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

Influenza Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00645411
• Other study ID #: V58P12
• Secondary ID: Eudract Number:
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: March 21, 2008
• Last updated: October 20, 2015
• Start date: October 2007
• Est. completion date: July 2008

Study information

• Verified date: October 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: Hungary: National Institute of PharmacyRomania: National Medicines AgencyLithuania: State Medicines Control AgencyITALY: Agenzia Italiana del Farmaco (AIFA)Finland: National Agency for Medicines (NAM)United States: Food and Drug AdministrationCroatia: Ministry of Health and Social Care
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3604
• Est. completion date: July 2008
• Est. primary completion date: February 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 3 Years to 17 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Influenza
• Influenza, Human

Intervention

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.
• Egg derived influenza subunit vaccine (eTIV)
One 0.5 ml injection of the conventional egg-derived influenza vaccine in the deltoid muscle, preferably of the nondominant arm.
• 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.
• Egg derived influenza subunit vaccine (eTIV)
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.

Locations

Country	Name	City	State
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 29: Institute of Public Health	Zagreb
Croatia	Site 40:Spec. Pediatric Dispensary	Zagreb
Croatia	Site 49: Spec. Pediatric Dispensary	Zagreb
Croatia	Site 50: Spec. Pediatric Dispensary	Zagreb
Croatia	Site 86: Spec. Pediatric Dispensary	Zagreb
Finland	Site 70: Espoon rokotetutkimusklinikka	Heikintori	Espoo
Finland	Site 71: Etelä-Helsingin rokotetutkimusklinikka	Helsinki
Finland	Site 72: Itä-Helsingin rokotetutkimusklinikka	Helsinki
Finland	Site 76: Järvenpään rokotetutkimusklinikka	Järvenpää
Finland	Site 77: Kotkan rokotetutkimusklinikka	Kotka
Finland	Site 67: Lahden rokotetutkimusklinikka	Lahti
Finland	Site 78: Kuopio Vaccine Research Clinic	Microkatu 1,Osa/Section A, 3rd floor PL1188	Kuopio
Finland	Site 75: Oulun rokotetutkimusklinikka	Oulu
Finland	Site 68: Porin rokotetutkimusklinikka	Pori
Finland	Site 79: Kokkola Vaccine Research Clinic	Rantakatu 7	Kokkola
Finland	Site 66: Tampereen rokotetutkimusklinikka	Tampere
Finland	Site 69: Turun rokotetutkimusklinikka	Turku
Finland	Site 73: Itä-Vantaan rokotetutkimusklinikka	Vantaa
Finland	Site 74: Länsi-Vantaan rokotetutkimusklinikka	Vantaa
Hungary	Site 52: Ferencvárosi Gyermekorvos Kft.	Budapest
Hungary	Site 53: Heim Pál Gyermekkórház	Budapest
Hungary	Site 54: Házi Gyermekorvosi Rendelo	Budapest
Hungary	Site 56: Házi Gyermekorvosi Rendelo	Budapest
Hungary	Site 57: Házi Gyermekorvosi Rendelo	Budapest
Hungary	Site 51: 5053. számú Gyermekorvosi Rendelo	Miskolc
Hungary	Site 55: Revamed kft.	Nyíregyháza
Hungary	Site 59: Vas Megyei Markusovszky Lajos, Általános, Rehabilitációs és Gyógyfürdo Kórház, Egyetemi Oktató Kórház	Szombathely
Italy	Site 42: Dipartimento di Medicina Clinica e Sperimentale - Sezione di Igiene e Medicina Preventiva	Ferrara
Italy	Site 47: Dipartimento Scienze della Salute, Sezione di Igiene e Medicina Preventiva, Univesità di Genova	Genova
Italy	Site 41: Ospedale Maggiore della Carità-Clinica Pediatrica	Novara
Italy	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	Site 45: AUSL 7	Ragusa
Lithuania	Site 35	Kaunas
Lithuania	Site 31	Vilnius
Lithuania	Site 32	Vilnius
Lithuania	Site 33	Vilnius
Lithuania	Site 34	Vilnius
Lithuania	Site 36	Vilnius
Romania	Site 25	Campulung Muscel	Arges
Romania	Site 21	Craiova	Dolj
United States	Site 02	Bardstown	Kentucky
United States	Site 08	Bountiful	Utah
United States	Site 06	Burke	Virginia
United States	Site 10	Downey	California
United States	Site 04	Edison	New Jersey
United States	Site 05	Endwell	New York
United States	Site 09	Fayetteville	Arkansas
United States	Site 16	Fort Worth	Texas
United States	Site 14	Metairie	Louisiana
United States	Site 11	Omaha	Nebraska
United States	Site 03	Salt Lake City	Utah
United States	Site 07	Salt Lake City	Utah
United States	Site 13	San Angelo	Texas
United States	Site 12	San Antonio	Texas
United States	Site 15	Spokane	Washington
United States	Site 01	St. Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Novartis	Novartis Vaccines

Countries where clinical trial is conducted

United States,  Croatia,  Finland,  Hungary,  Italy,  Lithuania,  Romania, 

References & Publications (1)

Vesikari T, Block SL, Guerra F, Lattanzi M, Holmes S, Izu A, Gaitatzis N, Hilbert AK, Groth N. Immunogenicity, safety and reactogenicity of a mammalian cell-culture-derived influenza vaccine in healthy children and adolescents three to seventeen years of — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Geometric Mean Titers of the Cell Culture-derived Vaccine Compared With the Egg-derived Vaccine in 3 to 8 Year-old Children	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) 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.	Day 50 post vaccination	No
Primary	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	To demonstrate non-inferiority of the cell culture-derived influenza (cTIV) vaccine to the egg-derived (eTIV) 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.	Day 50 post vaccination	No
Secondary	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	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.; GMTs were evaluated using two assays, HI egg derived antigen assay and HI cell derived antigen assay.	Day 29 post vaccination	No
Secondary	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.	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.; The criterion is met according to European (CHMP) guideline if the mean geometric increase GMR (day29/day1) in HI antibody titer is >2.5.	Day 29 post vaccination	No
Secondary	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	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 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%.	Day 29 post vaccination	No
Secondary	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	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%.	Day 29 post vaccination	No
Secondary	Geometric Mean Titers After Two Doses of the Cell Derived or the Egg Derived Vaccine in 3 to 8 Year-old Children	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,administered 4 weeks apart.	Day 29 and Day 50 post vaccination	No
Secondary	Geometric Mean Ratio After Two Doses of the Cell-derived or the Egg-derived Vaccine in 3 to 8 Year-old Children	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 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	Day 29 and Day 50 post vaccination	No
Secondary	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	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 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%.	Day 29 and Day 50 post vaccination	No
Secondary	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	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%.	Day 29 and Day 50 post vaccination	No
Secondary	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.	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 vaccine .	up to 7 days after vaccination	Yes
Secondary	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.	To evaluate the safety and tolerability of the cTIV and the eTIV influenza vaccines in 3 to 8 year-old children terms of number of participants reporting local and systemic reactions after each vaccination.	up to 7 days after each vaccination	Yes