Clinical Trial Results:
A phase III, open, randomized, controlled, multi-centre study to demonstrate the non-inferiority of the meningococcal serogroup C and the Haemophilus influenzae type b immune response of GlaxoSmithKline (GSK) Biologicals’ conjugate Hib-MenC vaccine co-administered with GSK Biologicals’ measles-mumps-rubella vaccine, Priorix™, versus MenC-CRM197 conjugate vaccine co-administered with GSK Biologicals’ Hib vaccine, Hiberix™, and Priorix™ in 12- to 18-month-old toddlers primed in infancy with a Hib vaccine but not with a meningococcal serogroup C vaccine; and to evaluate the long-term antibody persistence up to 5 years after the administration of the Hib-MenC vaccine.
Summary
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EudraCT number |
2011-005032-26 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
06 Oct 2012
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Results information
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Results version number |
v2 |
This version publication date |
19 Mar 2016
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First version publication date |
29 Jul 2015
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Other versions |
v1 , v3 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
106445
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00326118 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
106446: eTrack number, 106449: eTrack number, 106450: eTrack number, 106452: eTrack number, 106454: eTrack number | ||
Sponsors
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Sponsor organisation name |
GlaxoSmithKline Biologicals
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Sponsor organisation address |
Rue de l’Institut 89, Rixensart, Belgium, B-1330
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Public contact |
Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
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Scientific contact |
Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Feb 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
06 Oct 2012
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Oct 2012
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
One month after vaccination:
To demonstrate the non-inferiority of the meningococcal serogroup C and Hib responses induced by Hib-MenC vaccine, compared to separately administered MCC and Hib vaccines (with MMR co-administered in each group), when given as a single dose to toddlers 12-18 months of age primed with routine infant vaccines including Hib, but no MenC vaccine, in terms of:
-Percentage of subjects with meningococcal serogroup C serum bactericidal assay using rabbit complement (rSBA-MenC) titer ≥ 1:8.
-Percentage of subjects with anti-polyribosylribitol phosphate (anti-PRP) antibody concentration ≥ 0.15 µg/mL
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Protection of trial subjects |
All subjects were supervised for 30 min after vaccination/product administration with appropriate medical treatment readily available. Vaccines/products were administered by qualified and trained personnel. Vaccines/products were administered only to eligible subjects that had no contraindications to any components of the vaccines/products. Subjects were followed-up for 30 days after the last vaccination/product administration.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
17 Jun 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 433
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Worldwide total number of subjects |
433
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
433
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
Pre-assignment
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Screening details |
During the screening the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms. | ||||||||||||||||||
Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Menitorix Group | ||||||||||||||||||
Arm description |
Subjects received a single dose of Menitorix™ vaccine co-administered with Priorix™ vaccine. Menitorix vaccine was administered intramuscularly in the left deltoid region and the Priorix vaccine was administered subcutaneously in the right upper arm. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Menitorix™
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Investigational medicinal product code |
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Other name |
Hib-MenC
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
One intramuscular dose at 12-18 months of age, administered in the left deltoid region.
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Investigational medicinal product name |
Priorix™
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Investigational medicinal product code |
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Other name |
MMR
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
One subcutaneous dose at 12-18 months of age, administered in the right upper arm.
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Arm title
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Meningitec + Hiberix Group | ||||||||||||||||||
Arm description |
Subjects received a single dose of Meningitec™ vaccine co-administered with Hiberix™ and Priorix™ vaccines. The Meningitec vaccine was administered intramuscularly in the left deltoid region, the Hiberix vaccine was administered intramuscularly in the left thigh region and the Priorix vaccine was administered subcutaneously in the right upper arm. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Meningitec™
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Investigational medicinal product code |
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Other name |
MCC
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
One intramuscular dose at 12-18 months of age, administered in the left deltoid region.
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Investigational medicinal product name |
Hiberix™
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Investigational medicinal product code |
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Other name |
Hib
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
One intramuscular dose at 12-18 months of age, administered in the left tight region.
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Investigational medicinal product name |
Priorix™
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Investigational medicinal product code |
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Other name |
MMR
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
One subcutaneous dose at 12-18 months of age, administered in the right upper arm.
