A Study of Fluzone® High-Dose Vaccine Compared With Fluzone® Vaccine In Elderly Adults

Efficacy Study of Fluzone® High-Dose Vaccine Compared With Fluzone® Vaccine In Elderly Adults

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01427309

Enrollment

31989

Registered

2011-09-01

Start date

2011-09-30

Completion date

2013-11-30

Last updated

2015-04-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Influenza

Keywords

Influenza, Trivalent Inactivated Influenza Vaccine, High-Dose Trivalent Inactivated Influenza Vaccine, Fluzone® High-Dose, Influenza vaccines

Brief summary

The aim of this study is to determine the efficacy of Fluzone High-Dose compared to standard dose Fluzone for laboratory-confirmed or culture-confirmed influenza caused by influenza types/subtypes that are similar (for laboratory-confirmed) or antigenically similar (for culture-confirmed) to those contained in the respective annual vaccine formulations. Primary Objective: * To compare the clinical efficacy of Fluzone High-Dose to that of Fluzone in elderly adults, with respect to laboratory-confirmed influenza caused by any influenza viral types/subtypes, associated with the occurrence of a protocol-defined influenza-like-illnesses (ILI). Secondary Objectives: * To compare the clinical efficacy of Fluzone High-Dose to that of Fluzone in elderly adults, with respect to laboratory-confirmed influenza, caused by any influenza viral types/subtypes, associated with the occurrence of a protocol-defined ILI. * To compare the clinical efficacy of Fluzone High-Dose to that of Fluzone in elderly adults, with respect to culture-confirmed influenza, caused by any influenza viral types/subtypes, associated with the occurrence of a protocol-defined ILI. * To compare the clinical efficacy of Fluzone High-Dose to that of Fluzone in elderly adults, with respect to culture-confirmed influenza caused by viral types/subtypes antigenically similar to those contained in the respective annual vaccine formulations, associated with the occurrence of a modified Centers for Disease Control and Prevention (CDC)-defined ILI. * To compare the clinical efficacy of Fluzone High-Dose to that of Fluzone in elderly adults, with respect to culture-confirmed influenza caused by any influenza viral types/subtypes, associated with the occurrence of a modified CDC-defined ILI. * To compare the clinical efficacy of Fluzone High-Dose to that of Fluzone in elderly adults, with respect to culture-confirmed influenza caused by viral types/subtypes antigenically similar to those contained in the respective annual vaccine formulations, associated with the occurrence of a respiratory illness. * To compare the clinical efficacy of Fluzone High-Dose to that of Fluzone in elderly adults, with respect to culture-confirmed influenza caused by any influenza viral types/subtypes, associated with the occurrence of a respiratory illness.

Detailed description

The trial will span 2 influenza seasons. Each study year, participants will be randomized to receive one dose of either Fluzone® High-Dose or Fluzone® vaccine prior to the start of the influenza season and will be followed until the end of each season. The duration of each participant's participation in the respective study year will be 6 to 8 months, depending on the time of enrollment.

Interventions

BIOLOGICALHigh Dose Trivalent Inactivated Influenza Vaccine

0.5 mL Intramuscular

BIOLOGICALTrivalent Inactivated Influenza Vaccine

0.5 mL, Intramuscular

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

65 Years to No maximum

Healthy volunteers

Yes

Inclusion criteria

* Aged ≥ 65 years on the day of vaccination * Informed consent form signed and dated * Able to attend all scheduled visits and to comply with all trial procedures.

Exclusion criteria

* Participation at the time of study enrollment (or in the 4 weeks preceding the trial vaccination), or planned participation during each year of the trial period, in another clinical trial investigating a vaccine, drug, medical device, or medical procedure (Note: Concomitant participation in an observational trial is acceptable) * Vaccination against influenza in the 6 months preceding the trial vaccination * Systemic hypersensitivity to eggs, chicken proteins, or any of the vaccine components, or a history of a life-threatening reaction to Fluzone High-Dose or Fluzone vaccine or to a vaccine containing any of the same substances * Personal history of Guillain-Barré Syndrome * Dementia or any other cognitive condition at a stage that could interfere with following the trial procedures * Thrombocytopenia contraindicating intramuscular (IM) vaccination, as judged by the investigator * Bleeding disorder or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination, as judged by the investigator * Current alcohol abuse or drug addiction * Subject deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily * Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study * Moderate or severe acute illness with or without fever (oral temperature \> 99.0ºF \[\> 37.2ºC\]). If this contraindication exists, vaccination will be deferred until the individual has been medically stable and/or afebrile (temperature ≤ 99.0 ºF \[≤ 37.2ºC\]) for at least 24 hours * Signs and symptoms of an acute infectious respiratory illness. If this exists, vaccination will be deferred until the symptoms resolve.

