Safety and Immunogenicity of Trivalent Subunit Inactivated Flu Vaccine Administered to Healthy Children and Adolescents 3 to 17 Years of Age
Sponsor
Novartis Vaccines (Industry)
Overall Status
Completed
CT.gov ID
NCT01209780
Collaborator
(none)
3,116
13
4
12
239.7
20
Study Details
Study Description
Brief Summary
This study will evaluate the safety and immunogenicity in healthy children and adolescents after one or two IM dose(s) of trivalent subunit inactivated flu vaccine.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
3116 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Prevention
Official Title:
A Multi-center, Phase III, Randomized, Observer Blind Study to Evaluate the Safety, Tolerability and Immunogenicity of a Trivalent Subunit Inactivated Flu Vaccine in Healthy Children and Adolescents 3 to 17 Years of Age
Study Start Date
:
Sep 1, 2010
Actual Primary Completion Date
:
Mar 1, 2011
Actual Study Completion Date
:
Sep 1, 2011
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: TIV (3-8 years) Non-Naive subjects received one dose and naive subjects received two doses, administered 4 weeks apart, of investigational trivalent influenza vaccine (TIV) |
Biological: TIV
Investigational egg-derived trivalent subunit influenza vaccine.
|
| Active Comparator: Control TIV (3-8 years) Non-Naive subjects received one dose and Naive subjects received two doses, administered 4 weeks apart, of control vaccine. Subjects aged 3 to <4 years and subjects aged 4 to 8 years received different control TIV. |
Biological: TIVf
US licensed trivalent inactivated subunit influenza vaccine -Fluvirin (Novartis Vaccines and Diagnostics) is approved for use in subjects ≥4 years.
Biological: Comparator TIV
US licensed trivalent subunit inactivated influenza vaccine- Fluzone (Sanofi Pasteur) is approved for use in children <4 years.
|
| Experimental: TIV ( 9-17 years) All subjects received one dose of investigational TIV. The subjects in this cohort were included only for safety analysis. |
Biological: TIV
Investigational egg-derived trivalent subunit influenza vaccine.
|
| Active Comparator: Control TIV ( (9-17 years) All subjects received one dose of the control vaccine. The subjects from this cohort were included only for safety analysis. |
Biological: TIVf
US licensed trivalent inactivated subunit influenza vaccine -Fluvirin (Novartis Vaccines and Diagnostics) is approved for use in subjects ≥4 years.
|
Outcome Measures
Primary Outcome Measures
- Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of the Percentage of Subjects Achieving Seroconversion [Day 22 for non-naive/Day 50 for naive subjects]
The non-inferiority of the antibody responses of investigational TIV compared to control TIV assessed in terms of the percentage of subjects achieving seroconversion, against the three homologous vaccine strains,in children 3 to 8 years of age, at 21 days after last vaccination. Seroconversion was defined as a pre-vaccination haemagglutinin inhibition (HI) titer <1:10 and post-vaccination HI titer ≥1:40 or as a pre-vaccination HI titer ≥1:10 and at minimum four-fold rise in post-vaccination antibody titer
- Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of Post Vaccination Geometric Mean Titers (GMTs) [Day 22 for non-naive/Day 50 for naive subjects]
The non-inferiority of the antibody responses of investigational TIV compared to control vaccine assessed in terms of post vaccination GMTs, at 21 days after last vaccination against the three homologous vaccine strains in 3 to 8 year old children.
Secondary Outcome Measures
- Percentages of Subjects Achieving HI Titers ≥40 Following Vaccination With Investigational TIV or Control Vaccine. [Day 22 for non-naive/Day 50 for naive subjects]
The percentages of 3 to 8 year old subjects achieving HI titers ≥40 after receiving either one or two doses of investigational TIV or control vaccine, 21 days after last vaccination, are reported. This criterion 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 With Seroconversion in Antibody Titers Following Vaccination With Investigational TIV or Control Vaccine [Day 22 for non-naive/Day 50 for naive]
The percentages of 3 to 8 years-old subjects achieving seroconversion in HI antibody titers after receiving either one or two doses of investigational TIV or control vaccine, at 21 days after last vaccination, are reported. This criterion, according to the US (CBER) guideline, is met if the lower limit of 95% CI of percentage of subjects achieving seroconversion or significant increase at day 22 and day 50 (21 days after last vaccination) is ≥40.
