Safety and Immunogenicity of Flublok Quadrivalent vs IIV4 in Adults 18-49 Years of Age

• Sponsor: Protein Sciences Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02290509
• Collaborator: Syneos Health (Other), Department of Health and Human Services (U.S. Fed)
• Enrollment: 1,350
• Locations: 10
• Arms: 2
• Duration (Months): 7
• Patients Per Site: 135
• Patients Per Site Per Month: 19.4

Study Details

Study Description

Brief Summary

Randomized, double-blind trial of safety and immunogenicity of Flublok Quadrivalent versus Inactivated Influenza Vaccine (IIV4) in 1350 healthy, medically stable adults 18-49 years of age. Serum samples for Hemagglutinin Inhibition titers will be determined pre- and 28 days post-vaccination. Subjects will be followed for 6 months after vaccination for serious and/or medically-attended adverse events.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Biological: Flublok Quadrivalent; Biological: Inactivated Influenza Vaccine (IIV4)	Phase 3

Detailed Description

As the spectrum of influenza vaccines rapidly evolves to quadrivalent formulations with the intention of offering broader protection to include both lineages of influenza B strains, it is appropriate to transition Flublok from a trivalent to a quadrivalent formulation. The demonstration of non-inferior post-vaccination Hemagglutination Inhibition Assay (HAI) Geometric Mean Titers (GMTs) to antigens in the Flublok Quadrivalent formulation compared to those of the matching antigens in a US - approved IIV4 is intended to support licensure of Flublok Quadrivalent for the adult population for which Flublok trivalent is currently approved. The comparison of safety and reactogenicity of Flublok Quadrivalent to that of IIV4 is expected to confirm a similar safety profile.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1350 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Double-Blind, Randomized, Active-Controlled Comparison of the Immunogenicity and Safety of Flublok® Quadrivalent Versus IIV4 in Healthy, Medically Stable Adults 18-49 Years of Age
• Study Start Date: Oct 1, 2014
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Flublok Quadrivalent Influenza Vaccine Intramuscular injection of vaccine containing 4 x 45µg (180µg total) of each recombinant hemagglutinin (rHA) derived from influenza A/H1N1 and A/H3N2 and two lineages of influenza B viruses identified for the season in which the trial is conducted in a total volume of 0.5 mL	Biological: Flublok Quadrivalent; Intramuscular injection of study vaccine
Active Comparator: Inactivated Influenza Vaccine (IIV4) Intramuscular injection of vaccine contains 4 x 15µg (60µg total) of HA derived from the same influenza A/H1N1 and A/H3N2 and influenza B strains in a total volume of 0.5mL.	Biological: Inactivated Influenza Vaccine (IIV4); Intramuscular injection of study vaccine

Outcome Measures

Primary Outcome Measures

1. Seroconversion to Vaccine Antigens Following Vaccination With Quadrivalent Vaccine [Day 28 after final vaccination]

   Seroconversion is defined as: Either a pre vaccination titer < 10 (1/dil) and a post vaccination titer ≥ 40 (1/dil), or a pre vaccination titer ≥ 10 (1/dil) and a ≥ 4 fold increase in post vaccination titer at Day 28 after the final vaccination.

2. Geometric Mean Titers of Antibodies to Vaccine Antigens Following Vaccination With Quadrivalent Vaccine [Day 0 and Day 28 after final vaccination]

   Immunogenicity will be evaluated prior to vaccination and at 28 days after vaccination using the hemagglutination inhibition (HAI) technique. For each influenza vaccine strain, pre and post vaccination geometric mean titers (GMTs) were calculated.

Secondary Outcome Measures

1. Number of Participants With Systemic and Injection Site Reactogenicity [Days 0-7]

2. Number of Participants With Serious Adverse Events (SAEs) and Medically-attended Adverse Events (MAEs) [Six months post-vaccination]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 49 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Ambulatory, in good health or medically stable

• Able to understand and comply with planned study procedures

• Provide written informed consent

• Negative urine pregnancy test within 24 hours prior to vaccination (women of child-bearing potential)

Exclusion Criteria:

• Prior serious or severe reaction to influenza vaccine

• Known contraindication to either study vaccine

• Receipt of any other influenza vaccine within 180 days prior to enrollment

• Plan to receive another licensed influenza or other vaccine during the duration of this study

• Receipt of any significant new diagnosis, medication (licensed or investigational), or licensed vaccine within 30 days prior to enrollment in this study

• Underlying disease or therapeutic intervention that might adversely affect the immune response

• Plans to participate in any investigation involving an investigational product during this study.

