Study to Evaluate the Efficacy, Safety and Immunogenicity of Influenza Vaccine in Healthy Subjects (Aged 6 to <72 Months) Versus Control Vaccines

Influenza, Human Clinical Trial

Official title:

A Phase III, Randomized, Observer-blind, Controlled, Multi-center Clinical Trial to Evaluate the Efficacy, Safety and Immunogenicity of One and Two Intramuscular Doses of Influenza Vaccine Versus Control Vaccines in Healthy Subject Aged 6 to <72 Months

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00644059
• Other study ID #: V70P5
• Secondary ID: Eudract number 2
• Status: Completed
• Phase: Phase 3
• First received: March 20, 2008
• Last updated: August 31, 2015
• Start date: November 2007
• Est. completion date: August 2010

Study information

• Verified date: August 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Paul-Ehrlich-Institut
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the efficacy, safety and immunogenicity of one or two 0.25 mL or 0.5 mL intramuscular injections of an adjuvanted influenza vaccine compared with non-influenza and non-adjuvanted influenza control vaccines in subjects 6 to <72 months of age.

Other known NCT identifiers

• NCT01015885

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4902
• Est. completion date: August 2010
• Est. primary completion date: April 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 6 Months to 71 Months

Eligibility

Inclusion Criteria:

• Children whose parents/legal guardians have given written informed consent prior to study entry: a) aged 6 to <72 months (Part I and II of the study; influenza seasons 2007/2008 and 2008/2009) b) aged 6 to <36 months (Part III of the study; influenza season 2009/2010)

• In good health as determined by: a) medical history, b) physical examination, c) clinical judgment of the investigator

Exclusion criteria:

• Administration of licensed vaccines (including H1N1sw vaccines) within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to enrollment in this study. Routine vaccines, according to local recommendations, or any other vaccines not foreseen in the protocol could be given after the active trial phase (i.e., 21 days after last vaccination) has been concluded.

• Receipt of another investigational vaccine or any investigational agent within 30 days prior to enrollment in the study or before completion of the safety follow-up period in another study, whichever is longer, and participation in another clinical trial during the present study.

• Experience of a severe acute infectious disease in the month prior to study start or experience of a mild acute infection disease in the week prior the study start (untreated common cold is acceptable). The severity of the infectious disease occurred will be based on the investigator's judgment.

• Any severe acute respiratory disease and infection requiring systemic antibiotic or antiviral therapy ongoing or resolved within 2 days prior to study start.

• Experience an axillary temperature equal to or greater than 37.8°C (rectal temperature equal to or greater than 38.3°C) within the 2 days before enrollment.

• Any serious disease in the opinion of the investigator including, for example: a) cancer, b) autoimmune disease (including rheumatoid arthritis under immunosuppressive therapy), c) insulin dependent diabetes mellitus, d) chronic pulmonary disease, asthma under inhalative therapy only is acceptable, e) acute or progressive hepatic disease, f) acute or progressive renal disease.

• Known or suspected impairment/alteration of immune function, for example, resulting from: a) receipt of immunosuppressive therapy (corticosteroid -except topical or inhaled steroids- or cancer chemotherapy), b) receipt of immunostimulants, c) receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within the past 90 days and for the full length of the study, d) high risk for developing an immunocompromising disease (suspected or known HIV infection or HIV-related disease).

• Bleeding diathesis.

• History of hypersensitivity to any component of the study medication or chemically related substances.

• History of any anaphylaxis, serious vaccine reactions, or allergy to eggs, egg products or any other vaccine component.

• Laboratory confirmed influenza disease.

• History of neurological disorder or seizures (febrile seizures allowed).

• Received any influenza vaccine.

• Major surgery planned during the study period.

• Any condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives, e.g., planned travel or relocation of residence that would interfere with completion of study.

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, Human

Intervention

Biological:
• Adjuvanted trivalent inactivated subunit influenza vaccine
Either two intramuscular (IM) injections of half dose or one IM injection of full dose, depending on age of subject, were administered in the deltoid muscle preferably of the non-dominant arm.
• Non-adjuvanted trivalent inactivated subunit influenza vaccine or non-adjuvanted trivalent inactivated split influenza vaccine
For both vaccines, either two intramuscular (IM) injections of half dose or one IM injection of full dose, depending on age of subject, were administered in the deltoid muscle preferably of the non-dominant arm.
• Meningococcal C conjugate vaccine or tick-borne encephalitis vaccine
Meningococcal vaccine: two IM injections Tick-borne encephalitis vaccine: two IM injections

