| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of infections caused by Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, poliovirus type 1, 2 and 3, prevention against invasive infections caused by Haemophilus influenzae type b and infection caused by hepatitis B virus |
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| E.1.1.1 | Medical condition in easily understood language |
| Active immunisation against diphtheriae, tetanus, pertussis, hepatitis B, poliomyelitis and invasive infections caused by Haemophilus influenzae type b |
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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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036897 |
| E.1.2 | Term | Prophylactic vaccination |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10043413 |
| E.1.2 | Term | Therapeutic procedures and supportive care NEC |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021430 |
| E.1.2 | Term | Immunisation |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10021431 |
| E.1.2 | Term | Immunisations |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 |
Immunogenicity
Groups 1 and 2
• Assess the antibody persistence of DTaP-IPV-HB-Hib or Infanrix hexa following a 3-dose primary series at 2, 3, and 4 months of age (MoA) before the administration of a booster dose of either vaccine
• Describe the immunogenicity and booster effect of the DTaP-IPV-HB-Hib or Infanrix hexa vaccine given as a booster dose at 11 to 15 MoA concomitantly with PCV13 (after a primary series with the same vaccine)
• To describe the immunogenicity of a booster dose of PCV13 given from 11 to 15 MoA
Group 3
• Assess the antibody persistence of all valences contained in the vaccines administered in a mixed schedule following a 3-dose primary series at 2, 4, and 6 MoA before the administration of a booster dose of Pentavac
• Describe the immunogenicity and booster effect of Pentavac given at 18 MoA after the administration of a mixed schedule primary series combining a hexavalent and a pentavalent vaccine
To describe the safety profile for groups 1, 2 and 3 |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
An individual must fulfill all of the following criteria in order to be eligible for trial enrollment:
1) Infants/toddlers previously included in Study A3L39 who completed the 3-dose primary series vaccination according to protocol
2) Groups 1 and 2 (Germany and the Czech Republic) aged 11 to 15 months on the day of the first study visit; Group 3 (Spain) aged 18 months on the day of the first study visit
3) Informed consent form has been signed and dated by the parent(s) or other legally acceptable representative (and by an independent witness if required by local regulations)
4) Subject and parent/legally acceptable representative are able to attend all scheduled visits and to comply with all trial procedures
5) Covered by health insurance, if applicable |
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| E.4 | Principal exclusion criteria |
An individual fulfilling any of the following criteria is to be excluded from trial
enrollment:
1) Participation at the time of study enrollment (or 4 weeks preceding the booster vaccination) or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure
2) Receipt of any out-of-study vaccines within the 2-week period prior to Visit 01 and within the 4-week period following the receipt of study vaccines or until all Visit 02 study procedures have been completed
3) Receipt of immune globulins, blood or blood-derived products in the last 3 months
4) Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 3 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months)
5) History of diphtheria, tetanus, pertussis, poliomyelitis, Hep B or Haemophilus influenzae type b and pneumococcal infections, confirmed either clinically, serologically, or microbiologically
6) Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine(s) used in the trial or to a vaccine containing any of the same substances
7) Known thrombocytopenia, as reported by the parent/legally acceptable representative
8) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination
9) Subjects in an emergency setting, or hospitalized involuntarily
10) Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion
11) Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature ≥ 38.0°C). A prospective subject should not be included in the study until the condition has resolved or the febrile event has subsided.