- Percentages of Vaccine-naive Children Achieving HI Titers ≥40 After Receiving Two Doses of Investigational TIV or Control Vaccine. [Day 1, Day 29, and Day 50]
The percentage of 3 to 8 years-old vaccine-naive subjects achieving HI titers ≥40, after receiving two doses of investigational TIV or control vaccine. The time frame of evaluation was 28 days after first (Day 29) and 21 days after second vaccine dose (Day 50). This criterion 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%, for each vaccine strain.
- Percentages of Vaccine-naive Children Achieving Seroconversion in Antibody Titers, After Receiving Two Doses of Investigational TIV or Control Vaccine [Day 29 and Day 50]
The percentages of 3 to 8 years-old vaccine naive children achieving seroconversion or significant increase in HI antibody titers after receiving two doses of investigational TIV or control vaccine, are reported. The time frame of evaluation was 28 days after first (Day 29) and 21 days after the second dose (Day 50). This criterion, according to the US (CBER) guideline, is met if the lower limit of 95% CI of percentage of subjects achieving seroconversion or significant increase at day 29 and day 50 is ≥40, for each vaccine strain.
- Number of Subjects Reporting Solicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine [Day 1 to 7 after vaccination]
The number of 3-17 year old children with solicited local and systemic adverse events and other adverse events, after receiving either one or two doses of investigational TIV as compared to control vaccine are reported.
- Number of Subjects Reporting Unsolicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine [Day 1 to 180 (non-naive )/Day 1 to 209 (naive)]
The number of 3-17 year old children reporting any unsolicited adverse event and any serious adverse event (SAE) after receiving either one or two doses of investigational TIV and control vaccine are reported.
Eligibility Criteria
Criteria
Ages Eligible for Study:
3 Years
to 17 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
Inclusion Criteria:
-
Males and females aged 3 to 17 years, in good health as determined by medical history, physical examination and clinical judgment of the investigator
-
Documented consent provided by parents or legal guardians
-
For individuals 8 years of age and older, informed assent to participate in the study after the nature of the study had been explained to them in terms they could understand
-
Individuals and parents/guardians who were able to comply with all study procedures and were available for all clinic visits scheduled in the study
Exclusion Criteria:
-
Parents or legal guardians and individuals who are not able to comprehend and to follow all required study procedures for the whole period of the study
-
Parents or legal guardians and individuals providing assent who do not consent to the retention of the subject's serum samples after study completion
-
Individuals with behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may have interfered with the subject's ability to participate in the study
-
Individuals with history or any illness that, in the opinion of the investigator, might have interfered with the results of the study or posed additional risk to the subjects due to participation in the study
-
History of any anaphylaxis, serious vaccine reactions, or hypersensitivity to influenza viral proteins, latex, to any excipients, and to eggs (including ovalbumin), chicken protein, influenza viral protein, kanamycin, neomycin sulphate, cetyltrimethylammonium bromide (CTAB), polysorbate 80, neomycin, polymixin, formaldehyde, thimerosal, beta propiolactone, or nonoxynol-9
-
History of any serious disease, such as:
-
cancer
-
history of serious chronic, rheumatologic, neurologic and hematologic diseases
-
history of underlying medical condition such as inborn errors of metabolism
- Known or suspected impairment/alteration of immune function, including:
-
chronic use of oral steroids within 60 days prior to Visit 1 (use of inhaled, intranasal, or topical corticosteroids is allowed)
-
receipt of immunostimulants within 60 days prior to Visit 1
-
receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivates within 3 months prior to Visit 1 or planned during the full length of the study
-
HIV infection or HIV-related disease
-
Pregnant or breast-feeding female and any positive or indeterminate pregnancy test