Locations

Country	Name	City	State
Finland	East Vantaa Clinic	East Vaanta
Finland	Espoo Vaccine Research Clinic	Espoo
Finland	Helsinki East Vaccine Research Clinic	Helsinki
Finland	Helsinki South Vaccine Research Clinic	Helsinki
Finland	Jarvenpaa Vaccine Research Clinic	Jarvenpaa
Finland	Kokkola Vaccine Research Clinic	Kokkola
Finland	Kotka Clinic	Kotka
Finland	Kuopio Vaccine Clinic	Kuopio
Finland	Kuopio Vaccine Research Clinic	Kuopio
Finland	Lahti vaccine research Clinic	Lahti
Finland	Oulu Vaccine Research Clini	Oulu
Finland	Pori Vaccine Research Clinic	Pori
Finland	Seinajoki Clinic	Seinajoki
Finland	Tampere Vaccine Research Clinic	Tampere
Finland	Turku Clinic	Turku
Finland	Vantaa West Vaccine Research Clinic	Vantaa
Finland	West Vantaa Clinic	West Vantaa
Germany	Praxis Dr med Thilo Heising	Aalen Wasseralfingen
Germany	"Praxis Dr med Dietrich Lasius"	Berlin
Germany	Praxis Dipl med Andreas Muhmer	Berlin
Germany	Praxis Dipl. med. F. Temmler / Dipl. med. D. Wenzel	Berlin
Germany	Praxis Dr Luise Schroeter	Berlin
Germany	Praxis Dr med Dorothea Budde	Berlin
Germany	Praxis Dr med Eva Brand	Berlin
Germany	Praxis Dr med Klaus-Peter Falkowski	Berlin
Germany	Praxis Dr med Mechthild Vocks-Hauck	Berlin
Germany	Praxis Dr med Petra van Stiphout	Berlin
Germany	Praxis Dr med Thomas Richter	Berlin
Germany	Praxis Dr med Ursula Hornlein	Berlin
Germany	Praxis Dr. med. Cornelia Busse	Berlin
Germany	Praxis Dr. med. Petra Sandow	Berlin
Germany	Praxis Dr Norbert Meister	Bindlach
Germany	Praxis Dr med Thomas Tuschen	Binngen Rhein
Germany	Praxis Dr. Elmar Dietmair	Bobingen
Germany	Praxis Dr med Brigitta Becker	Bochum
Germany	Praxis Karl-Heinz Blattel	Braunfels
Germany	Praxis Dr. med. Roland Knecht	Bretten
Germany	Praxis Dr. med. Maria R. Holtorf	Brunsbuettel
Germany	Praxis Dr Klaus Helm	Detmold
Germany	Praxis Joseph Zakarian	Duesseldorf
Germany	Praxis Dr med Hans-Henning Peters	Eschwege
Germany	Praxis Dr. med. Dirk Straub	Essen
Germany	Peaxis Dr H Outzen jun	Flensburg
Germany	Praxis Dr med Rainer Haase	Flensburg
Germany	Praxis Dr. med. Per Gildberg	Flensburg
Germany	Praxis Dr Lothar MaurerJun	Frankenthal
Germany	Praxis Dr med Walter Otto	Fulda
Germany	Praxis Dr med Hans-Joachim Buttner	Gau-Odernheim
Germany	Praxis Dr med Christian Kayser	Gehrden
Germany	Praxis Ute Jessat	Gluecksburg
Germany	Praxis Dr. med. Dubravka Pock-Lutz	Grevenbroich
Germany	Praxid Dr. med. Karl-Heinrich Hansen	Hamburg
