| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prophylaxis for Influenza virus |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10022000 |
| E.1.2 | Term | Influenza |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 the vaccine (low dose or high dose aH5N1c) to be tested in Phase III based on achievement of CBER criteria 3 weeks after the second vaccine administration as measured by strain-specific hemagglutination inhibition (HI) assays.
Primary Safety Objective:
To evaluate the safety and tolerability of low dose and high dose aH5N1c vaccine in Subjects 6 months to 17 years of age.
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| E.2.2 | Secondary objectives of the trial |
Secondary Immunogenicity Objectives:
a. For each aH5N1c vaccine (low dose or high dose), to evaluate achievement of all CHMP criteria 3 weeks after the second vaccine administration as measured by strain-specific HI assay.
b. For each aH5N1c vaccine (low dose or high dose), to evaluate achievement of CBER and CHMP criteria 3 weeks after the first vaccine administration as measured by strain-specific HI assay.
c. To evaluate the immunogenicity of each aH5N1c vaccine (low dose or high dose) 12 months after the primary two-dose course with respect to CBER and CHMP criteria, as measured by strain-specific HI assays.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males and females of age 6 months to 17 years.
2. Children's parent(s) or legal guardian(s) who have given written consent after the nature of the study has been explained according to local regulatory requirements (and where applicable according to local regulations, informed assent for Subjects above the specified age).
3. Individuals in good health as determined by the outcome of medical history, physical assessment and clinical judgment of the investigator.
4. Individuals (where applicable) or children's parent(s) or legal guardian(s) willing to allow for serum samples to be stored beyond the study period, for potential additional future testing to better characterize the immune response.
5. For individuals who are at an age where informed assent is required by local policy, agreement of that individual to participate in the study after the nature of the study has been explained to they in terms they can understand.
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| E.4 | Principal exclusion criteria |
1. Children's parent(s) or legal guardian(s) or individuals who are not able to comprehend and to follow all required study procedures for the whole period of the study.
2. Individuals with history or any illness that may, in the opinion of the investigator, pose additional risk to the Subjects due to participation in the study.
3. Individuals with any serious chronic or progressive disease according to judgment of the investigator, including but not limited to:
- Medically significant advanced congestive heart failure (ie. NYHA class III and IV)Chronic obstructive pulmonary disease (COPD; i.e., GOLD Stage III and IV)
- Autoimmune disease (including any diagnosis as noted in the list of AESIs in appendix A, except for Hashimoto's thyroiditis that has been clinically stable for ≥ 5 years)
- Diabetes mellitus type I
- Poorly controlled diabetes mellitus type II
- Advanced arteriosclerotic disease
- History of underlying medical condition such as major congenital abnormalities requiring surgery, chronic treatment, or associated with developmental delay (e.g. Down’s syndrome)
- Acute or progressive hepatic disease
- Acute or progressive renal disease
- Severe neurological (e.g. Guillian-Barré syndrome) or psychiatric disorder
- Severe asthma
4. Medically significant Cancer (except for benign or localized skin cancer, cancer in remission for ≥10 years or localized prostate cancer that has been clinically stable for more than 2 years without treatment).
5. Individuals with known or suspected impairment/alteration of immune function, for example, resulting from:
- Use of systemic (oral or parenteral) corticosteroids at any dose within 60 days prior to Day 1. Use of inhaled, intranasal or topical corticosteroids is allowed
- Cancer chemotherapy within 10 years of Day 1
- Receipt of immunostimulants within 60 days prior to Day 1
- Known human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS)
- Receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within 90 days prior to Day 1 or planned during the full length of the study
6. Individuals with any progressive or severe neurologic disorder, seizure disorder or recent history of Guillian-Barré syndrome. Individuals with a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time resulting in a problem with intramuscular injections
7. Individuals with history of allergy to latex or vaccine components as outlined in the current IB.
8. Individuals receiving another investigational product within 30 days prior to first study visit or before completion of the safety follow-up period in another study and unwilling to refuse participation in another clinical study at any time during their participation in this study. Note: Concomitant participation in an observational study (not involving drugs, vaccines or medical devices) is acceptable.