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Baseline characteristics reporting groups
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Reporting group title |
Menitorix Group
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Reporting group description |
Subjects received a single dose of Menitorix™ vaccine co-administered with Priorix™ vaccine. Menitorix vaccine was administered intramuscularly in the left deltoid region and the Priorix vaccine was administered subcutaneously in the right upper arm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Meningitec + Hiberix Group
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Reporting group description |
Subjects received a single dose of Meningitec™ vaccine co-administered with Hiberix™ and Priorix™ vaccines. The Meningitec vaccine was administered intramuscularly in the left deltoid region, the Hiberix vaccine was administered intramuscularly in the left thigh region and the Priorix vaccine was administered subcutaneously in the right upper arm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Menitorix Group
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Reporting group description |
Subjects received a single dose of Menitorix™ vaccine co-administered with Priorix™ vaccine. Menitorix vaccine was administered intramuscularly in the left deltoid region and the Priorix vaccine was administered subcutaneously in the right upper arm. | ||
Reporting group title |
Meningitec + Hiberix Group
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Reporting group description |
Subjects received a single dose of Meningitec™ vaccine co-administered with Hiberix™ and Priorix™ vaccines. The Meningitec vaccine was administered intramuscularly in the left deltoid region, the Hiberix vaccine was administered intramuscularly in the left thigh region and the Priorix vaccine was administered subcutaneously in the right upper arm. |
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End point title |
Number of subjects with meningococcal polysaccharide C serum bactericidal assay, using baby rabbit complement (rSBA-MenC) titres ≥ 1:8 | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
One month after vaccination.
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Statistical analysis title |
Difference in % subjects with rSBA-MenC ≥ 1:8 | ||||||||||||
Statistical analysis description |
To demonstrate the non-inferiority of the meningococcal serogroup C and Hib responses induced by Hib-MenC vaccine, compared to separately administered MCC and Hib vaccines (with MMR co-administered in each group), when given as a single dose to toddlers 12-18 months of age primed with routine infant vaccines including Hib, but no MenC vaccine, in terms of percentage of subjects with meningococcal serogroup C serum bactericidal assay using rabbit complement (rSBA-MenC) titer ≥ 1:8.
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Comparison groups |
Menitorix Group v Meningitec + Hiberix Group
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Number of subjects included in analysis |
379
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
Method |
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Parameter type |
Difference in percentage | ||||||||||||
Point estimate |
-0.36
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.99 | ||||||||||||
upper limit |
3.43 | ||||||||||||
Notes [1] - Criterion for achieving the co-primary objectives: One month after vaccination, the lower limit of the standardized asymptotic 95% confidence interval on the difference between the study vaccine group and (minus) the control group was above -10%. |
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End point title |
Number of subjects with anti-polyribosylribitol phosphate (anti-PRP) antibody concentrations ≥ 0.15 μg/mL | ||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 0.15 μg/mL.
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End point type |
Primary
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End point timeframe |
One month after vaccination.
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Statistical analysis title |
Difference in % subjects with anti-PRP ≥0.15 μg/mL | ||||||||||||
Statistical analysis description |
To demonstrate the non-inferiority of the meningococcal serogroup C and Hib responses induced by Hib-MenC vaccine, compared to separately administered MCC and Hib vaccines (with MMR co-administered in each group), when given as a single dose to toddlers 12-18 months of age primed with routine infant vaccines including Hib, but no MenC vaccine, in terms of percentage of subjects with anti-polyribosylribitol phosphate (anti-PRP) antibody concentration ≥ 0.15 μg/mL.
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Comparison groups |
Menitorix Group v Meningitec + Hiberix Group
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Number of subjects included in analysis |
392
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | ||||||||||||
Method |
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Parameter type |
Difference in percentage | ||||||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.3 | ||||||||||||
upper limit |
3.71 | ||||||||||||
Notes [2] - Criterion for achieving the co-primary objectives: One month after vaccination, the lower limit of the standardized asymptotic 95% confidence interval on the difference between the study vaccine group and (minus) the control group was above -10%. |
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End point title |
Number of subjects with rSBA-MenC titers ≥ 1:8 | ||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 1:8.