Germany	Praxis Dr Anna Halat	Hamburg
Germany	Praxis Dr med Bernard Nast	Hamburg
Germany	Praxis Dr. med. Malte Klarczyk	Hamburg
Germany	Praxis Dr med Jurgen Schwalbe	Hameln
Germany	Praxis Dr med Hans-Heinrich Rohe	Hille
Germany	Praxis Dr Marlies Bolich	Jena
Germany	Praxis Peter Bosch	Karlsruhe-Oberreut
Germany	Praxis Dr Peter Andoko Soemantri	Kleve-Materborn
Germany	Praxis Dr. Michael Muehlschlegel	Lauffen
Germany	Praxis Dr Sibylle Hetzinger	Lobenstein
Germany	Praxis Dipl med Dagmar Manegold-Randel	Lohne
Germany	Praxis Dr. Renate Lang	Ludwigsburg
Germany	Praxis Dr med Julika Kelber	Luneburg
Germany	Johannes Gutenberg-University	Mainz
Germany	Praxis Uwe Jakob	Mainz
Germany	Praxis Dr med Falko Panzer	Mannheim
Germany	Praxis Dr med Volker Tempel	Marbach a. N.
Germany	Praxis Dr. med. Herbert Kollaschinski	Marktredwitz
Germany	Praxis Dr med Matthias Donner	Moenchengladbach
Germany	Praxis Ralph Koellges	Moenchengladbach
Germany	Praxis Dr. med. Janina Joiko	Muenchen
Germany	"Praxis Prof Dr med Stefan Walter Eber"	Munchen
Germany	Praxis Dr med Peter Dietl	Munchen
Germany	Praxis Dr med Philip Fellner von Feldegg	Munster / NRW
Germany	Praxis Dipl Med Ute Macholdt	Neuhaus am Rennweg
Germany	Praxis Dr Rossius	Neumuenster
Germany	Praxis Dr Sabine Maruschke	Neumuenster
Germany	Praxis Drs J und K Kandzora	Neumuenster
Germany	Praxis Dr. med. S. Mohns-Petersen	Niebuell
Germany	Praxis Dr med Hartmut Scheele	Niedernhausen
Germany	Praxis Dr med Stefan Noll	Porta Westfalica
Germany	Praxis Zlatka Zochev Donkov	Rendsburg
Germany	Praxis Thomas Morandini	Schönenberg
Germany	Praxis Dr med Michael Vomstein	Schwabisch Hall
Germany	"Praxis Dr med Gunther Knapp"	Schwieberdingen
Germany	Praxis Dr med Ulrich Soergel	Stadthagen
Germany	Praxis Dr Ulrich Pfletschinger	Stuttgart
Germany	Praxis Dr. med Heidi B. John-Wagenmann	Stuttgart
Germany	Praxis Dr. med Manfred Heitz	Stuttgart
Germany	Praxis Dr. med. Rolf Ebert	Tauberbischofsheim
Germany	Praxis Dr med Karl-Eugen Mai	Tettnang
Germany	Praxis Dr med Klaus Kindler	Trier
Germany	Praxis Dr med Ralph Maier	Tuttlingen
Germany	Praxis Dr med Ulrich Umpfenbach	Viersen
Germany	Praxis Dr med Volker Kemmerich	Weinstadt
Germany	Praxis Dr Per Bergmann	Winsen
Germany	Praxis Dr med Steffi Bulst	Wurzen
Italy	Fondazione IRCCS Policlinico Mangiagalli e Regina Elena	Milano
Italy	Ospedale Maggiore della Carita	Novara

