Varicella, Measles, Mumps, Rubella, Diphtheria, Tetanus, Pertussis, Poliomyelitis, Hepatitis B, Haemophilus Infections
Conditions
Keywords
Mumps and Rubella, Haemophilus influenzae type b (Infanrix® hexa)
Brief summary
Primary Objective: * To demonstrate that ProQuad® can be administered concomitantly with a booster dose of Infanrix® hexa to healthy children 12 to 23 months of age without impairing either the antibody response rates to measles, mumps, rubella, varicella, hepatitis B and Haemophilus influenzae type b; or to the 3 pertussis antibody titres measured at 42 days following vaccination. Secondary Objectives: * To describe the antibody titres and the antibody response rates to measles, mumps, rubella, varicella, diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type b as measured at 42 days following vaccination by an Infanrix® hexa primary series schedule and all data are pooled. * To evaluate the safety profile of ProQuad® when administered concomitantly with a booster dose of Infanrix® hexa by an Infanrix® hexa primary series schedule and all data are pooled.
Interventions
BIOLOGICALProQuad®
Participants received a 0.5 mL subcutaneous injection of ProQuad® containing the following live attenuated virus strains: measles virus Enders' Edmonston strain (≥3.00 log10 50% cell culture infectious dose \[CCID\]50), mumps virus Jeryl Lynn™ (Level B) strain (≥4.30 log10 CCID50), rubella virus Wistar RA 27/3 strain (≥3.00 log10 CCID50), and varicella virus Oka/Merck strain (≥3.99 log10 plaque-forming units \[PFU\]).
BIOLOGICALInfanrix® hexa
Participants received a 0.5 mL intramuscular injection of Infanrix® hexa containing the following: diphtheria toxoid (≥30 IU), tetanus toxoid (≥40 IU), 3-component acellular pertussis (pertussis taxoid, filamentous haemagglutinin, and pertactin) (25 ug), Hepatitis B surface antigen recombinant (S protein) (10 ug), inactivated poliovirus types 1-3 (type 1: 40 D-antigen units; type 2: 8 D-antigen units; type 3: 32 D-antigen units), and Haemophilus influenzae type B (Hib) polysaccharide conjugate to tetanus toxoid (20-40 ug).
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to 23 Months
Healthy volunteers
Yes
Inclusion criteria
* Healthy participants of either gender * Aged 12 to 23 months * No clinical history of measles, mumps, rubella, varicella and zoster * For Italy: Primary vaccination with the combined diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type b vaccine Infanrix® hexa as a 2-dose schedule, with receipt of the second dose ≥ 6 months prior to inclusion * For Germany: Primary vaccination with the combined diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type b vaccine Infanrix® hexa as a 3-dose schedule, with receipt of the third dose ≥ 6 months prior to inclusion * Consent form signed by parent(s) according to local regulations or by the legal representative properly informed about the study * Parent(s)/legal representative able to understand the protocol requirements and to fill in the Diary Card.
Exclusion criteria
* Prior receipt of measles, mumps, rubella and/or varicella vaccine either alone or in any combination * Any recent (\<= 30 days) exposure to measles, mumps, rubella, varicella and/or zoster * Receipt of any other diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and/or Haemophilus influenzae type b containing vaccine (either alone or in any combination) than Infanrix® hexa * Any recent (\<= 3 days) history of febrile illness * Any severe chronic disease * Active untreated tuberculosis * Known personal history of encephalopathy, seizure disorder or progressive, evolving or unstable neurological condition * Any known blood dyscrasia, leukemia, lymphomas of any type, or other malignant neoplasms affecting the haematopoietic or lymphatic systems * Any severe thrombocytopenia or any other coagulation disorder that would contraindicate intramuscular injection * Prior known sensitivity/allergy to any component of the vaccines including neomycin, sorbitol or gelatin * Any immune impairment or humoral/cellular deficiency, neoplastic disease or depressed immunity * Any recent (\<= 2 days) tuberculin test or scheduled tuberculin test through Visit 2 * Any previous (\<= 150 days) receipt of immune serum globulin or any blood-derived products or scheduled to be administered through Visit 2 * Any recent (\<= 30 days) receipt of an inactivated or a live non-study vaccine or scheduled non-study vaccination through Visit 2 * Any medical condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives * Any recent (≤30 days) participation or