-
Received an influenza vaccine within 6 months prior to Visit 1
-
Laboratory-confirmed or suspected influenza disease within 6 months prior to Visit 1
-
Receipt of another vaccine within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) prior to enrollment in this study
-
Experienced a fever and/or any acute illness within 3 days prior to each study vaccination
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Centro de Atención e Investigación Medica - CAIMED | Carrera 42A # 17-50, Bogotá | Colombia | ||
| 2 | Clinical research institute ,S.C(CRI), Blvd Manuel Avila Camacho 1994 Consultorio 1103 Col. San Lucas Tepetlacalco, C.P.54055 Tlalnepantla | Estado de México | Mexico | ||
| 3 | Centro de Salud Magally Ruiz, Street Bolivar | Panama - La Chorrera | Panama | ||
| 4 | Clinica Hospital San Fernando, Floor 4 Office 419 via España las Sabanas | Panamá | Panama | ||
| 5 | Consultorios America Floor 2 Office 201-1, Via España Vista Hermosa | Panamá | Panama | ||
| 6 | Consultorios Medicos San Judas Tadeo Principal Street, Floor 5 Office 507, Villa Lucre | Panamá | Panama | ||
| 7 | Philippine General Hospital | Taft Avenue, Manila | Manila | Philippines | 1000 |
| 8 | Research Institute for Tropical Medicine, Department of Health Compound | FILINVEST Corporate City, Alabang | Muntinlupa City | Philippines | 1781 |
| 9 | Research Institute for Tropical Medicine, Department of Health Compound, FILINVEST Corporate City | Alabang, Muntinlupa City | Philippines | 1781 | |
| 10 | University of the East Ramon Magsaysay Medical Center, 64 Aurora Boulevard | Barangay Dona Imelda Quezon City | Philippines | 1113 | |
| 11 | De La Salle Health Sciences Institute | Dasmarinas Cavite | Philippines | 4115 | |
| 12 | Mary Chiles General Hospital, 667 Gastambide St. Sampaloc | Manila | Philippines | 1008 | |
| 13 | Philippine Children's Medical Center, Quezon Avenue corner Agham Road | Quezon City | Philippines |
Sponsors and Collaborators
- Novartis Vaccines
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Novartis Vaccines
ClinicalTrials.gov Identifier:
NCT01209780
Other Study ID Numbers:
- V71_18
First Posted:
Sep 27, 2010
Last Update Posted:
Mar 11, 2014
Last Verified:
Feb 1, 2014
Keywords provided by Novartis Vaccines
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | The study was conducted in 13 centers across 4 countries: Mexico, Colombia, Panama and Philippines. |
|---|---|
| Pre-assignment Detail | Due to GCP non-compliance at the Mexico site, data of 312 subjects (3-8 year olds) enrolled from this site were excluded from the final immunogenicity and safety analysis. The population was analyzed in the enrolled set. |
| Arm/Group Title | TIV (3-8 Years Old) | Control (4-8 Years) | Control (3 to < 4 Years) | TIV (9-17 Years) | Control (9-17 Years) |
|---|---|---|---|---|---|
| Arm/Group Description | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of investigational TIV. | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of US licensed control vaccine- TIVf. | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination.The non-naive subjects received one dose and naive subjects received two doses of US licensed control vaccine- comparator TIV. | All subjects in this group were non-naive and received one dose of investigational TIV. | All subjects in this group were non-naive and received one dose of US licensed control vaccine TIVf. |
| Period Title: Overall Study | |||||
| STARTED | 1042 | 485 | 48 | 817 | 412 |
| COMPLETED | 1016 | 467 | 44 | 807 | 407 |
| NOT COMPLETED | 26 | 18 | 4 | 10 | 5 |
Baseline Characteristics
| Arm/Group Title | TIV (3-8 Years) | Control (3-8 Years) | TIV (9-17 Years) | Control (9-17 Years) | Total |
|---|---|---|---|---|---|
| Arm/Group Description | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of investigational TIV. | The group [control (4-8 years) + control (3 to<4 years)] consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received comparator TIV. The non-naive subjects received one dose and naive subjects received two doses of vaccine. | All subjects received one dose of investigational TIV. | All subjects received one dose of control TIV (eTIV_f). | Total of all reporting groups |
| Overall Participants | 1042 | 533 | 817 | 412 | 2804 |
| Age (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
5.6
(1.6)
|
5.6
(1.6)
|