Sponsors (2)

Lead Sponsor	Collaborator
Novartis	Novartis Vaccines

Countries where clinical trial is conducted

Finland,  Germany,  Italy, 

References & Publications (1)

Vesikari T, Knuf M, Wutzler P, Karvonen A, Kieninger-Baum D, Schmitt HJ, Baehner F, Borkowski A, Tsai TF, Clemens R. Oil-in-water emulsion adjuvant with influenza vaccine in young children. N Engl J Med. 2011 Oct 13;365(15):1406-16. doi: 10.1056/NEJMoa101 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Subjects (Unprimed) 6 to <36 Months Age With Local and Systemic Reactions After Any Vaccination for All Seasons, Comparison of Adjuvanted Trivalent Influenza Vaccine (aTIV) and Flu Vaccine Control.	Safety was assessed in terms of number of subjects experiencing each of the local and systemic reactions within 7-days after any vaccination for all seasons, comparison of adjuvanted Trivalent influenza vaccine (aTIV) and flu vaccine control.	7 days post-vaccination	Yes
Primary	Percentage of Subjects (Unprimed) Aged 6 to <36 Months With Virus-Confirmed Influenza, Comparison of aTIV and Non-flu Vaccine Control (Men C/TBE Vaccine)	Virus-confirmed influenza illnesses were assessed and compared between the adjuvanted influenza vaccine (TIV-adj) and non-influenza vaccines (Non-flu control) in 6 to <36 month unprimed subjects for Absolute Efficacy. This primary endpoint is only for homologous strains.	3 weeks after 2nd vaccination	No
Secondary	Number of Subjects (Unprimed) of 6 to <72 Months Age With Local and Systemic Reactions After Any Vaccination	Safety was assessed as the number of subjects aged 6 to <72 months who reported solicited local or systemic adverse events after any vaccination with TIV-adj for all seasons.	7 days post-vaccination	Yes
Secondary	Number of Subjects (Unprimed) With Unsolicited Adverse Events Reported After Any Vaccination	Number of subjects aged 6 to <36 months and in the overall age cohort (unprimed children aged 6 to <72 months) experiencing each of the unsolicited adverse events (AEs) throughout the study	Study day 1 to Study day 181	Yes
Secondary	Percentage of Subjects (Unprimed) Aged 6 to <72 Months With Virus-Confirmed Influenza, Comparison of aTIV to Non-flu Vaccine Control and Flu-vaccine Control (Matched Strains)	Virus-confirmed influenza illnesses were assessed and compared between the adjuvanted influenza vaccine (TIV-adj) and non-influenza vaccines (Non-flu control) in subjects aged 6 to <72 months (unprimed) for Absolute Efficacy.; For Relative efficacy, the comparison was made between adjuvanted influenza vaccine (TIV-adj) and flu vaccine control.	3 weeks after 2nd vaccination	No
Secondary	Percentage of Subjects (Unprimed) Aged 6 to <72 Months With Virus-Confirmed Influenza, Comparison of aTIV to Non-flu Vaccine Control and Flu Vaccine Control (Any Strains).	Virus-confirmed influenza illnesses (regardless of antigenic match to those contained in the vaccine) were assessed and compared between the adjuvanted influenza vaccine (TIV-adj) and non-influenza vaccines (Non-flu control) in subjects aged 6 to <72 months (unprimed) for Absolute Efficacy.; For Relative efficacy, the comparison was made between adjuvanted influenza vaccine (TIV-adj) and flu vaccine control.	3 weeks after 2nd vaccination	No
Secondary	Number of Subjects (Unprimed) With Influenza Like Illnesses (ILIs) in the 6 to <72 Months Age Cohort for Combined Seasons 2007/08 and 2008/09	Virus-confirmed influenza illnesses were assessed and trivalent adjuvanted influenza vaccine (TIV-adj) was compared with Non-flu control vaccine and Flu-control vaccine in 6 to <72 month old subjects for Influenza like illnesses for seasons 2007/08 and 2008/09.	3 weeks after 2nd vaccination	No
Secondary	Number of Subjects With Influenza Like Illnesses (ILIs) in the 6 to <36 Months and in Overall Age Cohort (Unprimed Subjects Aged 6 to <72 Months) for Combined Seasons 2007/08 and 2008/09	Virus-confirmed influenza illnesses were assessed and trivalent adjuvanted influenza vaccine (TIV-adj) was compared with Non-flu control vaccine and Flu-control vaccine for Influenza like illnesses for seasons 2007/08 and 2008/09.	3 weeks after 2nd vaccination	No
Secondary	Loss of Days of Usual Activity (Job, School, Day Care, Household/Family/Community Activities) Due to Influenza Like Illness (ILI) in Subjects in Aged 6 to <72 and 6 to <36 Months and in Direct Caregivers Living in the Household.	Virus-confirmed influenza illnesses were assessed and trivalent adjuvanted influenza vaccine (TIV-adj) was compared with Non-flu control vaccine and Flu-control vaccine for Influenza like illnesses for seasons 2007/08 and 2008/09.	3 weeks after 2nd vaccination	No
Secondary	Number of Events of Influenza Like Illness for Combined Seasons 2007/08 and 2008/09.	The number of events of Influenza like Illness reported by subjects aged 6 to <72 months was assessed for combined seasons 2007/08 and 2008/09	3 weeks after 2nd vaccination	No
Secondary	Immunogenicity of aTIV, Compared to Flu and Non-Flu-control, in Terms of GMRs, in Unprimed Subjects Aged 6 to <36 Months or Season 2008/09 (Homologous and Heterologous Strains)	The immunogenicity was assessed in terms of Geometric mean titer ratios (GMRs) of study day 29/study day 1, study day 50/study day 1, study day 181/study day 1 were evaluated.; The criteria for evaluation is GMR >2.5	On study days 1, 29, 50 and 181	No