scheduled participation in any other clinical trial through Visit 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Meeting Antibody Response Rate Criteria to Measles, Mumps, Rubella, and Varicella | Day 42 | The percentage of participants with seronegative baseline values who met antibody response criteria in Arm 1: ProQuad® + Infanrix® hexa and Arm 2: ProQuad® was determined. Post-vaccination antibody response and baseline seronegativity criteria were as follows: measles antibody titre ≥255 mIU/mL in participants with baseline titre \<255 mIU/mL; mumps antibody titre ≥10 ELISA Ab units/mL in participants with baseline titre \<10 ELISA Ab units mL; rubella antibody titre ≥10 IU/mL in participants with baseline titre \<10 IU/mL; varicella antibody titre ≥5 gpELISA units/mL in participants with baseline titre \<1.25 gpELISA units/mL. Measles, mumps and rubella antibody levels were determined using enzyme-linked immunosorbent assay (ELISA) and varicella antibody levels were determined with glycoprotein-based ELISA (gpELISA). |
| Percentage of Participants Meeting Post-vaccination Antibody Response Rates to Hepatitis B and Haemophilus Influenzae Type B | Day 42 | The percentage of participants with seronegative baseline values who met antibody response criteria in Arm 1: ProQuad® + Infanrix® hexa and Arm 3: Infanrix® hexa was determined. Post-vaccination antibody response and baseline seronegativity criteria were as follows: Hepatitis B antibody titre ≥10 IU/mL and Haemophilus Influenzae Type b antibody titre ≥1 ug/mL. Hepatitis B antibody levels were determined using anti-HBs ORTHO ECi Immunodiagnostic Assay. Haemophilus Influenzae Type b antibody (anti-polyribosylribitol phosphate \[PRP\]) levels were determined with radioimmunoassay (RIA) or with enzyme immunoassay (EIA). |
| Post-vaccination Geometric Mean Titres (GMT) to Pertussis | Day 42 | The GMT to pertussis were compared in Arm1: ProQuad® + Infanrix® hexa and Arm 3: Infanrix® hexa. Anti-pertussis toxin (anti-PT), anti-filamentous hemagglutinin (anti-FHA), and anti-pertactin (anti-PRN) were determined using ELISA on solid phase based on sandwich principle. |
Countries
Germany, Italy
Participant flow
Recruitment details
A total of 963 participants were screened at study centers in Italy and Germany.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: ProQuad® + Infanrix® Hexa Pediatric (12 to 23 months of age) participants received ProQuad® and Infanrix® hexa (booster dose) concomitantly on Visit 1 (Day 0). Blood samples were taken on Visit 1 and Visit 2 (Day 42). | 479 |
| Arm 2: ProQuad® Pediatric (12 to 23 months of age) participants received ProQuad® on Visit 1 (Day 0). Blood samples were taken on Visit 1 and Visit 2 (Day 42). | 235 |
| Arm 3: Infanrix® Hexa Pediatric (12 to 23 months of age) participants received Infanrix® hexa (booster dose) on Visit 1 (Day 0). Blood samples were taken on Visit 1 and Visit 2 (Day 42). | 241 |
| Total | 955 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Arm 1: ProQuad® + Infanrix® Hexa | Arm 2: ProQuad® | Arm 3: Infanrix® Hexa | Total |
|---|---|---|---|---|
| Age, Continuous | 13.6 Months STANDARD_DEVIATION 1.9 | 13.4 Months STANDARD_DEVIATION 1.5 | 13.5 Months STANDARD_DEVIATION 1.7 | 13.5 Months STANDARD_DEVIATION 1.7 |
| Sex: Female, Male Female | 222 Participants | 112 Participants | 114 Participants | 448 Participants |
| Sex: Female, Male Male | 257 Participants | 123 Participants | 127 Participants | 507 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 409 / 474 | 134 / 234 | 184 / 239 |
| serious Total, serious adverse events | 7 / 474 | 6 / 234 | 4 / 239 |
Outcome results
Primary
Percentage of Participants Meeting Antibody Response Rate Criteria to Measles, Mumps, Rubella, and Varicella
The percentage of participants with seronegative baseline values who met antibody response criteria in Arm 1: ProQuad® + Infanrix® hexa and Arm 2: ProQuad® was determined. Post-vaccination antibody response and baseline seronegativity criteria were as follows: measles antibody titre ≥255 mIU/mL in participants with baseline titre \<255 mIU/mL; mumps antibody titre ≥10 ELISA Ab units/mL in participants with baseline titre \<10 ELISA Ab units mL; rubella antibody titre ≥10 IU/mL in participants with baseline titre \<10 IU/mL; varicella antibody titre ≥5 gpELISA units/mL in participants with baseline titre \<1.25 gpELISA units/mL. Measles, mumps and rubella antibody levels were determined using enzyme-linked immunosorbent assay (ELISA) and varicella antibody levels were determined with glycoprotein-based ELISA (gpELISA).