9. Individuals who have received an H5N1 vaccine.
10. Individuals who have received any other type of influenza vaccination (e.g., “seasonal”) within 60 days prior to enrollment (influenza vaccination is allowed after Day 43.
11. Individuals who received any other vaccines within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) prior to enrollment in this study or who are planning to receive any vaccine within 4 weeks from the study vaccines.
12. Individuals who have experienced a temperature ≥38.0° C (≥100.4◦F) and/or any acute illness within 3 days of intended study vaccination.
13. Pregnant or breastfeeding.
14. Females of childbearing potential who refuse to use an acceptable method of birth control from Day 1 (1st vaccination) to Day 43 and, if sexually active, who have not used a reliable birth control method for at least two months prior to study entry. Body mass index (BMI) ≥ 35 kg/m2; BMI is calculated by dividing the subject’s weight in kilograms by the subject’s height in meters multiplied by the subject’s height in meters.
15. History of (or current) drug or alcohol abuse that in the investigator’s opinion would interfere with safety of the Subject or the evaluation of study objectives.
16. Surgery planned during the study period that in the investigator’s opinion would interfere with the study visits schedule.
17. Individuals who are research staff involved with the clinical study or family/household members of research staff.
18. Individuals with behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the subject's ability to participate in the trial.
19. Individuals who have been diagnosed with any disorders in growth such as failure to thrive or short stature.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Immunogenicity Endpoints
The primary measures of immunogenicity, as determined by the HI assays, against the H5N1 homologous strain, include the following:
- Percentage of Subjects achieving seroconversion (defined as: HI ≥1:40 for Subjects negative at baseline [<1:10]; or a minimum 4-fold increase in HI titer for Subjects positive at baseline [HI≥1:10]) on Day 43.
- Percentage of Subjects with a HI titer ≥1:40 on Day 43.
Safety Endpoints
The measures for assessing safety and tolerability are as follows:
1. Percentages of subjects with solicited local, solicited systemic and other AEs as measured for 7 days (inclusive) following each (1st dose, 2nd dose and booster dose, if applicable) and any (1st dose and 2nd dose if applicable) vaccination and calculated for four time intervals after vaccination : 30 minutes, 1 to 3 days (without 30 min), 4 to 7 days, and 1 to 7 days (without 30 min).
2. Percentages of subjects with any unsolicited AEs reported through 21 days after each (1st dose and 2nd dose if applicable) and any (1st dose and 2nd dose if applicable) vaccination within each vaccine group.
3. Percentages of subjects reporting SAEs, new onset of chronic diseases, medically attended AEs, AESIs, AEs leading to withdrawal from the study, and concomitant medications associated with these events as collected from Day 1 to Day 387.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Immunogenicity timepoints of evaluation - Day 43
Throughout entire treatment (Day 1-Day 42) and follow-up period (Day 43-Day 387) |
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| E.5.2 | Secondary end point(s) |
Secondary Immunogenicity Endpoints
The secondary measures of immunogenicity, as determined by the HI assays, against the H5N1 homologous strain, include the following:
- Geometric mean HI titer (GMT) on Day 1, Day 22, Day 43 and Day 387.
- Day 22/Day 1, Day 43/Day 1, Day 387/Day 1 geometric mean ratio (GMR) of HI.
- Percentage of Subjects achieving seroconversion (defined as: HI ≥1:40 for Subjects negative at baseline [HI<1:10]; or a minimum 4-fold increase in HI titer for Subjects positive at baseline [HI≥1:10]) on Day 22, Day 43 and Day 387.
- Percentage of Subjects with a HI titer ≥1:40 on Day 1, Day 22, Day 43, and Day 387.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 1, Day 22, Day 43 and Day 387 |
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| 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 | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| different formulations of the IMP |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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