12.4
(2.4)
|
12.3
(2.3)
|
8.6
(3.9)
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
517
49.6%
|
269
50.5%
|
398
48.7%
|
215
52.2%
|
1399
49.9%
|
| Male |
525
50.4%
|
264
49.5%
|
419
51.3%
|
197
47.8%
|
1405
50.1%
|
Outcome Measures
| Title | Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of the Percentage of Subjects Achieving Seroconversion |
|---|---|
| Description | The non-inferiority of the antibody responses of investigational TIV compared to control TIV assessed in terms of the percentage of subjects achieving seroconversion, against the three homologous vaccine strains,in children 3 to 8 years of age, at 21 days after last vaccination. Seroconversion was defined as a pre-vaccination haemagglutinin inhibition (HI) titer <1:10 and post-vaccination HI titer ≥1:40 or as a pre-vaccination HI titer ≥1:10 and at minimum four-fold rise in post-vaccination antibody titer |
| Time Frame | Day 22 for non-naive/Day 50 for naive subjects |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was done on per protocol population i.e-all subjects who correctly received study vaccinations,provided evaluable serum samples at the relevant time points, and had no major protocol violation as defined prior to unblinding. |
| Arm/Group Title | TIV (3-8 Years) | Control (3-8 Years) |
|---|---|---|
| Arm/Group Description | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of investigational TIV. | The group [control (4-8 years) + control (3 to<4 years)] consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received comparator TIV. The non-naive subjects received one dose and naive subjects received two doses of control vaccine. |
| Measure Participants | 918 | 468 |
| H1N1 strain (N=916,467) |
95
|
94
|
| H3N2 strain (N=917,468) |
78
|
87
|
| B strain |
87
|
85
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TIV (3-8 Years), Control (3-8 Years) |
|---|---|---|
| Comments | Non-inferiority of investigational TIV to control TIV against A/H1N1 influenza strain | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The investigational TIV was to be considered non-inferior to the control TIV if for all three strains the upper bound of the two-sided 95% CI on the difference between the seroconversion rates (Seroconversion control - Seroconversion investigational) at 21 days after last vaccination does not exceed 10 percentage points. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Vaccine group difference (%) |
| Estimated Value | -1 | |
| Confidence Interval |
(2-Sided) 95% -4 to 2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | TIV (3-8 Years), Control (3-8 Years) |
|---|---|---|
| Comments | Non-inferiority of investigational TIV to control TIV against A/H3N2 influenza strain | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The investigational TIV was to be considered non-inferior to the control TIV if, for all three strains, the upper bound of the two-sided 95% CI on the difference between the seroconversion rates (Seroconversion control - Seroconversion investigational), at 21 days after last vaccination, does not exceed 10 percentage points | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Vaccine group difference (%) |
| Estimated Value | 10 | |
| Confidence Interval |
(2-Sided) 95% 6 to 14 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | TIV (3-8 Years), Control (3-8 Years) |
|---|---|---|
| Comments | Non-inferiority of investigational TIV to the control TIV against B influenza strain | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The investigational TIV was to be considered non-inferior to the control TIV if, for all three strains, the upper bound of the two-sided 95% CI on the difference between the seroconversion rates (Seroconversion control - Seroconversion investigational), at 21 days after last vaccination, does not exceed 10 percentage points | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Vaccine group difference (%) |
| Estimated Value | -1 | |
| Confidence Interval |
(2-Sided) 95% -5 to 3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentages of Subjects Achieving HI Titers ≥40 Following Vaccination With Investigational TIV or Control Vaccine. |
|---|---|
| Description | The percentages of 3 to 8 year old subjects achieving HI titers ≥40 after receiving either one or two doses of investigational TIV or control vaccine, 21 days after last vaccination, are reported. This criterion 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%. |
