| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy volunteers (Active immunization against influenza A virus H5N1 subtype). |
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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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Doses
• To assess the performance of alternative dosing regimens for primary immunization with Q-Pan H5N1 vaccine using an immunogenicity-fever index that considers:
- immunogenicity by Hemagglutination Inhibition (HI) assay 21 days after the second priming dose.
- fever scores after the first and second priming doses.
- immunogenicity by Microneutralization (MN) assay 21 days after the second priming dose.
- fever scores after the first and second priming doses.
Booster Dose
• To assess the performance of dosing regimens for booster immunization with Q-Pan H5N1 vaccine considering:
- immune response (IR) by HI assay 7 days after a 12-month booster dose of Hemagglutinin (HA) Q-Pan H5N1 plain antigen.
- immune response by MN assay 7 days after a 12-month booster dose of HA Q-Pan H5N1 plain antigen. |
|
| E.2.2 | Secondary objectives of the trial |
To assess:
• performance of alternative dosing regimens for primary immunization with H5N1 vaccine considering persistence of IR by HI & MN assay at D 385 in terms of persistence index.
• performance of the H5N1 vaccine regimens in terms of vaccine-homologous HI & MN antibody titers on Days 0 ,42, 385 & 392.
• immunogenicity of the H5N1 vaccine regimens in terms of vaccine-heterologous HI antibody titers on Days 0, 42, 385 & 392.
• vaccine induced cell-mediated IR on Days 0, 42, 385 & 392.
To describe:
• HI IR to the vaccine-homologous virus 21 days after dose 2 for each dosing regimen
• reactogenicity and safety of the different priming regimens in terms of solicited (7-days after each vaccination) & unsolicited (21 days after each vaccination) adverse events (AEs).
• safety of the unadjuvanted booster dose in terms of solicited (7 days post boost) & unsolicited (30 days post boost) AEs.
• safety in terms of MAEs, pIMDs, SAEs, AESIs, during the entire study period. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Subject's parent(s)/ Legally Acceptable Representative(s) [LAR(s)] who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
• Male or female children 6 months to less than 36 months old at the time of the first vaccination. Children who are not 36 months old as of Day 0, the day of first vaccine dose under this protocol, can be enrolled.
• Written informed consent obtained from the parent(s)/legally acceptable representative(s) [LAR(s)] of the subject prior to performance of any study specific procedure.
• Healthy subjects as established by medical history and standard physical examination before entering into the study.
• Born full-term to be confirmed by interview with parent/LAR or available medical records. |
|
| E.4 | Principal exclusion criteria |
• Child in care
• Medical history of physician-confirmed infection with an H5N1 virus.
• Previous vaccination at any time with an H5N1 vaccine.
• Concurrently participating in another clinical study, or use of an investigational or a non-registered vaccine, pharmaceutical product, or device within 30 days preceding the first dose of study vaccine, or planned use during the study period.
• Presence in the parent(s) / LAR(s) of evidence of substance abuse or of neurological or psychiatric diagnoses which, even if stable, are deemed by the investigator to render the parent(s)/LAR(s) unable/unlikely to provide accurate safety reports.
• Acute disease and/or fever at the time of enrolment.
• Administration of immunoglobulins, any blood products, or long-acting immune-modifying drugs during the period starting 3 months before the first dose of study vaccine, or planned administration during the study period.
• History of any neurological disorders or seizures, or Guillain-Barré Syndrome.
• Diagnosed with excessive daytime sleepiness or narcolepsy; or history of narcolepsy in a subject’s parent or sibling.
• Administration of an inactive vaccine within 14 days or of a live attenuated vaccine within 30 days before the first vaccination.
• Planned administration of any vaccine not foreseen by the study protocol between Day 0 and Day 42 or planned administration of an inactive vaccine within 14 days or of a live attenuated vaccine within 30 days be-fore through 30 days after the booster vaccination. Note: routine vaccinations may be provided on Day 42 after all study assessments have been performed.
• History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine; a history of anaphylactic-type reaction to consumption of eggs; or a history of severe adverse reaction to a previous influenza vaccine.
• Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
• Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine. For corticosteroids, this will mean a dose of prednisone or equivalent of > 2 mg/kg/day of body weight or ≥ 20 mg/day (for persons who weigh ≥ 10 kg). Inhaled and topical steroids are allowed.
