Pediatric Safety and Immunogenicity Study of Cell-Culture Derived and Egg-based Subunit Influenza Vaccines in Healthy Children and Adolescents

This study has been completed.
Sponsor:
Collaborator:
Novartis Vaccines
Information provided by (Responsible Party):
Novartis
ClinicalTrials.gov Identifier:
NCT00645411
First received: March 21, 2008
Last updated: January 15, 2013
Last verified: January 2013
  Purpose

The present study is the first study designed to evaluate safety, tolerability and immunogenicity of the cell culture-derived influenza vaccine in healthy children and adolescents aged 3 to 17 years. A step-down approach is utilized in which reactogenicity and safety will be assessed in children and adolescents 9 to 17 years of age (Cohort 1) prior to enrolling additional children and adolescents 9 to 17 years of age (Cohort 2) and children 3 to 8 years of age (Cohort 3).


Condition Intervention Phase
Influenza
Biological: Cell culture-derived influenza subunit vaccine (cTIV)
Biological: Egg derived influenza subunit vaccine (eTIV_f)
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Prevention
Official Title: A Combined Phase II/III, Observer-Blind, Randomized, Multi-center Study to Evaluate Safety, Tolerability and Immunogenicity of Trivalent Subunit Influenza Vaccines, Produced Either in Mammalian Cell Culture or in Embryonated Hen Eggs, in Healthy Children and Adolescents

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Geometric Mean Titers of the Cell Culture-derived Vaccine Compared With the Egg-derived Vaccine in 3 to 8 Year-old Children [ Time Frame: Day 50 post vaccination ] [ Designated as safety issue: No ]

    To demonstrate non-inferiority of the post vaccination hemagglutination inhibition (HI) geometric mean titer (GMT) of the cell culture-derived influenza (cTIV) vaccine to the corresponding GMT of the egg-derived (eTIV_f) influenza vaccine, for all three strains, after two injections administered four weeks apart to a subset of children 3 to 8 years of age.

    GMTs were evaluated using two assays, HI egg derived antigen assay and HI cell derived antigen assay.


  • Percentages of Subjects Who Attained Seroconversion or Significant Increase in Antibody Titers in the Cell Culture-derived Vaccine Compared With the Egg-derived Vaccine in 3 to 8 Year-old Children [ Time Frame: Day 50 post vaccination ] [ Designated as safety issue: No ]

    To demonstrate non-inferiority of the cell culture-derived influenza (cTIV) vaccine to the egg-derived (eTIV_f) influenza vaccine in the percentage of subjects achieving seroconversion or significant increase in antibody titer post vaccination, for all three strains, after two injections administered four weeks apart in children 3 to 8 years of age.

    Seroconversion rate was evaluated using two assays- HI egg derived antigen assay and HI cell derived antigen assay.



Secondary Outcome Measures:
  • Geometric Mean Titers After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine in 9 to 17 Year-old Children and Adolescents [ Time Frame: Day 29 post vaccination ] [ Designated as safety issue: No ]

    To evaluate immunogenicity in terms of Geometric Mean Titers (GMTs) in children 9 to 17 years of age after one injection of either cTIV vaccine or eTIV_f.

    GMTs were evaluated using two assays, HI egg derived antigen assay and HI cell derived antigen assay.


  • Geometric Mean Ratio After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine in 9 to 17 Year-old Children and Adolescents. [ Time Frame: Day 29 post vaccination ] [ Designated as safety issue: No ]

    Immunogenicity was evaluated in terms of Geometric Mean Ratio (GMRs) in 9 to 17 year-old children and adolescents after one injection of either cTIV vaccine or eTIV_f.

    The criterion is met according to European (CHMP) guideline if the mean geometric increase GMR (day29/day1) in HI antibody titer is >2.5.


  • Percentages of Subjects Who Achieved HI Titers ≥40 After 1 Dose of the Cell Culture-derived Vaccine or the Egg-derived Influenza Vaccine in 9 to 17 Year-old Children and Adolescents [ Time Frame: Day 29 post vaccination ] [ Designated as safety issue: No ]

    To evaluate immunogenicity in terms of percentage of 9 to 17 year-old children and adolescents achieving HI titers ≥40, after one injection of either the cTIV vaccine or the eTIV_f vaccine.