Design outcomes

Primary

Measure	Time frame	Description
Occurrences of Culture- or Polymerase Chain Reaction (PCR)-Confirmed Influenza Caused by Any Influenza Viral Types/Subtypes, in Association With a Protocol-defined Influenza-like Illness (ILI).	≥14 days post-vaccination	Influenza positive cultures were confirmed using direct immunofluorescence techniques with influenza type-specific antibodies. 3 culture methods were utilized for each NP sample (Classic Flu A and B culture using Madin Darby Canine Kidney cells, Classic Flu A and B culture using Rhesus Monkey Kidney cells, and R Mix Flu A and B culture). The initial molecular test (PCR) was the validated ProFlu+™ assay by Prodesse, Inc., Waukesha, WI, which had been approved by the Food and Drug Administration through a 510K evaluation for specific detection of Influenza A, B or Respiratory Syncytial Virus. A protocol-defined influenza-like illness was determined by the occurrence of at least 1 of the following respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrently with at least one of the following systemic symptoms: fever (defined as temperature \> 99.0°F \[\> 37.2°C\]), chills (shivering), tiredness (fatigue), headache, or myalgia (muscle aches).

Secondary

Measure	Time frame	Description
Occurrences of Culture-confirmed Influenza Caused by Influenza Viral Types/Subtypes That Are Antigenically Similar to Those Contained in the Vaccine Formulations, in Association With a Protocol-defined Influenza-like Illness (ILI)	≥14 days post-vaccination	Influenza positive cultures were confirmed by using direct immunofluorescence techniques with influenza type-specific (i.e., for Influenza A and Influenza B) antibodies. For culture confirmation of influenza, 3 different culture methods were utilized for each NP sample (Classic Flu A and B culture using Madin Darby Canine Kidney \[MDCK\] cells, Classic Flu A and B culture using Rhesus Monkey Kidney \[RhMK\] cells, and R Mix Flu A and B culture. For antigenic similarity determinations, a standard hemagglutination inhibition test using a panel of ferret antisera (ferret antigenicity testing) was used.
Occurrences of Culture-confirmed Influenza Caused by Any Influenza Viral Types/Subtypes, in Association With a Protocol-defined Influenza-like Illness	≥14 days post-vaccination	For culture confirmation of influenza, 3 different culture methods were utilized for each NP sample (Classic Flu A and B culture using Madin Darby Canine Kidney \[MDCK\] cells, Classic Flu A and B culture using Rhesus Monkey Kidney \[RhMK\] cells, and R Mix Flu A and B culture). A protocol-defined influenza-like illness (ILI) was determined by the occurrence of at least one of the following respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrently with at least one of the following systemic symptoms: fever (defined as temperature \> 99.0°F \[\> 37.2°C\]), chills (shivering), tiredness (fatigue), headache, or myalgia (muscle aches).
Occurrences of Culture-confirmed Influenza Caused by Influenza Viral Types/Subtypes That Are Antigenically Similar to Those Contained in the Vaccine Formulations, in Association With a Modified CDC-defined Influenza-like Illness.	≥14 days post-vaccination	Influenza positive cultures were confirmed by using direct immunofluorescence techniques with influenza type-specific antibodies. For culture confirmation of influenza, 3 different culture methods were utilized for each NP sample (Classic Flu A and B culture using Madin Darby Canine Kidney cells, Classic Flu A and B culture using Rhesus Monkey Kidney cells, and R Mix Flu A and B culture). For antigenic similarity determinations, a standard hemagglutination inhibition test using a panel of ferret antisera (ferret antigenicity testing) was used. The modified Centers for Disease Control and Prevention-defined influenza-like illness is the occurrence of fever (defined as temperature \> 99.0°F \[\> 37.2°C\]) with cough or sore throat.
Occurrences of Culture-confirmed Influenza Caused by Influenza Viral Types/Subtypes That Are Antigenically Similar to Those Contained in the Vaccine Formulations, in Association With a Respiratory Illness	≥14 days post-vaccination	Influenza positive cultures were confirmed by using direct immunofluorescence techniques with influenza type-specific antibodies. For culture confirmation of influenza, 3 different culture methods were utilized for each NP sample (Classic Flu A and B culture using Madin Darby Canine Kidney cells, Classic Flu A and B culture using Rhesus Monkey Kidney cells, and R Mix Flu A and B culture). For antigenic similarity determinations, a standard hemagglutination inhibition test using a panel of ferret antisera (ferret antigenicity testing) was used. Respiratory illness was defined as the occurrence of a new onset (or exacerbation of a pre-existing condition/symptom) of one or more of the following symptoms (that persist for or reoccur after a period of at least 12 hours): sneezing, stuffy or runny nose (nasal congestion), sore throat, cough, sputum production, wheezing, or difficulty breathing.
Occurrences of Culture-confirmed Influenza Caused by Any Influenza Viral Types/Subtypes, in Association With a Respiratory Illness	≥14 days post-vaccination	Influenza positive cultures were confirmed by using direct immunofluorescence techniques with influenza type-specific (i.e., for Influenza A and Influenza B) antibodies. For culture confirmation of influenza, 3 different culture methods were utilized for each NP sample (Classic Flu A and B culture using Madin Darby Canine Kidney cells, Classic Flu A and B culture using Rhesus Monkey Kidney cells, and R Mix Flu A and B culture). Respiratory illness is defined as the occurrence of a new onset (or exacerbation of a pre-existing condition/symptom) of one or more of the following symptoms (that persist for or reoccur after a period of at least 12 hours): sneezing, stuffy or runny nose (nasal congestion), sore throat, cough, sputum production, wheezing, or difficulty breathing.
Occurrences of Culture-confirmed Influenza Caused by Any Influenza Viral Types/Subtypes, in Association With a Modified CDC-defined Influenza-like Illness	≥14 days post-vaccination	Influenza positive cultures were confirmed by using direct immunofluorescence techniques with influenza type-specific antibodies. For culture confirmation of influenza, 3 different culture methods were utilized for each NP sample (Classic Flu A and B culture using Madin Darby Canine Kidney cells, Classic Flu A and B culture using Rhesus Monkey Kidney cells, and R Mix Flu A and B culture). For antigenic similarity determinations, a standard hemagglutination inhibition test using a panel of ferret antisera (ferret antigenicity testing) was used. The modified Centers for Disease Control and Prevention-defined influenza-like illness is the occurrence of fever (defined as temperature \> 99.0°F \[\> 37.2°C\]) with cough or sore throat.

