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

A Phase III, Randomized, Controlled, Observer-Blind, Multicenter Study to Evaluate the Safety and Immunogenicity and the Consistency of Three Consecutive Lots of a MF59C.1 Adjuvanted Trivalent Subunit Influenza Vaccine in Elderly Subjects Aged 65 Years and Older

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

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Biological: MF59 adjuvanted trivalent subunit influenza vaccine (aTIV); Biological: Non-adjuvanted trivalent subunit influenza vaccine (TIV)

• Study Type: Interventional
• Enrollment (Actual): 7109
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. Individuals with behavioral or cognitive impairment or a psychiatric condition or with a history of any illness that,in the opinion of the investigator, would have interfered with the subject's ability to participate in the study.
2. Individuals who were not able to comprehend and/or follow all required study procedures for the whole period of the study.
3. Known or suspected impairment/alteration of immune function.
4. Individuals with a known bleeding diathesis.
5. History of Guillain-Barré syndrome.
6. Individuals with history of allergy to vaccine components and/or a history of any anaphylaxis, serious vaccine reactions or hypersensitivity to influenza viral proteins, egg proteins (including ovalbumin), polymyxin, neomycin, betapropiolactone, thimerosal/ sodium ethylmercurothiosalicylate/ mercury and nonylphenolethoxylate/ nonoxynol-9 (spermicide).
7. Receipt of another investigational agent within 30 days prior to enrollment in the study or before completion of the safety follow-up period in another study.
8. Individuals who had received any other vaccines within 2 weeks for inactivated vaccines or 4 weeks for live vaccines prior to enrollment in this study or who had planned to receive any vaccine within 3 weeks from the study vaccine.
9. Individuals who had received vaccination against seasonal influenza in the previous 6 months.
10. Individuals with oral temperature ≥38.0°C (≥100.4°F) on day of study vaccination.
11. Individuals with history of substance or alcohol abuse within the past 2 years.
12. Individuals providing consent who did not consent to the retention of their serum samples after study completion.
13. Elective surgery or hospitalization planned to occur during the treatment phase or during the follow-up phase that, according to the opinion of the investigator, might have poses additional risk to the subject.
14. Subjects from whom blood could not be drawn at visit 1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean Titers in Subjects After Receiving One Dose of Lot 1 or Lot 2 or Lot 3 of aTIV	Immunologic equivalence of 3 consecutive production lots of aTIV (Lot 1, Lot 2 and Lot 3), was assessed in terms of Hemagglutination Inhibition (HI) Geometric Mean Titers (GMTs) in subjects, at three weeks after vaccination, against each vaccine strain.	Day 22 post vaccination
Comparison of aTIV Versus TIV in Terms of Geometric Mean Titers (GMTs) Against Homologous Strains - PPS	The non-inferiority of HI antibody responses of aTIV compared to TIV assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.	Day 22 post vaccination
Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-PPS	The non-inferiority of HI antibody responses of aTIV compared to TIV assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the three homologous vaccine strains. Seroconversion defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.	Day 22 post vaccination
Comparison of aTIV Versus TIV in Terms of GMTs Against Homologous Strains-Full Analysis Set (FAS)	The superiority of HI antibody responses of aTIV compared to TIV assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.	Day 22 post vaccination
Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-FAS	The superiority of HI antibody responses of aTIV compared to TIV assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the three homologous vaccine strains. Seroconversion defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.	Day 22 post vaccination
Percentage of Subjects With HI Titers ≥40 Against Homologous Strains	The percentage of subjects demonstrating HI titers ≥40, in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV.	Day 22 post vaccination
Percentage of Subjects Achieving Seroconversion in HI Titers, Against Homologous Strains	The percentage of subjects achieving seroconversion in HI titers from baseline, in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.	Day 22 post vaccination
Geometric Mean Ratio (GMR) of Post- Versus Pre-vaccination HI Titers Against Homologous Strains	The GMR of post-vaccination versus pre-vaccination HI titers (day 22/day 1) in overall group and in subjects with pre-defined co-morbidities (high risk group), against homologous strains, three weeks after vaccination with aTIV or TIV.	Day 22 post vaccination
Percentage of Subjects With HI Titers ≥40 Against Heterologous Strains	The percentage of subjects demonstrating HI titers ≥40, in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV.	Day 22 post vaccination
Geometric Mean Ratio (GMR) of Post- Versus Pre-vaccination HI Titers, Against Heterologous Strains	The GMR of post-vaccination versus pre-vaccination HI titers (day 22/day 1) in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV.	Day 22 post vaccination
Percentage of Subjects Achieving Seroconversion in HI Titers, Against Heterologous Strains	The percentage of subjects achieving seroconversion in HI titers from baseline, in overall group and in subjects with pre-defined co-morbidities (high risk group), against heterologous strains, three weeks after vaccination with aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.	Day 22 post vaccination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of aTIV Versus TIV in High Risk Group in Terms of GMTs Against Homologous Strains-PPS	The non-inferiority of HI antibody responses of ATIV compared to TIV, in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.	Day 22 post vaccination