    This criterion is met according to European (CHMP) guideline if the percentage of subjects achieving HI titers ≥40 is >70% and according to the US (CBER)guideline is met if the lower bound of the two sided 95%CI for percentage of subjects achieving HI titers ≥40 is ≥70%.


  • Percentages of Subjects Who Attained Seroconversion or Significant Increase After 1 Dose of the Cell Culture-derived Vaccine or the Egg-derived Influenza Vaccine in 9 to 17 Year-old Children and Adolescents [ Time Frame: Day 29 post vaccination ] [ Designated as safety issue: No ]

    Seroconversion or significant increase as per CHMP criteria is defined as percentage of subjects with a pre vaccination HI titer <10 to a post vaccination titer ≥40 or a pre vaccination HI titer ≥10 and a ≥4-fold increase in post vaccination HI antibody titer. According to the CHMP criteria, the percentage of subjects achieving seroconversion or significant increase should be >40%.

    According to the CBER criteria, the lower bound of the two-sided 95% CI for the percentage of subjects achieving seroconversion/significant increase should be ≥40%.


  • Geometric Mean Titers After Two Doses of the Cell Derived or the Egg Derived Vaccine in 3 to 8 Year-old Children [ Time Frame: Day 29 and Day 50 post vaccination ] [ Designated as safety issue: No ]
    To evaluate immunogenicity in terms of Geometric Mean Titers (GMTs) in children 3 to 8 years of age after two doses of either cTIV vaccine or eTIV_f,administered 4 weeks apart.

  • Geometric Mean Ratio After Two Doses of the Cell-derived or the Egg-derived Vaccine in 3 to 8 Year-old Children [ Time Frame: Day 29 and Day 50 post vaccination ] [ Designated as safety issue: No ]

    To evaluate immunogenicity in terms of Geometric Mean Ratio (GMR) in children 3 to 8 years of age after two doses of either the cTIV vaccine or the eTIV_f vaccine, administered 4 weeks apart according to the CHMP criteria.

    The criterion is met according to the European (CHMP) guideline if the mean geometric increase(GMR day 29/day 1 and GMR day 50/day 1) in HI antibody titer is >2.5


  • Percentages of Subjects Who Achieved HI Titers ≥40 After Two Doses of the Cell Culture Derived or the Egg Derived Influenza Vaccine in 3 to 8 Year-old Children [ Time Frame: Day 29 and Day 50 post vaccination ] [ Designated as safety issue: No ]

    To evaluate immunogenicity in terms of HI titers ≥40, in children 3-8 years of age after two doses of either cTIV vaccine or eTIV_f vaccine, administered 4 weeks apart.

    The criterion is met according to European (CHMP) guideline if the percentage of subjects achieving HI titers ≥40 is >70% and according to the US (CBER) guideline if the lower bound of the two sided 95%CI for percentage of subjects achieving HI titers ≥40 is ≥70%.


  • Percentages of Subjects Who Achieved Seroconversion or Significant Increase in HI Titers After Two Doses of the Cell Culture-derived Vaccine or the Egg-derived Influenza Vaccine in 3 to 8 Year-old Children [ Time Frame: Day 29 and Day 50 post vaccination ] [ Designated as safety issue: No ]

    Seroconversion or significant increase as per CHMP criteria is defined as percentage of subjects with a pre vaccination HI titer <10 to a post vaccination titer ≥40 or a pre vaccination HI titer ≥10 and a ≥4-fold increase in post vaccination HI antibody titer. According to the CHMP criteria, the percentage of subjects achieving seroconversion or significant increase should be >40%.

    According to the CBER criteria, the lower bound of the two-sided 95% CI for the percentage of subjects achieving seroconversion/significant increase should be ≥40%.


  • Number of Subjects Reporting Local* and Systemic Reactions After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine in 9 to 17 Year-old Children and Adolescents. [ Time Frame: up to 7 days after vaccination ] [ Designated as safety issue: Yes ]
    To evaluate safety and tolerability in terms of number of 9 to 17 year-old children and adolescents (cohorts 1 and 2)reporting local* and systemic reactions following of one injection of the cTIV or the eTIV_f vaccine .