12) Identified as a natural or adopted child of the investigator or employee with direct involvement in the proposed study
13) If any of the following events are known to have occurred in temporal relation to the receipt of a pertussis-containing vaccine, the decision to give further doses of pertussis-containing vaccines should be carefully considered:
• Encephalopathy
• Temperature of ≥ 40°C within 48 hours not due to another identifiable cause
• Collapse of shock-like state (hypotonic-hyporesponsive episode [HHE]) within 48 hours of vaccination
• Persistent, inconsolable crying lasting ≥ 3 hours, occurring within 48 hours if vaccination
• Convulsions with or without fever, occurring within 3 days of vaccination |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Immunogenicity
Ab Persistence
The following endpoints will be used to assess the Ab persistence (for all valences except PCV13 antigens) before the booster doses at Day 0 (D0) (Visit 1 [V01]) of the study vaccines:
• Ab concentrations/titers for each valence
• Ab concentrations/titers above a pre-determined cut-off:
• Anti-D Ab concentrations ≥ 0.01 IU/mL and ≥ 0.1 IU/mL
• Anti-T Ab concentrations ≥ 0.01 IU/mL and ≥ 0.1 IU/mL
• Anti-poliovirus 1, 2 and 3 titers ≥ 8 (1/dil)
• Anti-Hep B Ab concentrations ≥ 10 mIU/mL and ≥ 100 mIU/mL
• Anti-PRP Ab concentrations ≥ 0.15 μg/mL and ≥ 1.0 μg/mL
• Anti-PT and anti-FHA Ab concentrations ≥ Lower Limit Of Quantitation (LLOQ)
Booster Effect:
The following endpoints will be used to assess the booster response for all antigens at D30 (V02):
• Ab concentrations/titers for each valence (including PCV13 for Groups 1 and 2 only)
• Ab concentrations/titers levels higher than a pre-determined cut-off:
• Anti-D Ab concentrations ≥ 0.01 IU/mL, ≥ 0.1 IU/mL, and ≥ 1.0 IU/mL
• Anti-T Ab concentrations ≥ 0.01 IU/mL, ≥ 0.1 IU/mL, and ≥ 1.0 IU/mL
• Anti-poliovirus 1, 2 and 3 titers ≥ 8 (1/dil)
• Anti-Hep B Ab concentrations ≥ 10 mIU/mL and ≥ 100 mIU/mL (Groups 1 and 2 only)
• Anti-PRP Ab concentrations ≥ 0.15 μg/mL and ≥ 1.0 μg/mL
• Anti-pneumococcal serotype 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F concentrations ≥ 0.35 μg/mL (Groups 1 and 2 only)
• Individual concentration/titer ratio for each valence (D30 [V02]/D0 [V01]), except for PCV13 antigens
• Seroconversion for pertussis Ab (anti-PT and anti-FHA) defined as:
• Anti-PT and anti-FHA ≥ 4-fold Ab titers increase from D0 (V01) to D30 (V02)
• Booster response to pertussis (PT and FHA) defined as:
• Post-booster Ab concentrations ≥ 4-fold rise if pre-booster Ab concentrations < 4x LLOQ
• Post-booster Ab concentrations ≥ 2-fold rise if pre-booster Ab concentrations ≥ 4x LLOQ
Safety
• Occurrence of any unsolicited systemic adverse events (AEs) reported in the 30 minutes after booster vaccination
• Occurrence of solicited, i.e. pre-listed in the subject’s diary and electronic case report form (eCRF), injection site and systemic reactions occurring up to 7 days after booster vaccination
• Occurrence of unsolicited (spontaneously reported) AEs up to 30 days after booster vaccination
• Occurrence of adverse events of special interest (AESIs) and SAEs, throughout the trial period
• Other endpoints recorded or derived will be described at the time of statistical analysis plan. Depending on the item, these could include: nature (MedDRA preferred term), time of onset, duration, number of days of occurrence, grade of severity, relationship to vaccine, action taken, whether the AE led to early termination from the study, seriousness, or outcome |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Blood sampling
All subjects will provide a pre-vaccination blood sample at D0 (V01) and a post-vaccination sample at D30 (V02).
Collection of safety data
Subjects’ parents/legal representatives will record information about solicited reactions in a diary card (DC) from Days 0-7 post-vaccination, and will record information about unsolicited AEs from Days 0-30. Solicited reactions will be collected for DTaP-IPV-HB-Hib, Infanrix hexa, Pentavac and PCV13 vaccines.
The SAEs will be recorded throughout the trial period.
Staff will contact subjects' parents/legal representative by telephone at 2-3 days and 8-10 days after vaccination to discuss any safety information.
Staff will review the Days 0-30 safety data with subjects' parents/legal
representatives at V02. |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| blind-observer (group 1 and group 2) and open-label (group 3) |
|
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 25 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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