Secondary	Immunogenicity of aTIV, Compared to Flu and Non-Flu-control, in Terms of Geometric Mean Titers (GMTs), in Unprimed Subjects Aged 6 to <36 Months for Season 2008/09 (Homologous and Heterologous Strains)	Immunogenicity was analyzed in terms of Geometric Mean Titers (GMTs) as measured by hemagglutination inhibition (HI) assay. For each strain and each vaccine group, least squares GMTs, associated 2-sided 95% confidence interval were determined for all time points.; Superiority analysis: GMT-TIV-adj/GMT-Flu-control >1 should be elicited to show that GMT-TIV-adj is superior to GMT-Flu-control	On study days 1, 29, 50 and 181	No
Secondary	Percentage (95% CI) of Unprimed Subjects Aged 6 to <36 Months With HI Titer =1:40 in Season 2008/09 HI Assay(Homologous and Heterologous Strains)	Percentage of subjects achieving seroprotection (i.e., with HI titer =1:40) at study day 1, study day 29, study day 50 and a study day 181 and associated 95% CI. The lower bound of the two-sided 95% CI for the percentage of subjects achieving an HI antibody titer =1:40 should meet or exceed 70%.	On study days 1, 29, 50, 181	No
Secondary	Percentage (95% CI) of Unprimed Subjects Aged 6 to <36 Months With Seroconversion From Baseline, for Season 2008/09 (Homologous and Heterologous Strains)	HI assay was used for the analysis. Seroconversion is defined as negative pre-vaccination serum (<10)/ post-vaccination HI titer =1:40.; Seroconversion is defined as either pre-vaccination HI titer <10 and a post-vaccination HI titer =1:40 or a prevaccination HI titer =10 and a minimum four-fold rise in post-vaccination HI antibody titer.; The lower bound of the two-sided 95% confidence interval (CI) for the percentage of subjects achieving seroconversion for HI antibody should meet or exceed 40%.	On study days 1, 29, 50, 181	No
Secondary	Immunogenicity of aTIV, Compared to Flu and Non-Flu-control, in Terms of GMTs, in Unprimed Subjects Aged 6 to <72 Months for Season 2008/09 (Homologous and Heterologous Strains)	Immunogenicity was analyzed in terms of Geometric Mean Titers (GMTs) as measured by hemagglutination inhibition (HI) assay. For each strain and each vaccine group, least squares GMTs, associated 2-sided 95% confidence interval were determined for all time points Superiority analysis: GMT-TIV-adj/GMT-Flu-control >1 and GMT-TIV-adj/GMT-Non Flu-control >1 should be elicited to show that GMT-TIV-adj is superior to GMT-Flu-control/Non Flu-control.	On study days 1, 29, 50 , 181	No
Secondary	Immunogenicity of aTIV, Compared to Flu and Non-Flu-control, in Terms of GMRs, in Unprimed Subjects Aged 6 to <72 Months for Season 2008/09 (Homologous and Heterologous Strains)	Hemagglutination Inhibition (HI) assay was used for the analysis. Geometric mean titer ratios (GMRs) of study day 29/study day 1, study day 50/study day 1, study day 181/study day 1 were evaluated.; The criteria for evaluation is GMR >2.5	On study days 1, 29, 50, 181	No
Secondary	Percentages of Subjects With HI Titers = 1:40 in Unprimed Subjects 6 to <72 Months of Age for Season 2008/09 Homologous and Heterologous Strains	Hemagglutination Inhibition (HI) assay was used for the analysis.; Percentage of subjects achieving seroprotection (i.e., with HI titer =1:40) at study day 1, study day 29, study day 50 and a study day 181 and associated 95% Confidence Intervals. The lower bound of the two-sided 95% CI for the percentage of subjects achieving an HI antibody titer =1:40 should meet or exceed 70%.	On study days 1, 29, 50, 181	No
Secondary	Percentages of Subjects With Seroconversion and Vaccine Group Differences in Unprimed Subjects 6 to <72 Months of Age for Season 2008/09 (Homologous and Heterologous Strains)	HI assay was used for the analysis. Seroconversion is defined as negative pre-vaccination serum (<10)/ post-vaccination HI titer =1:40.; Seroconversion is defined as either pre-vaccination HI titer <10 and a post-vaccination HI titer =1:40 or a prevaccination HI titer =10 and a minimum 4-fold rise in post-vaccination HI antibody titer. The lower bound of the two-sided 95% confidence interval (CI) for the percentage of subjects achieving seroconversion for HI antibody should meet or exceed 40%.	On study days 1, 29, 50, 181	No
Secondary	Number of Subjects With Local and Systemic Reactions for Egg and Cell Derived Inactivated Novel Swine Origin A/H1N1 Subunit Influenza Vaccines After Each Vaccination for All Seasons		7 days post-vaccination	Yes
Secondary	Indirect Protective Effect of Fluad (NH Composition 2007/2008), Compared to Non-flu Control and Flu Control, in Connection to Household-contact Persons Via a Questioning of the Parents About ILI of Persons Living in the Same Household as the Study Child		3 weeks after 2nd vaccination	No
Secondary	Incidence Rate of the 2009-2010 H1N1 Swine Pandemic Caused by a Novel Influenza A (H1N1) Virus of Swine Origin in Unprimed Children Aged 6 to <36 and 6 to <72 Months		3 weeks after 2nd vaccination	No