Time frame: Day 42
Population: Participants in Arm 1 and Arm 2 who were initially seronegative to measles, mumps, rubella, or varicella; had post-vaccination serology results; and who did not have protocol violations that may have interfered with immunogenicity results were included. As analysis of Arm 3 was not planned it was not included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: ProQuad® + Infanrix® Hexa | Percentage of Participants Meeting Antibody Response Rate Criteria to Measles, Mumps, Rubella, and Varicella | Measles | 97.4 Percentage of Participants |
| Arm 1: ProQuad® + Infanrix® Hexa | Percentage of Participants Meeting Antibody Response Rate Criteria to Measles, Mumps, Rubella, and Varicella | Mumps | 96.7 Percentage of Participants |
| Arm 1: ProQuad® + Infanrix® Hexa | Percentage of Participants Meeting Antibody Response Rate Criteria to Measles, Mumps, Rubella, and Varicella | Rubella | 97.9 Percentage of Participants |
| Arm 1: ProQuad® + Infanrix® Hexa | Percentage of Participants Meeting Antibody Response Rate Criteria to Measles, Mumps, Rubella, and Varicella | Varicella | 97.7 Percentage of Participants |
| Arm 2: ProQuad® | Percentage of Participants Meeting Antibody Response Rate Criteria to Measles, Mumps, Rubella, and Varicella | Varicella | 95.1 Percentage of Participants |
| Arm 2: ProQuad® | Percentage of Participants Meeting Antibody Response Rate Criteria to Measles, Mumps, Rubella, and Varicella | Measles | 96.3 Percentage of Participants |
| Arm 2: ProQuad® | Percentage of Participants Meeting Antibody Response Rate Criteria to Measles, Mumps, Rubella, and Varicella | Rubella | 99.1 Percentage of Participants |
| Arm 2: ProQuad® | Percentage of Participants Meeting Antibody Response Rate Criteria to Measles, Mumps, Rubella, and Varicella | Mumps | 98.6 Percentage of Participants |
95% CI: [-1.62, 4.82]
95% CI: [-4.21, 1.1]
95% CI: [-3.19, 1.35]
95% CI: [-0.41, 6.58]
Primary
Percentage of Participants Meeting Post-vaccination Antibody Response Rates to Hepatitis B and Haemophilus Influenzae Type B
The percentage of participants with seronegative baseline values who met antibody response criteria in Arm 1: ProQuad® + Infanrix® hexa and Arm 3: Infanrix® hexa was determined. Post-vaccination antibody response and baseline seronegativity criteria were as follows: Hepatitis B antibody titre ≥10 IU/mL and Haemophilus Influenzae Type b antibody titre ≥1 ug/mL. Hepatitis B antibody levels were determined using anti-HBs ORTHO ECi Immunodiagnostic Assay. Haemophilus Influenzae Type b antibody (anti-polyribosylribitol phosphate \[PRP\]) levels were determined with radioimmunoassay (RIA) or with enzyme immunoassay (EIA).
Time frame: Day 42
Population: Participants in Arm 1 and Arm 3 who had post-vaccination serology results and who did not have protocol violations that may have interfered with immunogenicity results were included. As analysis of Arm 2 was not planned it was not included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: ProQuad® + Infanrix® Hexa | Percentage of Participants Meeting Post-vaccination Antibody Response Rates to Hepatitis B and Haemophilus Influenzae Type B | Hepatitis B | 99.5 Percentage of participants |
| Arm 1: ProQuad® + Infanrix® Hexa | Percentage of Participants Meeting Post-vaccination Antibody Response Rates to Hepatitis B and Haemophilus Influenzae Type B | Haemophilus Influenzae Type B | 98.2 Percentage of participants |
| Arm 2: ProQuad® | Percentage of Participants Meeting Post-vaccination Antibody Response Rates to Hepatitis B and Haemophilus Influenzae Type B | Hepatitis B | 98.1 Percentage of participants |
| Arm 2: ProQuad® | Percentage of Participants Meeting Post-vaccination Antibody Response Rates to Hepatitis B and Haemophilus Influenzae Type B | Haemophilus Influenzae Type B | 95.3 Percentage of participants |
95% CI: [-0.29, 4.24]
95% CI: [-0.17, 6.89]
Primary
Post-vaccination Geometric Mean Titres (GMT) to Pertussis
The GMT to pertussis were compared in Arm1: ProQuad® + Infanrix® hexa and Arm 3: Infanrix® hexa. Anti-pertussis toxin (anti-PT), anti-filamentous hemagglutinin (anti-FHA), and anti-pertactin (anti-PRN) were determined using ELISA on solid phase based on sandwich principle.
Time frame: Day 42
Population: Participants in Arm 1 and Arm 3 who had post-vaccination serology results and who did not have protocol violations that may have interfered with immunogenicity results were included. As analysis of Arm 2 was not planned it was not included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: ProQuad® + Infanrix® Hexa | Post-vaccination Geometric Mean Titres (GMT) to Pertussis | Anti-PT GMT | 132.6 GMT (IU/mL) |
| Arm 1: ProQuad® + Infanrix® Hexa | Post-vaccination Geometric Mean Titres (GMT) to Pertussis | Anti-FHA GMT | 210.9 GMT (IU/mL) |
| Arm 1: ProQuad® + Infanrix® Hexa | Post-vaccination Geometric Mean Titres (GMT) to Pertussis | Anti-PRN GMT | 310.0 GMT (IU/mL) |
| Arm 2: ProQuad® | Post-vaccination Geometric Mean Titres (GMT) to Pertussis | Anti-PT GMT | 139.1 GMT (IU/mL) |
| Arm 2: ProQuad® | Post-vaccination Geometric Mean Titres (GMT) to Pertussis | Anti-FHA GMT | 189.9 GMT (IU/mL) |
| Arm 2: ProQuad® | Post-vaccination Geometric Mean Titres (GMT) to Pertussis | Anti-PRN GMT | 259.7 GMT (IU/mL) |
95% CI: [0.88, 1.08]
95% CI: [0.98, 1.23]
95% CI: [1.03, 1.36]