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End point type |
Secondary
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End point timeframe |
Prior to vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects with anti-PRP antibody concentrations ≥ 0.15 µg/mL | ||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 0.15 μg/mL.
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End point type |
Secondary
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End point timeframe |
Prior to vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects with rSBA-MenC titers ≥ 1:128 | |||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 1:128.
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End point type |
Secondary
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End point timeframe |
Prior to vaccination and one month after vaccination
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No statistical analyses for this end point |
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End point title |
rSBA-MenC antibody titers | ||||||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 1:8 and ≥ 1:128.
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End point type |
Secondary
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End point timeframe |
Prior to vaccination and one month after vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects with anti-PRP antibody concentrations ≥1.0 µg/mL | |||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 1.0 μg/mL.
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End point type |
Secondary
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End point timeframe |
Prior to vaccination and one month after vaccination
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No statistical analyses for this end point |
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End point title |
Anti-PRP antibody concentrations | ||||||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 1.0 μg/mL.
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End point type |
Secondary
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End point timeframe |
Prior to vaccination and one month after vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects with anti-polysaccharide C (anti-PSC) antibody concentrations ≥ 0.30 μg/mL and ≥ 2.0 μg/mL | |||||||||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 0.30 μg/mL and ≥ 2.0 μg/mL.
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End point type |
Secondary
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End point timeframe |
Prior to vaccination and one month after vaccination
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No statistical analyses for this end point |
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End point title |
Anti-polysaccharide C (anti-PSC) antibody concentrations | ||||||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 0.30 μg/mL and ≥ 2.0 μg/mL.
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End point type |
Secondary
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End point timeframe |
Prior to vaccination and one month after vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects with rSBA-MenC titers ≥ 1:8 and ≥ 1:128 | |||||||||||||||||||||||||||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 1:8 and ≥ 1:128 and starting with year 4 Public Health England (PHE) continued with the laboratory assay.
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End point type |
Secondary
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End point timeframe |
At 1, 2, 3, 4, and 5 years after vaccination
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No statistical analyses for this end point |
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End point title |
rSBA-MenC antibody titers | |||||||||||||||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 1:8 and ≥ 1:128. The analyses were performed at the GSK Biologicals’ laboratory, and starting with year 4 GSK Biologicals laboratory was replaced with Public Health England (PHE) laboratory.
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End point type |
Secondary
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End point timeframe |
At 1, 2, 3, 4, and 5 years after vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects with anti-PRP ≥ 0.15 μg/mL, ≥ 1.0 μg/mL | |||||||||||||||||||||||||||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 0.15 μg/mL and ≥ 1.0 μg/mL. The analyses were performed at the GSK Biologicals’ laboratory, and starting with year 4 GSK Biologicals laboratory was replaced with Public Health England (PHE) laboratory.
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End point type |
Secondary
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End point timeframe |
At 1, 2, 3, 4, and 5 years after vaccination
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No statistical analyses for this end point |
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End point title |
Anti-PRP antibody concentrations | |||||||||||||||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 0.15 μg/mL and ≥ 1.0 μg/mL. The analyses were performed at the GSK Biologicals’ laboratory, and starting with year 4 GSK Biologicals laboratory was replaced with Public Health England (PHE) laboratory.
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End point type |
Secondary
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End point timeframe |
At 1, 2, 3, 4, and 5 years after vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects with anti-PSC antibody concentrations ≥ 0.30 μg/mL and ≥ 2.0 μg/mL | |||||||||||||||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 0.30 μg/mL and ≥ 2.0 μg/mL.
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End point type |
Secondary
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End point timeframe |
At 1, 2 and 3 years after vaccination.
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No statistical analyses for this end point |
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End point title |
Anti-PSC antibody concentrations | |||||||||||||||||||||
End point description |
The cut-off values assessed were greater than or equal to (≥) 0.30 μg/mL and ≥ 2.0 μg/mL.