  • Number of Subjects Reporting Local* and Systemic Reactions After One and Two Doses of the Cell Culture-derived Vaccine or Egg-derived Influenza Vaccine in 3 to 8 Year-old Children. [ Time Frame: up to 7 days after each vaccination ] [ Designated as safety issue: Yes ]
    To evaluate the safety and tolerability of the cTIV and the eTIV_f influenza vaccines in 3 to 8 year-old children terms of number of participants reporting local* and systemic reactions after each vaccination.


Enrollment: 3604
Study Start Date: October 2007
Study Completion Date: July 2008
Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohorts 1 + Cohort 2 (9-17 Yrs) cTIV
All subjects received one 0.5 mL IM injection, of cell culture-derived trivalent influenza vaccine containing 15μg of HA for each strain (A/Solomon Islands/3/2006 [H1N1]-like, A/Wisconsin/67/2005 [H3N2]-like, and B/Malaysia/ 2506/2004-like), recommended for the 2007-2008 influenza season in the Northern Hemisphere
Biological: Cell culture-derived influenza subunit vaccine (cTIV)
One 0.5 ml injection of the cell culture-derived influenza vaccine in the deltoid muscle, preferably of the nondominant arm.
Active Comparator: Cohorts 1 + Cohort 2 (9-17 Yrs) eTIV_f
All subjects received one 0.5 mL injection, of egg -derived trivalent influenza vaccine containing 15μg of HA for each strain (A/Solomon Islands/3/2006 [H1N1]-like, A/Wisconsin/67/2005 [H3N2]-like and B/Malaysia/ 2506/2004-like), recommended for the 2007-2008 influenza season in the Northern Hemisphere.
Biological: Egg derived influenza subunit vaccine (eTIV_f)
One 0.5 ml injection of the conventional egg-derived influenza vaccine in the deltoid muscle, preferably of the nondominant arm.
Experimental: Cohort 3 (3-8 Yrs) cTIV
All subjects received two 0.5 mL injections, administered four weeks apart, of cell culture-derived trivalent influenza vaccine containing 15μg of HA for each strain (A/Solomon Islands/3/2006 [H1N1]-like, A/Wisconsin/67/2005 [H3N2]-like and B/Malaysia/ 2506/2004-like), recommended for the 2007-2008 influenza season in the Northern Hemisphere
Biological: Cell culture-derived influenza subunit vaccine (cTIV)
Two 0.5 mL injections,of the cell culture-derived influenza vaccine in the deltoid muscle, preferably of the nondominant arm, administered four weeks apart.
Active Comparator: Cohort 3 (3-8 Yrs) eTIV_f
All subjects received two 0.5 mL injections, administered four weeks apart of egg -derived trivalent influenza vaccine containing 15μg of HA for each strain (A/Solomon Islands/3/2006 [H1N1]-like, A/Wisconsin/67/2005 [H3N2]-like and B/Malaysia/ 2506/2004-like), recommended for the 2007-2008 influenza season in the Northern Hemisphere
Biological: Egg derived influenza subunit vaccine (eTIV_f)
Two 0.5 mL injections of the conventional egg-derived influenza vaccine in the deltoid muscle, preferably of the nondominant arm,administered four weeks apart.

  Eligibility

Ages Eligible for Study:   3 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Subjects aged 9 to 17 years (Cohorts 1 and 2) and 3 to 8 years (Cohort 3), whose parents/legal guardians have given written informed consent prior to study entry. Assent will be obtained from subjects according to age requirements of the ECs/IRBs;
  2. In good health as determined by:

    1. medical history,
    2. physical examination,
    3. clinical judgment of the Investigator;
  3. Able to comply with all study procedures and available for all clinic visits and telephone calls scheduled in the study.

Exclusion Criteria:

  1. Any serious disease, such as:

    1. cancer,
    2. autoimmune disease (including rheumatoid arthritis),
    3. diabetes mellitus,
    4. chronic pulmonary disease,
    5. acute or progressive hepatic disease,
    6. acute or progressive renal disease;
  2. History of any anaphylaxis or serious reaction following administration of vaccine, or hypersensitivity to eggs, egg protein, chicken feathers, influenza viral protein, neomycin, polymyxin, or any other vaccine component, chemically related substance, or component of the potential packaging materials;
  3. Known or suspected impairment/alteration of immune function, including:

