| 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 | 16.1 |
| 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 | 16.1 |
| 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 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| 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 | 16.1 |
| 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 |
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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 |
| To demonstrate the non-inferiority of the Hexaxim vaccine to the licensed Infanrix hexa vaccine, both co-administered with Prevenar 13, in terms of seroprotection or vaccine response rates to all antigens contained in both investigational and control vaccines, 1 month after a 2+1-dose schedule. |
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| E.2.2 | Secondary objectives of the trial |
Immunogenicity
• To describe in each group and in all subjects, the immunogenicity parameters before the first dose for PT and FHA antigens, and before and 1 month after the third dose for all the antigens contained in the hexavalent combined vaccines
• To describe in each group the immune responses to Prevenar 13 antigens in a subset of subjects, 1 month after a 2+1-dose schedule
Safety
To describe the safety profile after each and any injection in both vaccine groups. |
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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 85 to 95 days on the day of the first study visit
2) Born at full term of pregnancy (≥ 37 weeks) and/or with a birth weight ≥ 2.5 kg
3) Healthy subjects as established by medical history and clinical examination before entering into the study
4) Informed consent form has been signed and dated by the parent(s) or other legally acceptable representative
5) Subject and parent/legally acceptable representative are able to attend all scheduled visits and to comply with all trial procedures
6) Covered by health insurance |
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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 in the 4 weeks preceding the first trial 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 vaccine in the 4 weeks preceding each trial vaccination or planned receipt of any vaccine in the 4 weeks following each trial vaccination (except rotavirus vaccination)
3) Previous vaccination against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, Haemophilus influenzae type b or pneumococcal infections with another vaccine(s)
4) Receipt of immune globulins, blood or blood-derived products since birth
5) Known or suspected congenital, hereditary or acquired immunodeficiency or other immunosuppressive or immunodeficient condition
6) Receipt of immunosuppressive therapy or other immune-modifying drugs, such as anti-cancer chemotherapy or radiation therapy, since birth; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks since birth).
7) Known personal or maternal history of hepatitis B (HBsAg) or hepatitis C seropositivity
8) History of diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, Haemophilus influenzae type b, or pneumococcal infection(s), confirmed either clinically, serologically, or microbiologically
9) 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
10) History of seizures or encephalopathy
11) Known thrombocytopenia, as reported by the parent/legally acceptable representative
12) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination
13) Subjects in an emergency setting, or hospitalized involuntarily
14) Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion
15) 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.
16) Identified as a natural or adopted child of the Investigator or employee with direct involvement in the proposed study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The following serological endpoints will be assessed 1-month after the 3rd dose (i.e., at V05 = Day 270 to Day 300) with seroprotection and vaccine response being respectively defined as:
Seroprotection for D, T, poliovirus 1, 2, and 3, Hep B, and PRP defined as follows:
• Anti-D and anti-T antibody (Ab) concentrations ≥ 0.1 international units (IU)/mL
• Anti-poliovirus 1, 2, and 3 Ab titers ≥ 8 (1/dil)
• Anti-Hep B Ab concentrations ≥ 10 mIU/mL
• Anti-PRP Ab concentrations ≥ 1 µg/mL
Vaccine response for PT and FHA defined as follows:
• Post-Dose 3 Ab concentrations ≥ 4 x Lower Level Of Quantitation (LLOQ), if pre-Dose 1 Ab concentrations < 4 x LLOQ
• Post-Dose 3 Ab concentrations ≥ pre-Dose 1 Ab concentrations, if pre-Dose 1 Ab concentrations ≥ 4 x LLOQ |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Vaccination
All subjects will receive 3 doses of either Hexaxim or Infanrix hexa vaccines, co-administered with Prevenar 13 at 3, 5 and 11 to 12 months of age (D0 [V01], D60 [V02], and D240 to D270 [V04]).
Blood sampling
All subjects will provide a blood sample 1 month post-Dose 3 (V05; D270 to D300).
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| E.5.2 | Secondary end point(s) |
Immunogenicity
Pre-Dose 1 (D0, V01) :
• Ab concentrations for PT and FHA antigens
• Ab concentrations above a cut-off:
• Anti-PT Ab titers ≥ LLOQ
• Anti-FHA Ab titers ≥ LLOQ
Pre-Dose 3 (D240 to D270, V04):
• Ab concentrations/titers for each valence (except pneumococcal serotypes)
• Ab concentrations/titers above a 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 PT Ab concentrations ≥ LLOQ and ≥ 2 x LLOQ (4 ELISA units [EU]/mL)
• Anti FHA Ab concentrations ≥ LLOQ and ≥ 2 x LLOQ (4 EU/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
Post-Dose 3 (D270 to D300, V05):
• Ab concentrations/titers for each valence
• Ab concentrations/titers above a cut-off :
• Anti-D Ab concentrations ≥ 0.01 IU/mL and ≥ 1.0 IU/mL
• Anti-T Ab concentrations ≥ 0.01 IU/mL and ≥ 1.0 IU/mL
• Anti-PT Ab concentrations ≥ 2 x LLOQ (4 EU/mL)
• Anti-FHA Ab concentrations ≥ 2 x LLOQ (4 EU/mL)
• Anti-Hep B Ab concentrations ≥ 100 mIU/mL
• Anti-PRP Ab concentrations ≥ 0.15 µg/mL
• Anti-pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F concentrations ≥ 0.35 µg/mL (in a subset of subjects only)
• Ab individual concentration ratios for anti-PT and FHA (post-Dose 3/pre-Dose 1 and post-Dose 3/pre-Dose 3).
• Ab individual concentration/titer ratios for D, T, poliovirus 1, 2, and 3, Hep B, PRP (post-Dose 3/pre-Dose 3)
• Seroconversion for anti PT and anti FHA, defined as anti PT and anti FHA ≥ 4 fold Ab concentrations increase from pre-Dose 1 (V01) to post-Dose 3 (V05)
• Booster response for anti-PT and anti-FHA defined as follows:
• Post-Dose 3 Ab concentrations ≥ 4-fold rise if pre-Dose 3 Ab concentrations < 4x LLOQ
• Post-Dose 3 Ab concentrations ≥ 2-fold rise if pre-Dose 3 Ab concentrations ≥ 4x LLOQ
Safety
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Vaccination
All subjects will receive 3 doses of either Hexaxim or Infanrix hexa vaccines, co-administered with Prevenar 13 at 3, 5 and 11 to 12 months of age (D0 [V01], D60 [V02], and D240 to D270 [V04]).
Blood sampling
All subjects will provide a blood sample prior to Dose 1 (V01; D0), prior to Dose 3 (V04; D240 to D270), and 1 month post-Dose 3 (V05; D270 to D300). |
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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 | 2 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
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