| Time Frame | Day 22 for non-naive/Day 50 for naive subjects |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on per protocol population. |
| Arm/Group Title | TIV (3-8 Years) | Control (3-8 Years) |
|---|---|---|
| Arm/Group Description | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of investigational TIV. | The group [control (4-8 years) + control (3 to<4 years)] consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received comparator TIV. The non-naive subjects received one dose and naive subjects received two doses of control vaccine. |
| Measure Participants | 918 | 468 |
| Baseline (H1N1strain, N=917,467) |
49
|
48
|
| Day 22 or Day 50 (H1N1strain; N=917,468) |
97
|
95
|
| Baseline (H3N2 strain) |
84
|
85
|
| Day 22 or Day 50 (H3N2 strain; N=917,468) |
100
|
100
|
| Baseline (B strain) |
23
|
26
|
| Day 22 or Day 50 (B strain) |
95
|
92
|
| Title | Comparison of Antibody Responses of Investigational TIV to Control Vaccine in Terms of Post Vaccination Geometric Mean Titers (GMTs) |
|---|---|
| Description | The non-inferiority of the antibody responses of investigational TIV compared to control vaccine assessed in terms of post vaccination GMTs, at 21 days after last vaccination against the three homologous vaccine strains in 3 to 8 year old children. |
| Time Frame | Day 22 for non-naive/Day 50 for naive subjects |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on the per protocol population. |
| Arm/Group Title | TIV (3-8 Years) | Control (3-8 Years) |
|---|---|---|
| Arm/Group Description | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of investigational TIV. | The group [control (4-8 years) + control (3 to<4 years)] consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received comparator TIV. The non-naive subjects received one dose and naive subjects received two doses of control vaccine. |
| Measure Participants | 918 | 468 |
| Baseline (H1N1 strain, N=917,467) |
26
|
28
|
| Day 22 or Day 50 (H1N1 strain,N=917,468) |
1157
|
1501
|
| Baseline (H3N2 strain) |
142
|
150
|
| Day 22 or Day 50 (H3N2 strain, N=917,468) |
1385
|
2032
|
| Baseline (B strain) |
12
|
13
|
| Day 22 or Day 50 (B strain) |
208
|
195
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TIV (3-8 Years), Control (3-8 Years) |
|---|---|---|
| Comments | Non-inferiority of investigational TIV to licensed control TIV against A/H1N1 influenza strain | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The investigational TIV was to be considered non-inferior to the control TIV, if for all three strains, the upper bound of the two-sided 95% CI on the ratio of the GMTs (GMTcontrol/GMTinvestigational) at 21 days after last vaccination does not exceed 1.5 | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of GMTs |
| Estimated Value | 1.32 | |
| Confidence Interval |
(2-Sided) 95% 1.11 to 1.56 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | TIV (3-8 Years), Control (3-8 Years) |
|---|---|---|
| Comments | Non-inferiority of investigational TIV to licensed control TIV against A/H3N2 influenza strain | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The investigational TIV was to be considered non-inferior to the control TIV, if for all three strains, the upper bound of the two-sided 95% CI on the ratio of the GMTs (GMTcontrol/GMTinvestigational) at 21 days after last vaccination does not exceed 1.5 | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of GMTs |
| Estimated Value | 1.48 | |
| Confidence Interval |
(2-Sided) 95% 1.34 to 1.64 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | TIV (3-8 Years), Control (3-8 Years) |
|---|---|---|
| Comments | Non-inferiority of investigational TIV to licensed control TIV against B influenza strain | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | The investigational TIV was to be considered non-inferior to the control TIV, if for all three strains, the upper bound of the two-sided 95% CI on the ratio of the GMTs (GMTcontrol/GMTinvestigational) at 21 days after last vaccination does not exceed 1.5 | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of GMTs |
| Estimated Value | 0.95 | |
| Confidence Interval |
(2-Sided) 95% 0.85 to 1.07 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentages of Subjects With Seroconversion in Antibody Titers Following Vaccination With Investigational TIV or Control Vaccine |