    1. use of immunosuppressive therapy such as systemic corticosteroids known to be associated with the suppression of hypothalamic-pituitary-adrenal (HPA) axis or chronic use of inhaled high-potency corticosteroids within 60 days prior to Visit 1,
    2. cancer chemotherapy,
    3. receipt of immunostimulants within 60 days prior to Visit 1,
    4. receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within 3 months prior to Visit 1 or planned during the full length of the study,
    5. known HIV infection or HIV-related disease;
  4. History of Guillain-Barré syndrome;
  5. Bleeding diathesis;
  6. Surgery planned during the study period;
  7. Receipt of another investigational agent within 90 days, or before completion of the safety follow-up period in another study, whichever is longer, prior to enrollment and unwilling to refuse participation in another clinical study through the end of the study;
  8. Receipt of another vaccine within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) prior to Visit 1;
  9. Laboratory-confirmed influenza disease within 6 months prior to Visit 1;
  10. For subjects aged 3 to 8 years old, ever received two doses of an influenza vaccine in one influenza season;
  11. Receipt of an influenza vaccine within 6 months prior to Visit 1;
  12. Experienced a temperature 38.0°C [100.4°F]) and/or any acute illness within 3 days prior to Visit 1;
  13. Pregnant or nursing mother;
  14. Female of childbearing potential who is sexually active and has not used acceptable birth control measures for at least 2 months prior to study entry and who does not plan to use acceptable birth control measures during the 3 weeks following vaccination or refuses to have a urine pregnancy test prior to enrollment. Oral, injected, inserted or implanted hormonal contraceptive, diaphragm or condom with spermicidal agent or intrauterine device are considered acceptable forms of birth control;
  15. Children of research staff or those living with research staff directly involved with the clinical study. Research staff are individuals with direct study subject contact, indirect contact with study subjects, or study site personnel who have access to any study documents containing subject information. This would include receptionists, persons scheduling appointments or making screening calls, regulatory specialists, laboratory technicians, etc.;
  16. Any condition, which in the opinion of the Investigator, might interfere with the evaluation of the study objectives.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00645411

