| 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 types 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 diphtheria,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 | 14.1 |
| 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 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 | 14.1 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 |
|
| 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
• To describe the antibody (Ab) persistence for all valences (except Prevenar [PCV7] and Rotarix), following a three-dose primary series vaccination, of either DTaP-IPV-Hep B-PRP-T or Infanrix hexa at 2, 4 and 6 months of age
• To describe the immunogenicity of a booster dose of DTaP-IPV-Hep B-PRP-T or Infanrix hexa given at 12 to 24 months concomitantly with a booster dose of Prevenar (PCV7)
• To describe the immunogenicity of a booster dose of Prevenar (PCV7) given at 12 to 24 months in the same subset of subjects that participated in the Prevenar (PCV7) immunogenicity analysis in A3L24 Study (maximum of 544 subjects)
Safety
To describe the safety profile after a booster dose of DTaP-IPV-Hep B-PRP-T or Infanrix hexa given at 12 to 24 months of age concomitantly with a booster dose of Prevenar (PCV7) |
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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) Aged 12 to 24 months on the day of inclusion
2) Informed consent form has been signed and dated by the parent(s) or other legally acceptable representative (and by independent witness(es) if required by local regulations)
3) Subject and parent/guardian are able to attend all scheduled visits and to comply with all trial procedures
4) Toddlers previously included in Study A3L24 who completed the three-dose primary series vaccination of either DTaP-IPV-Hep B-PRP-T or Infanrix hexa at 2, 4 and 6 months of age according to protocol (both concomitantly administered with Prevenar [PCV7] and Rotarix) |
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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 in another clinical trial investigating a vaccine, drug, medical device, or medical procedure in the 4 weeks preceding the booster vaccinations
2) Planned participation in another clinical trial during the present trial period
3) Receipt of any vaccine in the 4 weeks preceding the booster vaccinations
4) Planned receipt of any vaccine in the 4 weeks following the trial vaccinations
5) Previous booster vaccination against pertussis, tetanus, diphtheria, Haemophilus influenzae type b, hepatitis B and pneumococcal infection(s) with either the trial vaccine or another vaccine
6) Receipt of blood or blood-derived products in the past 3 months, which might interfere with assessment of the immune response
7) 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)
8) Laboratory-confirmed or clinical suspicion of personal or maternal seropositivity for Human Immunodeficiency Virus (HIV), hepatitis B, or hepatitis C, as reported by the parent/guardian
9) History of pertussis, tetanus, diphtheria, poliomyelitis, Haemophilus influenzae type b, hepatitis B and pneumococcal infection(s), confirmed either clinically, serologically, or microbiologically
10) At high risk for opportunistic infection during the trial
11) 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
12) History of contraindication to receipt of pertussis-containing vaccine:
• Encephalopathy
• Temperature > 40.0°C within 48 hours following a vaccine injection, not due to another identifiable cause during the primary series
• Inconsolable crying that occurred for > 3 hours within 48 hours following vaccine injection during the primary series
• Hypotonic hyporesponsive episode within 48 hours following vaccine injection during the primary series
• Seizures with or without fever within 3 days following vaccine injection
13) Laboratory-confirmed or clinical suspicion of thrombocytopenia contraindicating IM vaccination
14) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating IM vaccination
15) Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion
16) Receipt of oral or injected antibiotic therapy within 72 hours prior to the first blood draw
17) Febrile illness (temperature ≥ 38.0°C) or moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination. A prospective subject should not be included in the study until the condition has resolved or the febrile event has subsided. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Immunogenicity
The following endpoints will be used to assess the Ab persistence (for all valences) before the booster doses at day 0 (D0) (Visit 1 [V01]) of DTaP-IPV-Hep B-PRP-T vaccine and Infanrix hexa vaccine:
• Ab titers for each valence
• Ab titers above a pre-determined cut-off:
• Anti-D Ab titers ≥ 0.01 IU/mL and ≥ 0.1 IU/mL
• Anti-T Ab titers ≥ 0.01 IU/mL and ≥ 0.1 IU/mL
• Anti-poliovirus 1, 2, and 3 titers ≥ 8 (1/dil)
• Anti-Hep B Ab titers ≥ 10 mIU/mL and ≥ 100 mIU/mL
• Anti-PRP Ab titers ≥ 0.15 μg/mL and ≥ 1.0 μg/mL
• Anti-PT and anti-FHA ≥ LLOQ
The following endpoints will be used to assess the booster responses at D30 (V02):
• Ab titers for each valence (including Prevenar [PCV7] vaccine)
• Ab titers above a pre determined cut-off:
• Anti-D Ab titers ≥ 0.01 IU/mL, ≥ 0.1 IU/mL, and ≥ 1.0 IU/mL
• Anti-T Ab titers ≥ 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 titers ≥ 10 mIU/mL and ≥ 100 mIU/mL
• Anti-PRP Ab titers ≥ 0.15 μg/mL and ≥ 1.0 μg/mL
• Anti-pneumococcal serotype 4, 6B, 9V, 14, 18C, 19F, and 23F titers
≥ 0.35 μg/mL (in a subset of subjects only, maximum of 544 subjects)
• Individual titer ratio for each valence (V02/V01), except for Prevenar (PCV7)
• Seroconversion for pertussis Ab (anti-acellular pertussis toxoid [anti-PT] and anti-filamentous hemagglutinin [anti-FHA]) defined as:
• Anti-PT and anti-FHA ≥ 4-fold Ab titers increase from V01 to V02
• Booster response to pertussis antigens (PT and FHA) defined as:
• Subjects whose pre-vaccination Ab concentrations are less than the Lower Limit Of Quantitation (< LLOQ), will demonstrate the booster response if they have post-vaccination levels ≥ 4 x LLOQ
• Subjects whose pre-vaccination Ab concentrations are ≥ LLOQ but < 4 x LLOQ, will demonstrate the booster response if they have a 4-fold response (i.e. post-/pre-vaccination ≥ 4)
• Subjects whose pre-vaccination Ab concentrations are ≥ 4 x LLOQ, will demonstrate the booster response if they have a 2-fold response (i.e., post-/pre-vaccination ≥ 2)
Safety
• Occurrence, nature (Medical Dictionary for Regulatory Activities [MedDRA] preferred term), duration, intensity, and relationship to vaccination for any unsolicited systemic adverse events (AEs) reported in the 30 minutes after each vaccination
• Occurrence, time to onset, number of days of occurrence, and severity for solicited (prelisted in the subject diary and case report form [eCRF]) injection site and systemic reactions occurring up to 7 days after each vaccination
• Occurrence, nature (MedDRA preferred term), time to onset, duration, severity, and relationship to vaccination (for systemic adverse events only) of unsolicited (spontaneously reported) adverse events up to 30 days after each vaccination
• Occurrence of SAEs throughout the trial (including the 6-month follow up period) |
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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 of approximately 5 mL at D0 (V01) and a post-vaccination sample of approximately 5 mL at D30 (V02).
Collection of safety data
Subjects will record information in terms of immediate reactions within 30 minutes after booster vaccination, solicited reactions within 7 days and unsolicited adverse events within 30 days after booster vaccination, and SAEs will be collected throughout the trial period (within 180 days after the booster vaccination). Related SAE which occur between the primary series and the booster phase should be reported. |
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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 |
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| 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 |
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 | 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.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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