Comparison of HI Antibody Responses of aTIV Versus TIV, in High Risk Group in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-PPS	The non-inferiority of HI antibody responses of ATIV compared to TIV, in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the homologous vaccine strains. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.	Day 22 post vaccination
Comparison of aTIV Versus TIV in High Risk Group in Terms of GMTs Against Homologous Strains-FAS	The superiority of HI antibody responses of aTIV compared to TIV, in subjects with predefined co-morbidities (high risk group) assessed in terms of post vaccination GMTs at three weeks after vaccination against the three homologous vaccine strains.	Day 22 post vaccination
Comparison of HI Antibody Responses of aTIV Versus TIV, in High Risk Group in Terms of Percentage of Subjects Achieving Seroconversion Against Homologous Strains-FAS	The superiority of HI antibody responses of aTIV compared to TIV, in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination against the homologous vaccine strains. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.	Day 22 postvaccination
Comparison of aTIV Versus TIV in Terms of GMTs Against Heterologous Strains-PPS	The non-inferiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination .	Day 22 post vaccination
Comparison of aTIV Versus TIV in Terms of GMTs Against Heterologous Strains-FAS	The superiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of post vaccination GMTs at three weeks after vaccination.	Day 22 post vaccination
Comparison of HI Antibody Responses of aTIV Versus TIV, in Terms of Percentage of Subjects Achieving Seroconversion Against Heterologous Strains-PPS	The non-inferiority of HI antibody responses of aTIV compared to TIV against the heterologous strains, in overall group and in subjects with pre-defined co-morbidities (high risk group), assessed in terms of percentage of subjects achieving seroconversion at three weeks after vaccination. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.	Day 22 postvaccination
Comparison of aTIV Versus TIV in Terms of Percentage of Subjects Achieving Seroconversion Against Heterologous Strains-FAS	The superiority of HI antibody responses of aTIV compared to TIV against the heterologous vaccine strains, in overall group and in subjects with pre-defined co-morbidities (high risk subjects), was assessed in terms of percentage of subjects achieving seroconversion, at three weeks after vaccination. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.	Day 22 post vaccination
Persistence of GMTs Against Homologous and Heterologous Strains	The GMTs against homologous and heterologous strains, persisting in subjects at six months (day 181) and one year (day 366) after vaccination with either aTIV or TIV.	Day 181, Day 366 post vaccination
Percentage of Subjects With Seroconversion Upto One Year After Vaccination, Against Homologous and Heterologous Strains	The percentage of subjects demonstrating seroconversion in HI titers against homologous and heterologous strains, at six months (day 181) and one year (day 366) after vaccination with either aTIV or TIV. Seroconversion is defined as prevaccination HI titer <10 and postvaccination HI titer ≥40 or at least a 4-fold increase in HI titers from prevaccination HI titer ≥10.	Day 181, Day 366 post vaccination
Number of Subjects Reporting Influenza Like Illness (ILI) Across Vaccine Groups	The number of subjects reporting ILI from three weeks after vaccination to up to one year in aTIV group compared to TIV group, by country.	Day 22 through Day 366 post vaccination
Number of High Risk Subjects With Exacerbation of Preexisting Chronic Disease, Across Vaccine Groups	The number of high risk subjects reporting exacerbation of preexisting chronic conditions (i.e.congestive heart failure, Chronic Obstructive Pulmonary disease (COPD), asthma, hepatic disease, renal insufficiency, and neurological/neuromuscular or metabolic disorders including diabetes mellitus) in aTIV group compared to TIV group.	Day 1 through Day 366 post vaccination
Number of Subjects Reporting Healthcare Utilization Across Vaccine Groups	The number of subjects with emergency room visits, unscheduled physician visits, and hospitalizations due to community acquired influenza or pneumonia, cardiopulmonary disease, cardiac disease, respiratory or pulmonary disease,in aTIV group compared to TIV group.	Day 1 through Day 366 post vaccination
All Cause Mortality Rate, Across Vaccine Groups	The all-cause mortality rate (excluding injury)reported in aTIV group compared to TIV group, by country.	Day 1 through Day 366 post vaccination
Number of Subjects Reporting Solicited Adverse Events Following Vaccination	The number of subjects reporting solicited local and systemic adverse events and other adverse events in aTIV group compared to TIV group.	Day 1 through Day 7 post vaccination

Collaborators and Investigators

• Sponsor: Novartis Vaccines

Publications and helpful links

General Publications

• Frey SE, Reyes MR, Reynales H, Bermal NN, Nicolay U, Narasimhan V, Forleo-Neto E, Arora AK. Comparison of the safety and immunogenicity of an MF59(R)-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects. Vaccine. 2014 Sep 3;32(39):5027-34. doi: 10.1016/j.vaccine.2014.07.013. Epub 2014 Jul 18.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): November 1, 2011

Study Registration Dates

• First Submitted: July 13, 2010
• First Submitted That Met QC Criteria: July 13, 2010
• First Posted (Estimate): July 14, 2010

Study Record Updates

• Last Update Posted (Estimate): June 26, 2014
• Last Update Submitted That Met QC Criteria: June 16, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Elderly; Safety; Influenza; Vaccines; Immunogenicity; Adjuvant; Adjuvants; Adjuvanted
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: V70_27