  Hide Study Locations
Locations
United States, Arkansas
Site 09
Fayetteville, Arkansas, United States, 72703
United States, California
Site 10
Downey, California, United States, 90241
United States, Kentucky
Site 02
Bardstown, Kentucky, United States, 40004
United States, Louisiana
Site 14
Metairie, Louisiana, United States, 70006
United States, Missouri
Site 01
St. Louis, Missouri, United States, 63104
United States, Nebraska
Site 11
Omaha, Nebraska, United States, 68134
United States, New Jersey
Site 04
Edison, New Jersey, United States, 08817
United States, New York
Site 05
Endwell, New York, United States, 13760
United States, Texas
Site 16
Fort Worth, Texas, United States, 76135
Site 13
San Angelo, Texas, United States, 76904
Site 12
San Antonio, Texas, United States, 78205
United States, Utah
Site 08
Bountiful, Utah, United States, 84010
Site 03
Salt Lake City, Utah, United States, 84121
Site 07
Salt Lake City, Utah, United States, 84109
United States, Virginia
Site 06
Burke, Virginia, United States, 22105
United States, Washington
Site 15
Spokane, Washington, United States, 99202
Croatia
Site 44:Spec. Pediatric Dispensary
Dakovo, Croatia
Site 83
Ljudevita Gaja 2, Djakovo, Croatia
Site 43: Spec. Pediatric Dispensary
Sisak, Croatia
Site 27:Institute of Public Health
Zagreb, Croatia
Site 49: Spec. Pediatric Dispensary
Zagreb, Croatia
Site 29: Institute of Public Health
Zagreb, Croatia
Site 86: Spec. Pediatric Dispensary
Zagreb, Croatia
Site 40:Spec. Pediatric Dispensary
Zagreb, Croatia
Site 50: Spec. Pediatric Dispensary
Zagreb, Croatia
Finland
Site 70: Espoon rokotetutkimusklinikka
Heikintori, Espoo, Finland, 02100
Site 79: Kokkola Vaccine Research Clinic
Rantakatu 7, Kokkola, Finland, 67100
Site 78: Kuopio Vaccine Research Clinic
Microkatu 1,Osa/Section A, 3rd floor PL1188, Kuopio, Finland, 70211
Site 71: Etelä-Helsingin rokotetutkimusklinikka
Helsinki, Finland, 00100
Site 72: Itä-Helsingin rokotetutkimusklinikka
Helsinki, Finland, 00930
Site 76: Järvenpään rokotetutkimusklinikka
Järvenpää, Finland, 04400
Site 77: Kotkan rokotetutkimusklinikka
Kotka, Finland, 48600
Site 67: Lahden rokotetutkimusklinikka
Lahti, Finland, 15140
Site 75: Oulun rokotetutkimusklinikka
Oulu, Finland, 90100
Site 68: Porin rokotetutkimusklinikka
Pori, Finland, 28120
Site 66: Tampereen rokotetutkimusklinikka
Tampere, Finland, 33100
Site 69: Turun rokotetutkimusklinikka
Turku, Finland, 20520
Site 73: Itä-Vantaan rokotetutkimusklinikka
Vantaa, Finland, 01300
Site 74: Länsi-Vantaan rokotetutkimusklinikka
Vantaa, Finland, 01600
Hungary
Site 53: Heim Pál Gyermekkórház
Budapest, Hungary, 1089
Site 54: Házi Gyermekorvosi Rendelő
Budapest, Hungary, 1173
Site 56: Házi Gyermekorvosi Rendelő
Budapest, Hungary, 1136
Site 57: Házi Gyermekorvosi Rendelő
Budapest, Hungary, 1042
Site 52: Ferencvárosi Gyermekorvos Kft.
Budapest, Hungary, 1097
Site 51: 5053. számú Gyermekorvosi Rendelő
Miskolc, Hungary, 3534
Site 55: Revamed kft.
Nyíregyháza, Hungary, 4481
Site 59: Vas Megyei Markusovszky Lajos, Általános, Rehabilitációs és Gyógyfürdő Kórház, Egyetemi Oktató Kórház
Szombathely, Hungary, 9700
Italy
Site 42: Dipartimento di Medicina Clinica e Sperimentale - Sezione di Igiene e Medicina Preventiva
Ferrara, Italy, 44100
Site 47: Dipartimento Scienze della Salute, Sezione di Igiene e Medicina Preventiva, Univesità di Genova
Genova, Italy, 16132
Site 41: Ospedale Maggiore della Carità-Clinica Pediatrica
Novara, Italy, 28100
Site 46: USL 2 Perugia, Distretto del perugino, Centro di Salute n. 4 (Madonna Alta) e n. 6 (Ellera di Corciano del distretto del perugino)
Perugia, Italy, 06070
Site 45: AUSL 7
Ragusa, Italy, 97100
Lithuania
Site 35
Kaunas, Lithuania, 48259
Site 36
Vilnius, Lithuania, 01117
Site 34
Vilnius, Lithuania, 04318
Site 33
Vilnius, Lithuania, 11200
Site 31
Vilnius, Lithuania, 10207
Site 32
Vilnius, Lithuania, 02169
Romania
Site 25
Campulung Muscel, Arges, Romania, 115100
Site 21
Craiova, Dolj, Romania, 200642
Sponsors and Collaborators
Novartis
Novartis Vaccines
Investigators
Study Chair: Novartis Vaccines Novartis Vaccines
  More Information

Publications:
Responsible Party: Novartis
ClinicalTrials.gov Identifier: NCT00645411     History of Changes
Other Study ID Numbers: V58P12, Eudract Number: 2007-001534-13
Study First Received: March 21, 2008
Results First Received: November 21, 2012
Last Updated: January 15, 2013
Health Authority: Hungary: National Institute of Pharmacy
Romania: National Medicines Agency
Lithuania: State Medicines Control Agency
ITALY: Agenzia Italiana del Farmaco (AIFA)
Finland: National Agency for Medicines (NAM)
United States: Food and Drug Administration
Croatia: Ministry of Health and Social Care

Keywords provided by Novartis:
Influenza
Flu
Cell Culture-Derived
Egg-Derived
Healthy Children
Healthy Adolescents
Safety
Immunogenicity
Trivalent
Inactivated
Vaccination

Additional relevant MeSH terms:
Influenza, Human
Orthomyxoviridae Infections
Respiratory Tract Diseases
Respiratory Tract Infections
RNA Virus Infections
Virus Diseases

ClinicalTrials.gov processed this record on October 23, 2014