|---|---|
| Description | The percentages of 3 to 8 years-old subjects achieving seroconversion in HI antibody titers after receiving either one or two doses of investigational TIV or control vaccine, at 21 days after last vaccination, are reported. This criterion, according to the US (CBER) guideline, is met if the lower limit of 95% CI of percentage of subjects achieving seroconversion or significant increase at day 22 and day 50 (21 days after last vaccination) is ≥40. |
| Time Frame | Day 22 for non-naive/Day 50 for naive |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on the per protocol population. |
| Arm/Group Title | TIV (3-8 Years) | Control (3-8 Years) |
|---|---|---|
| Arm/Group Description | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of investigational TIV. | The group [control (4-8 years) + control (3 to<4 years)] consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received comparator TIV. The non-naive subjects received one dose and naive subjects received two doses of control vaccine. |
| Measure Participants | 918 | 468 |
| H1N1 strain (N= 916,467) |
95
|
94
|
| H3N2 strain ( N= 917,468) |
78
|
87
|
| B strain |
87
|
85
|
| Title | Percentages of Vaccine-naive Children Achieving HI Titers ≥40 After Receiving Two Doses of Investigational TIV or Control Vaccine. |
|---|---|
| Description | The percentage of 3 to 8 years-old vaccine-naive subjects achieving HI titers ≥40, after receiving two doses of investigational TIV or control vaccine. The time frame of evaluation was 28 days after first (Day 29) and 21 days after second vaccine dose (Day 50). This criterion 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%, for each vaccine strain. |
| Time Frame | Day 1, Day 29, and Day 50 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was done on the per protocol population. |
| Arm/Group Title | TIV (3-8 Years) | Control (3-8 Years) |
|---|---|---|
| Arm/Group Description | The group consisted of naive subjects (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) who received two doses of investigational TIV. | The group [control (4-8 years) + control (3 to <4 years)] consisted of naive subjects (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) who received two doses of control vaccine. Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received two doses of comparator TIV. |
| Measure Participants | 820 | 413 |
| Day 1 (H1N1 strain, N=819,412) |
49
|
48
|
| Day 29 (H1N1 strain, N=819,413) |
83
|
82
|
| Day 50 (H1N1 strain, N= 819,413) |
99
|
98
|
| Day 1 (H3N2 strain) |
88
|
90
|
| Day 29 (H3N2 strain, N= 819, 413) |
99
|
98
|
| Day 50 (H3N2 strain,N= 819, 413) |
100
|
100
|
| Day 1 (B strain) |
25
|
26
|
| Day 29 (B strain, N= 820,412) |
82
|
81
|
| Day 50 (B strain) |
98
|
94
|
| Title | Percentages of Vaccine-naive Children Achieving Seroconversion in Antibody Titers, After Receiving Two Doses of Investigational TIV or Control Vaccine |
|---|---|
| Description | The percentages of 3 to 8 years-old vaccine naive children achieving seroconversion or significant increase in HI antibody titers after receiving two doses of investigational TIV or control vaccine, are reported. The time frame of evaluation was 28 days after first (Day 29) and 21 days after the second dose (Day 50). This criterion, according to the US (CBER) guideline, is met if the lower limit of 95% CI of percentage of subjects achieving seroconversion or significant increase at day 29 and day 50 is ≥40, for each vaccine strain. |
| Time Frame | Day 29 and Day 50 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was done on the per protocol population. |
| Arm/Group Title | TIV (3-8 Years) | Control (3-8 Years) |
|---|---|---|
| Arm/Group Description | The group consisted of naive subjects (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) who received two doses of investigational TIV. | The group [control (4-8 years) + control (3 to <4 years)] consisted of naive subjects (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) who received two doses of control vaccine. Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received two doses of comparator TIV. |
| Measure Participants | 820 | 413 |
| Day 29 (H1N1 strain, N= 818,412) |
82
|
81
|
| Day 50 (H1N1 strain, N= 818,412) |
98
|
96
|
| Day 29 (H3N2 strain, N= 819,413) |
74
|
87
|
| Day 50 (H3N2 strain, N= 819,413) |
78
|
87
|
| Day 29 (B strain, N= 820,412) |
74
|
73
|
| Day 50 (B strain) |
89
|
88
|
| Title | Number of Subjects Reporting Solicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine |
|---|---|
| Description | The number of 3-17 year old children with solicited local and systemic adverse events and other adverse events, after receiving either one or two doses of investigational TIV as compared to control vaccine are reported. |
| Time Frame | Day 1 to 7 after vaccination |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was done on the safety set population i.e all subjects who received at least one study vaccine and provided post vaccination safety data. |
| Arm/Group Title | TIV (3-8 Years) | Control (3-8 Years) | TIV (9-17 Years) | Control (9-17 Years) |
|---|---|---|---|---|
| Arm/Group Description | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of investigational TIV. | The group [control (4-8 years) + control (3 to<4 years)] consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received comparator TIV. The non-naive subjects received one dose and naive subjects received two doses of control vaccine. | All subjects received one dose of investigational TIV. | All subjects received one dose of control vaccine(TIVf). |
| Measure Participants | 1037 | 531 | 817 | 412 |
| Any local |
364
|
216
|
270
|
148
|
| Injection site pain |
363
|
215
|
268
|
146
|
| Injection site ecchymosis |
1
|
1
|
2
|
0
|
| Injection site erythema |
1
|
1
|
2
|
1
|
| Injection site induration |
10
|
6
|
5
|
6
|
| Injection site swelling |
11
|
11
|
6
|
3
|
| Any systemic |
262
|
161
|
193
|
94
|
| Chills |
37
|
20
|
38
|
8
|
| Malaise |
77
|
51
|
68
|
27
|
| Myalgia |
78
|
50
|
54
|
34
|
| Arthralgia |
41
|
20
|
26
|
12
|
| Headache (N=1037,531,817,411) |
101
|
52
|
93
|
38
|
| Sweating |
37
|
29
|
43
|
22
|
| Fatigue |
34
|
22
|
52
|
21
|
| Fever (≥ 38°C) |
116
|
68
|
39
|
12
|
| Other |
153
|
89
|
103
|
54
|
| Analgesic/Antipyretic med.used(N=1032,531,816,412) |
91
|
52
|
22
|
9
|
| Stayed at home due to reaction(N=1019,524,809,411) |
93
|
54
|
89
|
49
|
| Title | Number of Subjects Reporting Unsolicited Adverse Events After Vaccination With Investigational TIV and Control Vaccine |
|---|---|
| Description | The number of 3-17 year old children reporting any unsolicited adverse event and any serious adverse event (SAE) after receiving either one or two doses of investigational TIV and control vaccine are reported. |
| Time Frame | Day 1 to 180 (non-naive )/Day 1 to 209 (naive) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was done on the safety set population. |
| Arm/Group Title | TIV (3-8 Years) | Control (3-8 Years) | TIV (9-17 Years) | Control (9-17 Years) |
|---|---|---|---|---|
| Arm/Group Description | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of investigational TIV. | The group [control (4-8 years) + control (3 to<4 years)] consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received comparator TIV. The non-naive subjects received one dose and naive subjects received two doses of control vaccine. | All subjects received one dose of investigational TIV. | All subjects received one dose of control vaccine (TIVf). |
| Measure Participants | 1039 | 531 | 817 | 412 |
| Any adverse event |
395
|
194
|
101
|
58
|
| At least possibly related adverse event |
64
|
36
|
23
|
11
|
| Serious adverse event |
14
|
3
|
4
|
3
|
| At least possibly related serious adverse event |
1
|
0
|
0
|
0
|
Adverse Events
| Time Frame | Solicited adverse events collected from Day 1-7 after each vaccination. Serious adverse events and other unsolicited adverse events were collected from Day 1-180 for non-naive and Day 1-209 for vaccine-naive subjects. | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | The population analyzed here is the safety set. | |||||||
| Arm/Group Title | TIV (3-8 Years) | Control (3-8 Years) | TIV (9-17 Years) | Control (9-17 Years) | ||||
| Arm/Group Description | The group consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). The non-naive subjects received one dose and naive subjects received two doses of investigational TIV. | The group [control (4-8 years) + control (3 to<4 years)] consisted of naive (who have never received influenza vaccination or had received only one influenza vaccine dose in the same season) and non-naive subjects (who had a record of previous influenza vaccination). Subjects (4-<9 years) received TIVf and subjects (3-<4 years) received comparator TIV. The non-naive subjects received one dose and naive subjects received two doses of control vaccine. | All subjects received one dose of investigational TIV. | All subjects received one dose of control vaccine (TIV_f). | ||||