• Pregnant, lactating or planning to become pregnant within 30 days of study vaccine.

• Any clinical or social circumstance that in the opinion of the investigator could interfere with compliance with study procedures or interfere with the interpretation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Benchmark Research - Sacramento	Sacramento	California	United States	95816
2	Clinical Research of South Florida	Coral Gables	Florida	United States	33134
3	Meridian Clinical Research	Savannah	Georgia	United States	31406
4	Heartland Research Associates, LLC	Wichita	Kansas	United States	67207
5	Benchmark Research	Metairie	Louisiana	United States	70006
6	Meridian Research	Bellevue	Nebraska	United States	68005
7	Meridian Clinical Research	Omaha	Nebraska	United States	68164
8	Meridian Research	Dakota Dunes	South Dakota	United States	57049
9	Benchmark Reseach	Austin	Texas	United States	78705
10	Benchmark Research - Fort Worth	Fort Worth	Texas	United States	76135

Sponsors and Collaborators

• Protein Sciences Corporation
• Syneos Health
• Department of Health and Human Services

Investigators

• Principal Investigator: William Seger, MD, Benchmark Research, Fort Worth, TX

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Protein Sciences Corporation
• ClinicalTrials.gov Identifier: NCT02290509
• Other Study ID Numbers: PSC16
• First Posted: Nov 14, 2014
• Last Update Posted: Oct 27, 2016
• Last Verified: Sep 1, 2016

Study Results

Participant Flow

Arm/Group Title	Flublok Quadrivalent Influenza Vaccine	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Intramuscular injection of vaccine containing 4 x 45µg (180µg total) of each recombinant hemagglutinin (rHA) derived from influenza A/H1N1 and A/H3N2 and two lineages of influenza B viruses identified for the season in which the trial is conducted in a total volume of 0.5 mL Flublok Quadrivalent: Intramuscular injection of study vaccine	Intramuscular injection of vaccine contains 4 x 15µg (60µg total) of HA derived from the same influenza A/H1N1 and A/H3N2 and influenza B strains in a total volume of 0.5mL. Inactivated Influenza Vaccine (IIV4): Intramuscular injection of study vaccine
Period Title: Overall Study
STARTED	1011	339
COMPLETED	962	325
NOT COMPLETED	49	14

Baseline Characteristics

Arm/Group Title	Flublok Quadrivalent Influenza Vaccine	Inactivated Influenza Vaccine (IIV4)	Total
Arm/Group Description	Intramuscular injection of vaccine containing 4 x 45µg (180µg total) of each recombinant hemagglutinin (rHA) derived from influenza A/H1N1 and A/H3N2 and two lineages of influenza B viruses identified for the season in which the trial is conducted in a total volume of 0.5 mL Flublok Quadrivalent: Intramuscular injection of study vaccine	Intramuscular injection of vaccine contains 4 x 15µg (60µg total) of HA derived from the same influenza A/H1N1 and A/H3N2 and influenza B strains in a total volume of 0.5mL. Inactivated Influenza Vaccine (IIV4): Intramuscular injection of study vaccine	Total of all reporting groups
Overall Participants	998	332	1330
Age, Customized (participants) [Number]
18-49 years	998 100%	332 100%	1330 100%
Sex: Female, Male (Count of Participants)
Female	639 64%	222 66.9%	861 64.7%
Male	359 36%	110 33.1%	469 35.3%
Region of Enrollment (participants) [Number]
United States	998 100%	332 100%	1330 100%

Outcome Measures

1. Primary Outcome

Title	Seroconversion to Vaccine Antigens Following Vaccination With Quadrivalent Vaccine
Description	Seroconversion is defined as: Either a pre vaccination titer < 10 (1/dil) and a post vaccination titer ≥ 40 (1/dil), or a pre vaccination titer ≥ 10 (1/dil) and a ≥ 4 fold increase in post vaccination titer at Day 28 after the final vaccination.
Time Frame	Day 28 after final vaccination

Outcome Measure Data

Analysis Population Description

The immunogenicity population includes all randomized subjects who received a dose of study vaccine, provided serum samples for baseline (Day 0) and Day 28 HAI titers (within the specified windows) and have no major protocol deviations that might have adversely affect the immune response.

