seroconversion is considered met if the lower limit of the two-sided 95% CI for the percentage of subjects with HI seroconversion is ≥40% (<65 years) or ≥30% (≥65 years). As per the CBER criteria, the lower limit of the two-sided 95% CI for the percentage of subjects who achieved HI titer ≥ 1:40 should be ≥70% (<65 years) or ≥60% (≥65 years).

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Males and females aged 50 years and above, mentally competent, willing and able to give written informed consent prior to study entry and after the nature of the study has been explained according to local regulatory requirements.
Individuals able to comply with all the study requirements.
Individuals in good health as determined by the outcome of medical history, physical examination and clinical judgment of the investigator.

Exclusion Criteria:

Individuals with behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the subject's ability to participate in the study.
Individuals with any progressive or severe neurologic disorder, seizure disorder or Guillain-Barré syndrome.
Individuals who are not able to comprehend and to follow all required study procedures for the whole period of the study.
Individuals who have received any seasonal or pandemic influenza vaccine or have had a laboratory confirmed seasonal or pandemic influenza disease within the past 6 months.
Individuals with history or any illness that, in the opinion of the investigator, might interfere with the results of the study or pose additional risk to the subjects due to participation in the study.
Individuals with positive HIV test result, with history of an autoimmune disorder or any other known or suspected impairment /alteration of the immune system, or under immunosuppressive therapy within 6 months or use of any parenteral or oral corticosteroids within the previous 30 days.
Individuals with a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time.
Individuals with any serious chronic or progressive disease according to judgment of the investigator (neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease).
Individuals who have any malignancy (excluding nonmelanotic skin cancer) or lymphoproliferative disorder.
Individuals with history of any anaphylactic adverse event and/or serious allergic adverse event following a vaccination, a proven hypersensitivity to any component of the study vaccine (eg, to eggs or eggs product as well as ovalbumin, chicken protein, chicken feathers, influenza viral protein, kanamycin and neomycin sulphate) or latex allergy.
Individuals participating in any clinical trial with another investigational product 30 days prior to first study visit or intent to participate in another clinical study at any time during the conduct of this study.
Receipt of nonstudy vaccines (with the exception of post-exposure vaccination in a medical emergency, eg, hepatitis, rabies, tetanus) within 3 weeks prior to Visit 1.
Individuals who have ever received blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation in the past 12 weeks.
Individuals who have received antibiotics within 6 days before vaccination.
Individuals with body temperature (axillary temperature) ≥38 degrees Celsius (≥ 100.4° F) within the last 3 days of intended study vaccination.
BMI > 35 kg/m2.
Female who are pregnant or nursing (breastfeeding) mothers or females of childbearing potential do not plan to use acceptable birth control measures, for the whole duration of the study. Adequate contraception is defined as hormonal (eg, oral, injection, transdermal patch, implant, cervical ring), barrier (eg, condom with spermicide or diaphragm with spermicide), intrauterine device (IUD), or monogamous relationship with vasectomized partner who has been vasectomized for 6 months or more prior to the subject's study entry; Abstinence.
Individuals who are part of study personnel or close family members conducting this study.
Individuals with history of substance or alcohol abuse within the past 2 years.

Name	Affiliation	Role
Novartis Vaccines	Novartis Vaccines	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Site 71 - Ordinace všeobecného lékaře		Kbel	Benátky Nad Jizerou	294 71	Czechia
Site 70 - Vaccination and Travel Medicine Centre

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Agriflu	Subjects ≥50 years of age who received one vaccination of an investigational vaccine TIV
FG001	Fluvirin	Subjects ≥50 years of age who received one vaccination of a control vaccine TIVf

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

ID	Title	Description
BG000	Agriflu	Subjects ≥50 years of age who received one vaccination of an investigational vaccine TIV
BG001	Fluvirin	Subjects ≥50 years of age who received one vaccination of a control vaccine TIVf
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG0001452 BG0011450 BG0022902

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Hemagglutination Inhibition (HI) Geometric Mean Titers (GMTs) of TIV Group and TIVf Group for All Three Strains, in Healthy Adults Aged ≥50 Years

Non-inferiority of Postvaccination Hemagglutination Inhibition (HI) Geometric Mean Titers (GMTs) of TIV (Trivalent Subunit Inactivated Influenza Vaccine) Group Over the Corresponding TIVf Group for All Three Strains, three weeks after vaccination (day 22).

The upper limit of the two-sided 95% confidence interval (CI) on the ratio of GMTs (GMT TIVf/GMT TIV) should not exceed the non-inferiority margin of 1.5.

Analysis was done on the per-protocol set 1 (PPS1) , ie, the subjects who received the vaccine correctly; provided evaluable serum samples at visit 2; and had no major protocol violations as defined prior to analysis.

Geometric Mean

95% Confidence Interval

Titers

Day 22

ID	Title	Description
OG000	Agriflu	Subjects ≥50 years of age who received one vaccination of an investigational vaccine TIV
OG001	Fluvirin	Subjects ≥50 years of age who received one vaccination of a control vaccine TIVf

Units	Counts
Participants	OG0001402 OG0011397

Title

Denominators

Categories

A/H1N1(1401, 1397)

Title	Measurements
	OG000315(281 to 352) OG001581(519 to 651)

A/H3N2(1401, 1397)

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Non-inferiority of HI GMTs of TIV vaccine over HI GMTs of TIVf vaccine for the strain A/H1N1 at day 22	ANCOVA	Not applicable(NA)			Ratio of GMTs	1.85			2-Sided	95	1.66	2.06				Yes	Non-Inferiority or Equivalence	The HI GMTs of TIV vaccine for strain A/H1N1 considered non-inferior to HI GMTs of TIVf vaccine if the upper limit of the two-sided 95% CI on the ratio of GMTs (GMT TIVf / GMT TIV) was ≤1.5

Primary

Percentages of Subjects Achieving Seroconversion (SC) in Antibody Titers in the TIV Group Compared With the Corresponding Percentages of Subjects in the TIVf Group for All Three Strains At Day 22, in Healthy Adults Aged ≥50 Years

Non-Inferiority was measured as the percentages of subjects who achieved seroconversion in HI titers three weeks (day 22) after vaccination of TIV compared with TIVf, against each of three vaccine strains.

Seroconversion is defined as a prevaccination titer <10 and postvaccination HI ≥40 or as a prevaccination titer ≥10 and at minimum four-fold rise in postvaccination antibody titer.

The upper limit of the two-sided 95% CI on the difference between the seroconversion rates (Seroconversion TIVf - SeroconversionTIV) should not exceed 10%.

Analysis was done on the PPS2, i.e. the subjects who received the vaccine correctly; provided evaluable serum samples at visit 1 and visit 2; and had no major protocol violations as defined prior to analysis

Number

95% Confidence Interval

percentages of subjects

Day 22

ID	Title	Description
OG000	Agriflu	Subjects ≥50 years of age who received one vaccination of an investigational vaccine TIV
OG001	Fluvirin	Subjects ≥50 years of age who received one vaccination of a control vaccine TIVf

Secondary

Evaluation of Percentages of Subjects Who Achieved HI Seroconversion and HI Titer ≥1:40 Against Each of Three Strains After One Vaccination of TIV and TIVf Vaccine

Percentage of subjects achieving HI seroconversion against each of three vaccine strains was measured three weeks after vaccination of TIV and TIVf vaccine (day 22).

Percentage of subjects who achieved HI titer ≥1:40 against each of three vaccine strains was measured three weeks after one vaccination of TIV and TIVf vaccine.

According to Center for Biologics Evaluation and Research recommendations (CBER 2007), the criterion for seroconversion is considered met if the lower limit of the two-sided 95% CI for the percentage of subjects with HI seroconversion is ≥40% (<65 years) or ≥30% (≥65 years).

As per the CBER criteria, the lower limit of the two-sided 95% CI for the percentage of subjects who achieved HI titer ≥ 1:40 should be ≥70% (<65 years) or ≥60% (≥65 years).

Analysis was done on the PPS1 for HI Titer ≥1:40 at day 22 and PPS2 for Seroconversion

Number

95% Confidence Interval

Percentages of subjects

Day 22

ID	Title	Description
OG000	≥50 to ≤64 years_Agriflu	Subjects ≥50 to ≤64 years of age who received an investigational vaccine TIV
OG001	≥50 to ≤64 years_Fluvirin	Subjects ≥50 to ≤64 years of age who received a control vaccine TIVf
OG002

Secondary

Geometric Mean Ratio of Subjects Against Each of Three Strains After One Vaccination of TIV and TIVf Vaccine

Geometric mean ratio (GMR) of subjects was calculated as the ratio of postvaccination to prevaccination HI GMTs against each of three vaccine strains, three weeks after vaccination of TIV and TIVf vaccine (day 22).