Other

Measure	Time frame	Description
Safety Overview After Injection With Either Fluzone High Dose or Fluzone Vaccine Through the End of Surveillance Period	Day 0 up to Day 240 post-vaccination	All serious adverse events, including deaths and adverse events (AEs) of special interest (Guillain Barre Syndrome, Bell's Palsy, encephalitis/myelitis, optic neuritis, Stevens Johnson Syndrome, and toxic epidermal necrolysis) were collected.

Countries

Canada, Puerto Rico, United States

Participant flow

Recruitment details

The study participants were enrolled from 06 September through 09 October 2011 for Year 1; and 09 through 21 October 2012 for Year 2 at 126 sites in the United States and Canada.

Pre-assignment details

A total of 31,989 participants were enrolled 31,983 were randomized and vaccinated in this study.

Participants by arm

Arm	Count
Fluzone® High Dose Vaccine (Year 1) Adults ≥65 years of age received one dose of Fluzone High Dose vaccine	7,253
Fluzone® Vaccine (Year 1) Adults ≥65 years of age received one dose of Fluzone vaccine	7,244
Fluzone® High Dose Vaccine (Year 2) Adults ≥65 years of age received one dose of Fluzone High Dose vaccine	8,737
Fluzone® Vaccine (Year 2) Adults ≥65 years of age received one dose of Fluzone vaccine	8,749
Total	31,983

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	0	0	3	1
Overall Study	Lost to Follow-up	130	145	122	135
Overall Study	Protocol Violation	42	69	125	124
Overall Study	Serious adverse event	52	45	50	61
Overall Study	Withdrawal by Subject	148	148	61	55

Baseline characteristics

Characteristic	Fluzone® High Dose Vaccine (Year 1)	Fluzone® Vaccine (Year 1)	Fluzone® High Dose Vaccine (Year 2)	Fluzone® Vaccine (Year 2)	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	7253 Participants	7244 Participants	8737 Participants	8749 Participants	31983 Participants
Age, Categorical Between 18 and 65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Continuous	73.3 Years STANDARD_DEVIATION 5.88	73.2 Years STANDARD_DEVIATION 5.82	73.3 Years STANDARD_DEVIATION 5.74	73.4 Years STANDARD_DEVIATION 5.85	73.3 Years STANDARD_DEVIATION 5.82
Region of Enrollment Canada	300 Participants	300 Participants	422 Participants	423 Participants	1445 Participants
Region of Enrollment United States	6953 Participants	6944 Participants	8315 Participants	8326 Participants	30538 Participants
Sex: Female, Male Female	4085 Participants	4041 Participants	5046 Participants	4922 Participants	18094 Participants
Sex: Female, Male Male	3168 Participants	3203 Participants	3691 Participants	3827 Participants	13889 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	0 / 7,254	0 / 7,243	0 / 8,738	0 / 8,748
serious Total, serious adverse events	680 / 7,254	704 / 7,243	643 / 8,738	738 / 8,748

Outcome results

Primary

Occurrences of Culture- or Polymerase Chain Reaction (PCR)-Confirmed Influenza Caused by Any Influenza Viral Types/Subtypes, in Association With a Protocol-defined Influenza-like Illness (ILI).

Influenza positive cultures were confirmed using direct immunofluorescence techniques with influenza type-specific antibodies. 3 culture methods were utilized for each NP sample (Classic Flu A and B culture using Madin Darby Canine Kidney cells, Classic Flu A and B culture using Rhesus Monkey Kidney cells, and R Mix Flu A and B culture). The initial molecular test (PCR) was the validated ProFlu+™ assay by Prodesse, Inc., Waukesha, WI, which had been approved by the Food and Drug Administration through a 510K evaluation for specific detection of Influenza A, B or Respiratory Syncytial Virus. A protocol-defined influenza-like illness was determined by the occurrence of at least 1 of the following respiratory symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrently with at least one of the following systemic symptoms: fever (defined as temperature \> 99.0°F \[\> 37.2°C\]), chills (shivering), tiredness (fatigue), headache, or myalgia (muscle aches).