Arm/Group Title	Flublok Quadrivalent Influenza Vaccine	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Intramuscular injection of vaccine containing 4 x 45µg (180µg total) of each recombinant hemagglutinin (rHA) derived from influenza A/H1N1 and A/H3N2 and two lineages of influenza B viruses identified for the season in which the trial is conducted in a total volume of 0.5 mL Flublok Quadrivalent: Intramuscular injection of study vaccine	Intramuscular injection of vaccine contains 4 x 15µg (60µg total) of HA derived from the same influenza A/H1N1 and A/H3N2 and influenza B strains in a total volume of 0.5mL. Inactivated Influenza Vaccine (IIV4): Intramuscular injection of study vaccine
Measure Participants	969	323
A/H1N1/California	66.7 6.7%	63.5 19.1%
A/H3N2/Texas	72.1 7.2%	57.0 17.2%
B/Massachusetts	59.6 6%	60.4 18.2%
B/Brisbane	40.6 4.1%	58.2 17.5%

2. Secondary Outcome

Title	Number of Participants With Systemic and Injection Site Reactogenicity
Time Frame	Days 0-7

Outcome Measure Data

Analysis Population Description

The Reactogenicity Population includes subjects who recorded any systemic reaction data and injection site reaction data following administration of study vaccine. This was two subjects less than the Safety Population.

Arm/Group Title	Flublok Quadrivalent Influenza Vaccine	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Intramuscular injection of vaccine containing 4 x 45µg (180µg total) of each recombinant hemagglutinin (rHA) derived from influenza A/H1N1 and A/H3N2 and two lineages of influenza B viruses identified for the season in which the trial is conducted in a total volume of 0.5 mL Flublok Quadrivalent: Intramuscular injection of study vaccine	Intramuscular injection of vaccine contains 4 x 15µg (60µg total) of HA derived from the same influenza A/H1N1 and A/H3N2 and influenza B strains in a total volume of 0.5mL. Inactivated Influenza Vaccine (IIV4): Intramuscular injection of study vaccine
Measure Participants	996	332
Subjects with one or more injection site reaction	510 51.1%	172 51.8%
Subjects with one or more systemic reaction event	339 34%	119 35.8%

3. Secondary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs) and Medically-attended Adverse Events (MAEs)
Time Frame	Six months post-vaccination

Outcome Measure Data

Analysis Population Description

The safety population includes all randomized and vaccinated subjects who provided any safety data (solicited or unsolicited) following administration of study vaccine.

Arm/Group Title	Flublok Quadrivalent Influenza Vaccine	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Intramuscular injection of vaccine containing 4 x 45µg (180µg total) of each recombinant hemagglutinin (rHA) derived from influenza A/H1N1 and A/H3N2 and two lineages of influenza B viruses identified for the season in which the trial is conducted in a total volume of 0.5 mL Flublok Quadrivalent: Intramuscular injection of study vaccine	Intramuscular injection of vaccine contains 4 x 15µg (60µg total) of HA derived from the same influenza A/H1N1 and A/H3N2 and influenza B strains in a total volume of 0.5mL. Inactivated Influenza Vaccine (IIV4): Intramuscular injection of study vaccine
Measure Participants	998	332
Serious adverse events (SAEs)	10 1%	2 0.6%
Medically-attended adverse events (MAEs)	80 8%	24 7.2%

4. Primary Outcome

Title	Geometric Mean Titers of Antibodies to Vaccine Antigens Following Vaccination With Quadrivalent Vaccine
Description	Immunogenicity will be evaluated prior to vaccination and at 28 days after vaccination using the hemagglutination inhibition (HAI) technique. For each influenza vaccine strain, pre and post vaccination geometric mean titers (GMTs) were calculated.
Time Frame	Day 0 and Day 28 after final vaccination

Outcome Measure Data

Analysis Population Description

The immunogenicity population includes all randomized subjects who received a dose of study vaccine, provided serum samples for baseline (Day 0) and Day 28 HAI titers (within the specified windows) and have no major protocol deviations that might have adversely affect the immune response.