Analysis was done on the PPS1

Geometric Mean

95% Confidence Interval

Ratios

Day 22

ID	Title	Description
OG000	≥50 to ≤64 years_Agriflu	Subjects ≥50 to ≤64 years of age who received an investigational vaccine TIV
OG001	≥50 to ≤64 years_Fluvirin	Subjects ≥50 to ≤64 years of age who received a control vaccine TIVf
OG002	≥65 years_Agriflu	Subjects ≥65 years of age who received an investigational vaccine TIV
OG003	≥65 years_Fluvirin	Subjects ≥65 years of age who received a control vaccine TIVf

Secondary

Number of Subjects Who Reported Solicited Local and Systemic Adverse Events After One Vaccination of TIV and TIVf

Safety was assessed as the number of subjects who reported solicited local and systemic adverse events from day 1 up to and including day 7 after vaccination of TIV and control.

Analysis was done on the safety dataset, i.e. the subjects in the exposed population who provided postvaccination safety data.

Number

Subjects

Day 1 to 7 postvaccination

ID	Title	Description
OG000	Agriflu	Subjects ≥50 years of age who received one vaccination of an investigational vaccine TIV
OG001	Fluvirin	Subjects ≥50 years of age who received one vaccination of a control vaccine TIVf

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
MYOCARDIAL INFARCTION	Cardiac disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected1,452 at risk EG0011 affected1,445 at risk EG0022 affected2,897 at risk
DYSPEPSIA	Gastrointestinal disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected1,452 at risk EG0010 affected1,445 at risk EG0021 affected2,897 at risk
PEPTIC ULCER	Gastrointestinal disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected1,452 at risk EG0010 affected1,445 at risk EG0021 affected2,897 at risk
CHOLELITHIASIS	Hepatobiliary disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected1,452 at risk EG0010 affected1,445 at risk EG0021 affected2,897 at risk
JAUNDICE CHOLESTATIC	Hepatobiliary disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected1,452 at risk EG0011 affected1,445 at risk EG0021 affected2,897 at risk
URINARY TRACT INFECTION	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0001 affected1,452 at risk EG0010 affected1,445 at risk EG0021 affected2,897 at risk
FEMUR FRACTURE	Injury, poisoning and procedural complications	MedDRA 16.1	Systematic Assessment	EG0000 affected1,452 at risk EG0011 affected1,445 at risk EG0021 affected2,897 at risk
BASAL GANGLIA HAEMORRHAGE	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected1,452 at risk EG0011 affected1,445 at risk EG0021 affected2,897 at risk
CEREBROVASCULAR ACCIDENT	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected1,452 at risk EG0011 affected1,445 at risk EG0021 affected2,897 at risk
HYPERTENSION	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected1,452 at risk EG0011 affected1,445 at risk EG0021 affected2,897 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Fatigue	General disorders	MedDRA 16.1	Systematic Assessment	EG000144 affected1,452 at risk EG001146 affected1,445 at risk EG002290 affected2,897 at risk
Injection Site Pain	General disorders	MedDRA 16.1	Systematic Assessment	EG000281 affected1,452 at risk EG001276 affected1,445 at risk EG002557 affected2,897 at risk
Malaise	General disorders	MedDRA 16.1	Systematic Assessment	EG00089 affected1,452 at risk EG00195 affected1,445 at risk EG002184 affected2,897 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG00085 affected1,452 at risk EG00188 affected1,445 at risk EG002173 affected2,897 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG000133 affected1,452 at risk EG001141 affected1,445 at risk EG002274 affected2,897 at risk
Headach	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG000159 affected1,452 at risk EG001164 affected1,445 at risk EG002323 affected2,897 at risk
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA 16.1	Systematic Assessment	EG00099 affected1,452 at risk EG001103 affected1,445 at risk EG002202 affected2,897 at risk

ID	Term
D012141	Respiratory Tract Infections
D007239	Infections
D009976	Orthomyxoviridae Infections
D012327	RNA Virus Infections
D014777	Virus Diseases
D012140	Respiratory Tract Diseases

ID	Term
D014765	Viral Vaccines
D014612	Vaccines
D001688	Biological Products
D045424	Complex Mixtures

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Agriflu	Subjects ≥50 years of age who received one vaccination of an investigational vaccine TIV	3	1,452	471	1,452
EG001	Fluvirin	Subjects ≥50 years of age who received one vaccination of a control vaccine TIVf	5	1,445	467	1,445
EG002	Total	Total number of Subjects	8	2,897	938	2,897