| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| healthy volunteers (protection against influenza) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Healthy volunteers (protection against flu (influenza)) |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10016794 |
| E.1.2 | Term | Flu vaccination |
| E.1.2 | System Organ Class | 100000004865 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Immunogenicity Objective
To select an optimal dose of TIVc for pediatric subjects 6 to < 48 months of age by desirability index score (The overall desirability index is based on comparison of post-vaccination haemagglutination inhibition (HI) assay results and specific solicited adverse events following any vaccination) |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Immunogenicity Objective
- To evaluate HI antibody responses to each study vaccine (TIVc and TIVe) according to CBER immunogenicity criteria in pediatric subjects
Secondary Immunogenicity Objectives
- To evaluate HI antibody responses to each study vaccine according to CHMP immunogenicity criteria in pediatric subjects
- To evaluate antibody responses to each study group by microneutralization (MN) assay in pediatric subjects
- To evaluate geometric mean titer (GMT) percentages of subjects with higher titers by HI assay, and reverse cumulative distribution function curves of HI antibody responses for each vaccine group in pediatric subjects
-To perform pairwise comparisons between vaccine groups of post-vaccination GMT by HI and MN assay and between vaccine groups for seroconversion by HI assay
Safety Objective
To evaluate the safety and tolerability of each study vaccine in pediatric subjects 6 to < 48 months of age. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is a healthy subject, male or female, 6 through < 48 months of age at the time of enrollment, who has never previously received an influenza vaccine
2. Has parent(s) or legal guardian(s) who have given written informed consent after the nature of the study has been explained according to local regulatory requirements
3. Is in good health as determined by medical history, the outcome of a physical examination, and the clinical judgment of the Investigator
4. Is able to comply with all study procedures and is available for all clinic visits scheduled in the study (including parents or guardians) |
|
| E.4 | Principal exclusion criteria |
1. Has parent(s) or legal guardian(s) who are not able to comprehend and to follow all required study procedures for the duration of the study
2. Has parent(s) or legal guardian(s) who are not able to read or write and are not able to delegate a designated person (information of whom will be entered in the study file) who:
a. Is an impartial person of legal age who is willing and able to witness the informed consent procedures as required by the protocol,
b. Is willing and able to undergo Diary Card training, and
c. Is willing and able to collect information on the Diary Card on a daily basis during the Post-vaccination Period through day 50 per protocol requirements;
3. Is a child from whom the minimal blood volume cannot be obtained prior to randomization, at the discretion of the investigator
4. Known or suspected impairment/alteration of immune function, including:
a. Long-term oral or parenteral corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months)
b. Any history of cancer chemotherapy
c. Receipt of immunostimulants within 60 days prior to day 1
d. Receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within 3 months prior to day 1 or planned during the full length of the study
e. Known HIV infection or HIV-related disease
5. Has a history of Guillain–Barré syndrome
6. Has a bleeding disorder that would be a contraindication to intramuscular injection
7. Has a history of non-febrile seizures
8. Has a history of or clinically suspected developmental delay
9. Has a history of premature birth (<36 weeks of gestation) and/or low birth weight (<2.5 kg)
10. Had laboratory-confirmed influenza disease within 6 months prior to visit 1
11. Has received an antipyretic or analgesic in the past 24 hours prior to vaccination
12. Has medical history or any illness that, in the opinion of the Investigator, might interfere with the results of the study or pose additional risk to the individual because of participation in the study
13. Has a history of any anaphylactic reaction and/or serious allergic reaction to any component of the study vaccine (see section 5.1)
14. Has experienced acute disease and/or fever (i.e., body temperature measurement ≥38.0°C [≥100.4°F]) within 3 days prior to vaccination.