Arm/Group Title	Flublok Quadrivalent Influenza Vaccine	Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Intramuscular injection of vaccine containing 4 x 45µg (180µg total) of each recombinant hemagglutinin (rHA) derived from influenza A/H1N1 and A/H3N2 and two lineages of influenza B viruses identified for the season in which the trial is conducted in a total volume of 0.5 mL Flublok Quadrivalent: Intramuscular injection of study vaccine	Intramuscular injection of vaccine contains 4 x 15µg (60µg total) of HA derived from the same influenza A/H1N1 and A/H3N2 and influenza B strains in a total volume of 0.5mL. Inactivated Influenza Vaccine (IIV4): Intramuscular injection of study vaccine
Measure Participants	969	323
Day 0 - A/H1N1/California	60	54
Day 28 - A/H1N1/California	502	407
Day 0 - A/H3N2/Texas	75	70
Day 28 - A/H3N2/Texas	757	385
Day 0 - B/Massachusetts	27	24
Day 28 - B/Massachusetts	159	136
Day 0 - B/Brisbane	12	11
Day 28 - B/Brisbane	43	64

Adverse Events

Time Frame	All AEs collected 28 days after study immunization and all Serious Adverse Events (SAEs) collected through six (6) months after study immunization.
Adverse Event Reporting Description	The safety population includes all randomized and vaccinated subjects who provided any safety data (solicited or unsolicited) following administration of study vaccine.
Arm/Group Title	Flublok Quadrivalent Influenza Vaccine		Inactivated Influenza Vaccine (IIV4)
Arm/Group Description	Intramuscular injection of vaccine containing 4 x 45µg (180µg total) of each recombinant hemagglutinin (rHA) derived from influenza A/H1N1 and A/H3N2 and two lineages of influenza B viruses identified for the season in which the trial is conducted in a total volume of 0.5 mL Flublok Quadrivalent: Intramuscular injection of study vaccine		Intramuscular injection of vaccine contains 4 x 15µg (60µg total) of HA derived from the same influenza A/H1N1 and A/H3N2 and influenza B strains in a total volume of 0.5mL. Inactivated Influenza Vaccine (IIV4): Intramuscular injection of study vaccine
All Cause Mortality
	Flublok Quadrivalent Influenza Vaccine		Inactivated Influenza Vaccine (IIV4)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Flublok Quadrivalent Influenza Vaccine		Inactivated Influenza Vaccine (IIV4)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/998 (1%)		2/332 (0.6%)
Cardiac disorders
Myocardial infarction	2/998 (0.2%)		0/332 (0%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	0/998 (0%)		1/332 (0.3%)
Pancreatitis	0/998 (0%)		1/332 (0.3%)
Small intestinal obstruction	1/998 (0.1%)		0/332 (0%)
Hepatobiliary disorders
Cholecystitis	0/998 (0%)		1/332 (0.3%)
Infections and infestations
Appendicitis	1/998 (0.1%)		0/332 (0%)
Periumbilical abcess	1/998 (0.1%)		0/332 (0%)
Injury, poisoning and procedural complications
Road traffic accident	1/998 (0.1%)		0/332 (0%)
Musculoskeletal and connective tissue disorders
Neck pain	1/998 (0.1%)		0/332 (0%)
Nervous system disorders
Metabolic encephalopathy	1/998 (0.1%)		0/332 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/998 (0.1%)		0/332 (0%)
Reproductive system and breast disorders
Ovarian cyst	1/998 (0.1%)		0/332 (0%)
Surgical and medical procedures
Arm amputation	1/998 (0.1%)		0/332 (0%)
Other (Not Including Serious) Adverse Events
	Flublok Quadrivalent Influenza Vaccine		Inactivated Influenza Vaccine (IIV4)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/998 (6.3%)		24/332 (7.2%)
Infections and infestations
Nasophayngitis	13/998 (1.3%)		5/332 (1.5%)
Upper respiratory tract infection	10/998 (1%)		5/332 (1.5%)
Sinusitis	6/998 (0.6%)		5/332 (1.5%)
Nervous system disorders
Headache	20/998 (2%)		5/332 (1.5%)
Respiratory, thoracic and mediastinal disorders
Cough	14/998 (1.4%)		4/332 (1.2%)

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 less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.