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
• Family history of congenital or hereditary immunodeficiency.
• Major congenital defects
• Any condition which, in the opinion of the investigator, prevents the subject from participating in the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Calculation of immunogenicity-fever indices based on evaluation of humoral immune response in terms of vaccine-homologous hemagglutination Inhibition (HI) and microneutralization (MN) antibodies for each group:
- Geometric Mean Titer (GMTs) – HI and MN and fever scores.
- For each subject, a fever index will be calculated using temperature measurements 3-days post Dose 1 (D0-D2) and 3-days post Dose 2 (D21-D23).
2. Evaluation of Mean Geometric Increase (MGI),in terms of HI and MN antibodies against vaccine-homologous antigen
- MGI is defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the pre-vaccination (Day 385) reciprocal HI titer for the vaccine virus. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. At Day 42
2. At Day 392 |
|
| E.5.2 | Secondary end point(s) |
1. Evaluation of humoral immune response in terms of HI antibodies against vaccine-homologous/heterologous antigens post primary immunization
- Seroconversion rates (SCR)*
- Seroprotection rates (SPR)**
- MGI
*SCR is defined as the proportion of subjects who have either a pre-vaccination reciprocal HI titer < 10 and a post-vaccination reciprocal titer ≥ 40, or a pre-vaccination reciprocal HI titer ≥ 10 and at least a 4-fold increase in post vaccination reciprocal titer against the vaccine virus.
**SPR is defined as the proportion of subjects with H5N1 reciprocal HI titers ≥ 40 against the tested vaccine virus.
2. Evaluation of humoral immune response in terms of vaccine-homologous MN antibody post the primary immunization
- MGI
3. Evaluation of humoral immune response in terms of HI antibodies against vaccine-homologous/heterologous antigens
- Seropositivity rates
- Geometric Mean Titer (GMT)
4. Evaluation of humoral immune response in terms of HI antibodies against vaccine-homologous/heterologous antigens
- Seroconversion rates (SCR)
- MGI
5. Evaluation of humoral immune response in terms of HI antibodies against vaccine-homologous/heterologous antigens
- Seroprotection rates (SPR)
6. Evaluation of humoral immune response in terms of vaccine-homologous MN antibody
- Seropositivity rates
- GMT
7. Evaluation of humoral immune response in terms of vaccine-homologous MN antibody
- Vaccine response rate (VRR)
8. Evaluation of Cell mediated Immunity (CMI) in terms of frequencies of antigen-specific cells(CD3+/CD4+/CD8+)
9. Occurrence of solicited local and general AEs
- Percentage, intensity and duration of solicited local AEs
- Percentage, intensity, duration and relationship to vaccination of solicited general AEs
10. Occurrence of unsolicited adverse events (AEs)
- For the primary series: Percentage, intensity and relationship to vaccination of unsolicited AEs
11. Occurrence of unsolicited adverse events (AEs)
- For the booster dose [unadjuvanted]: Percentage, intensity and relationship to vaccination of unsolicited AEs
12. Occurrence and relationship to vaccination of adverse events with medically attended events (MAEs)
- Percentage and relationship to vaccination of MAEs
13. Occurrence and relationship to vaccination of potential immune-mediated diseases (pIMDs), serious adverse events (SAEs) and adverse events of special interest (AESIs)
- Percentage and relationship to vaccination of pIMDs, SAEs, AESIs |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At Day 42
2. At Day 385
3. At Days 0, 42, 385 and Day 392
4. At Day 385 (relative to Day 0) and Day 392 (relative to Days 0 and 385)
5. At Days 0, 385 and Day 392
6. At Days 0, 42,385 and Day 392
7. At Days 42, 385 (relative to Day 0) and Day 392 (relative to Days 0 and 385)
8. At Days 0, 42, 385 and 392
9. During a 7-day follow-up period (Day 0-Day 6) after any vaccination
10. During a 21-day follow-up period (Day 0-Day 20) after each vaccine dose.
11. Within 30 days after vaccination
12. During the entire study period (Day 0 up to Day 415 approximately)
13. During the entire study period (Day 0 up to Day 415 approximately) |
|
| 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 | No |
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Different dosage of the same product that is the currently available H5N1 pediatric dosage |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
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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.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 11 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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