All Cause Mortality |
||||||||
| TIV (3-8 Years) | Control (3-8 Years) | TIV (9-17 Years) | Control (9-17 Years) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||
Serious Adverse Events |
||||||||
| TIV (3-8 Years) | Control (3-8 Years) | TIV (9-17 Years) | Control (9-17 Years) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 14/1039 (1.3%) | 3/531 (0.6%) | 4/817 (0.5%) | 3/412 (0.7%) | ||||
| Infections and infestations | ||||||||
| Abscess | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Amoebiasis | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Appendicitis | 0/1039 (0%) | 0/531 (0%) | 0/817 (0%) | 1/412 (0.2%) | ||||
| Ascariasis | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Bronchopneumonia | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Cellulitis | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Cholera | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Dengue fever | 1/1039 (0.1%) | 0/531 (0%) | 1/817 (0.1%) | 1/412 (0.2%) | ||||
| Gastroenteritis | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Gastroenteritis bacterial | 2/1039 (0.2%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Gastroenteritis viral | 0/1039 (0%) | 1/531 (0.2%) | 0/817 (0%) | 0/412 (0%) | ||||
| Measles | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Pneumonia | 0/1039 (0%) | 1/531 (0.2%) | 0/817 (0%) | 0/412 (0%) | ||||
| Urinary tract infection | 2/1039 (0.2%) | 0/531 (0%) | 1/817 (0.1%) | 0/412 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Injury | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Road traffic accident | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Soft tissue injury | 1/1039 (0.1%) | 0/531 (0%) | 0/817 (0%) | 0/412 (0%) | ||||
| Thermal burn | 0/1039 (0%) | 1/531 (0.2%) | 0/817 (0%) | 0/412 (0%) | ||||
| Nervous system disorders | ||||||||
| Headache | 0/1039 (0%) | 0/531 (0%) | 1/817 (0.1%) | 0/412 (0%) | ||||
| Psychiatric disorders | ||||||||
| Suicide attempt | 0/1039 (0%) | 0/531 (0%) | 0/817 (0%) | 1/412 (0.2%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Asthma | 1/1039 (0.1%) | 0/531 (0%) | 1/817 (0.1%) | 0/412 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| TIV (3-8 Years) | Control (3-8 Years) | TIV (9-17 Years) | Control (9-17 Years) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 657/1039 (63.2%) | 342/531 (64.4%) | 385/817 (47.1%) | 196/412 (47.6%) | ||||
| General disorders | ||||||||
| injection site pain | 363/1039 (34.9%) | 215/531 (40.5%) | 268/817 (32.8%) | 146/412 (35.4%) | ||||
| malaise | 77/1039 (7.4%) | 52/531 (9.8%) | 68/817 (8.3%) | 27/412 (6.6%) | ||||
| pyrexia | 164/1039 (15.8%) | 91/531 (17.1%) | 43/817 (5.3%) | 15/412 (3.6%) | ||||
| fatigue | 0/1039 (0%) | 0/531 (0%) | 52/817 (6.4%) | 21/412 (5.1%) | ||||
| Infections and infestations | ||||||||
| nasopharingitis | 85/1039 (8.2%) | 37/531 (7%) | 0/817 (0%) | 0/412 (0%) | ||||
| upper respiratory tract infection | 102/1039 (9.8%) | 41/531 (7.7%) | 0/817 (0%) | 0/412 (0%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| myalgia | 79/1039 (7.6%) | 51/531 (9.6%) | 54/817 (6.6%) | 34/412 (8.3%) | ||||
| Nervous system disorders | ||||||||
| headache | 106/1039 (10.2%) | 54/531 (10.2%) | 94/817 (11.5%) | 41/412 (10%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| hyperhidrosis | 37/1039 (3.6%) | 29/531 (5.5%) | 43/817 (5.3%) | 22/412 (5.3%) | ||||
Limitations/Caveats
Due to GCP non-compliance at the Mexico site, data of 312 subjects (3-8 year olds) enrolled from this site were excluded from the final immunogenicity and safety analysis.
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 more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Posting Director |
|---|---|
| Organization | Novartis Vaccines and Diagnostics |
| Phone | |
| RegistryContactVaccinesUS@novartis.com |
Responsible Party:
Novartis Vaccines
ClinicalTrials.gov Identifier:
NCT01209780
Other Study ID Numbers:
- V71_18
First Posted:
Sep 27, 2010
Last Update Posted:
Mar 11, 2014
Last Verified:
Feb 1, 2014