15. Has been participating in any clinical trial with another investigational product 4 weeks prior to first study visit or intends to participate in another clinical study at any time during the conduct of this study
16. Is the child of research staff involved with the clinical study at this institution or is otherwise related to research staff or has household members who are research staff associated with the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint - Identification of the optimal dosage of TIVc
The overall desirability index is defined as the weighted geometric mean of individual desirability indexes based on the following key immunogenicity and safety parameters:
1) Ratios of geometric mean titer (GMT) between each of TIVc dose group vs. TIVe
2) Differences in percentages of subjects achieving seroconversion (SC) by HI antibody titer in each TIVc group vs. TIVe
3) Percentages of subjects described as having severe local solicited AEs
4) Percentages of subjects described as having severe local systemic AEs
Desirability index scoring will be based on the results obtained from the
age group 6 to < 48 months |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| HI antibody responses will be evaluated at day 1 (seroconversion) and day 50 (geometric mean titer, seroconversion). Solicited adverse events will be measured for 7 days after each vaccination but the desirability index scoring will be based on the occurrence of these severe events within the first 3 days following any vaccination. |
|
| E.5.2 | Secondary end point(s) |
CBER criteria
Antibody responses to the study vaccine in subjects 6 to < 48 months of age will be evaluated by HI assay according the CBER immunogenicity criteria (CBER 2007).
CHMP criteria
Antibody responses to the all the vaccine groups in the age groups defined above will be evaluated by HI assay according to CHMP immunogenicity criteria specified in Guidance on Harmonization of Requirements for Influenza Vaccines (CPMP/BWP/214/96). In the absence of guidance for the assessment of immunogenicity in pediatric subjects, immunogenicity of each vaccine group will be evaluated according to criteria defined for adults.
High HI titer analyses
Antibody responses to the all the vaccine groups in the age groups defined above will be evaluated by percentages of subjects achieving specific HI titer threshold values as follows: ≥1:110, ≥1:151, ≥1:330, ≥1:629. These titers have been associated within potential for increased protection against confirmed influenza in a recent publication (Black 2011).
Pairwise comparisons
Ratios of geometric mean titer (GMT) between each of TIVc dose group vs. TIVe (A/B, A/C, A/D, B/C, B/D, C/D) for HI and MN assays. Differences in seroconversion rates at Day 50 between each of TIVc dose group vs. TIVe (A/B, A/C, A/D, B/C, B/D, C/D) by HI assay only.
Endpoint in terms of MN titers
- Percentage of subjects achieving post-vaccination MN titer ≥1:20 for subjects with baseline (day 1) MN titer <1:10, or a minimum 2-fold increase in titer on day 50 for subjects with baseline titer ≥1:10 and corresponding 95% CI
- Percentage of subjects achieving post-vaccination MN titer ≥1:40 for subjects with baseline (day 1) MN titer <1:10, or a minimum 4-fold increase in titer on day 50 for subjects with baseline titer ≥1:10 and corresponding 95% CI
RCDF
Reverse cumulative distribution function curves of HI and MN titers at Day 50 post-vaccinationpost-vaccinationpost-vaccinationpost-vaccination
Safety endpoints
Safety data endpoints are based on solicited and unsolicited reactions. The measures for assessing safety are as follows:
Percentages of subjects with solicited local, solicited systemic, and other solicited reactions as measured for 7 days (inclusive) following:
- each dose (day 1 and day 29) and
- any dose (day 1 or day 29) vaccination and calculated for four time intervals after vaccination: 30 minutes, 1 to 3 days (without 30 minutes value), 4 to 7 days, and 1 to 7 days (without 30 minutes value)
Percentages of subjects with any unsolicited reactions reported
- after each dose (day 1 [post-vaccination] to day 29 [pre-clinic visit] and day 29 [post-vaccination] to day 50 [pre-clinic visit])
- after any dose (day 1 [post-vaccination] to day 50 [pre-clinic visit])
- Percentages of subjects reporting SAEs, NOCDs, and AEs leading to withdrawal from the study, and concomitant medications associated with these events as collected from day 1 to day 209
Solicited local reactions will include injection-site erythema, injection-site induration, injection-site ecchymosis, and injection-site tenderness; solicited systemic AEs will include change in eating habits, shivering, sleepiness, irritability, vomiting, diarrhea, and body temperature ≥38.0°C (fever).
Other reactions that will be measured will include use of analgesic/antipyretic medication before and after vaccination and body temperature. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First administration to infants and children 6 to <48 Months of Age |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| High dose (0.75 ml), standard dose (0.5 ml) and half dose (0.25 ml) and active comparator |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Thailand |
| Philippines |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The last blood samples for the analysis of the primary and/or secondary objectives will be taken at Clinic visit 3 (Day 50). For the purpose of this protocol, end of study is defined as the completion of the testing of such biological samples, to be achieved no later than 8 months after collection of the last biological sample visit (Day 50). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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