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End point type |
Secondary
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End point timeframe |
At 1, 2 and 3 years after vaccination.
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Notes [3] - Lower and Upper limits of 95% confidence interval not reliable because of deviation from log normal [4] - Lower and Upper limits of 95% confidence interval not reliable because of deviation from log normal |
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting any solicited local symptoms | ||||||||||||||||||
End point description |
Assessed solicited local symptoms were pain, redness and swelling. Any = Occurrence of any solicited local symptom regardless of their intensity grade.
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End point type |
Secondary
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End point timeframe |
Within 4 days (Day 0-3) after vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting any solicited general symptoms | |||||||||||||||||||||
End point description |
Assessed solicited general symptoms were arthralgia, fatigue, gastrointestinal symptoms, headache, myalgia, rash, fever and urticaria. Any = Occurrence of any solicited general symptom regardless of intensity grade or relationship to vaccination. Any Fever = Axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C).
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End point type |
Secondary
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End point timeframe |
Within 4 days (Day 0-3) after vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting any unsolicited adverse events (AEs) | ||||||||||||
End point description |
An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any = Any unsolicited.
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End point type |
Secondary
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End point timeframe |
Within 31 days (Days 0–30) after vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting any serious adverse events (SAEs) | ||||||||||||
End point description |
Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Any was defined as occurrence of any symptom regardless of intensity grade or relation to vaccination and related was an event assessed by the investigator as causally related to the study vaccination.
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End point type |
Secondary
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End point timeframe |
During the Active Phase of the study
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting any solicited adverse events (SAEs) | ||||||||||||||||||||||||
End point description |
Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Any was defined as occurrence of any symptom regardless of intensity grade or relation to vaccination and related was an event assessed by the investigator as causally related to the study vaccination.
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End point type |
Secondary
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End point timeframe |
At each visit of the long-term persistence phase (at 1 year up to 5 years after vaccination)
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Solicited symptoms during the 4-day post-vaccination period, Unsolicited AEs during the 31-day post-vaccination period, SAEs during the entire period
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
Menitorix Group
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Meningitec + Hiberix Group
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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28 Jul 2006 |
The primary vaccination calendar in Australia was modified since the release of the present protocol, ie Hib-TT combined with DTPa containing vaccine are now routinely given to infants in some regions. As a result, the inclusion criteria and the statistical section have been amended to take into account these changes. |
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26 Feb 2007 |
In order to improve the enrolment of subjects in the study, some sites may perform home visits. At the first home visit, the parents/guardians will be asked to sign a preinformed consent to allow the sites to collect some personal identifying information. This information will be recorded on a register which will help GSK and the study staff better prepare for and manage the first study visit if the parent/guardian subsequently decide to have their child/ward participate in the study.
In order to be consistent throughout all study visits, the physical examinations during the persistence phase of the study do not need to be performed by the investigator. In protocol amendment 1, it was planned to perform all laboratory assays at Rixensart. The protocol was amended to allow for other validated laboratories designated by GSK Biologicals to perform the assays, if needed.
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27 Mar 2012 |
To support the data obtained by serum bactericidal assay (SBA) testing, antibody concentrations against meningococcal polysaccharides (PSs) were planned to be assessed by enzyme-linked immunosorbent assay (ELISA). The ELISA testing was performed at month 0, month 1 and 1, 2 and 3 years after vaccine administration, but the sponsor decided not to perform the ELISA testing at 4 and 5 years after vaccine administration for the following reasons:
- the World Health Organisation (WHO) considers SBA the primary means of assessing immune response to meningococcal conjugate vaccines [WHO, 2006; WHO, 1999].
- circulating bactericidal antibodies are more critical for persistent protection against meningococcal disease than non-functional antibodies against meningococcal polysaccharides [CDC, 2011;WHO, 2006].
Although antibody concentrations will not be determined by ELISA at 4 and 5 years after vaccine administration, all subjects will be informed of their SBA antibody titers at each immunogenicity time point when statistical analyses at that time point have been completed.
In addition, the protocol amendment clarifies in which laboratory the different assays will be performed.
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |