Clinical Trial Results:
A phase III, open, randomized, multicentre, multicountry study to compare the reactogenicity and evaluate the safety and immunogenicity of GSK Bio’s combined hepatitis A / hepatitis B vaccine (at least 720 EL.U of hepatitis A antigen and 20 µg of hepatitis B surface antigen per dose of 1 ml) administered according to a 0, 6 month schedule by intramuscular injection versus Twinrix Junior (at least 360 EL.U of hepatitis A antigen and 10 µg of hepatitis B surface antigen per dose of 0.5 ml) administered according to a 0, 1, 6 month schedule by intramuscular injection in healthy children between 1 to 11 years old.
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Summary
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EudraCT number |
2015-001515-12 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
25 Feb 2008
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Results information
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Results version number |
v2(current) |
This version publication date |
26 Apr 2023
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First version publication date |
26 Jul 2015
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Other versions |
v1 |
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 |
208127/120,/132,/133,/134,/137
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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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 Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
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Scientific contact |
Clinical Disclosure Advisor, 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 |
10 Dec 2004
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Feb 2008
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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 |
For the primary study:
To demonstrate that the combined hepatitis A / hepatitis B (720/20) vaccine is not more reactogenic than Twinrix Junior.
For the long term follow up (LTFU):
To evaluate anti-HAV and anti-HBs antibody persistence at Year 2, Year 3, Year 4 and Year 5 after the first vaccine dose of the primary vaccination course (a two-dose schedule of Twinrix Adult 720/20 vaccine or a three-dose schedule of Twinrix Junior 360/10 vaccine).
To evaluate the immune memory in the subjects who became seronegative for anti-HAV antibodies (i.e. anti-HAV antibody concentrations < 15 mIU/ml) or had anti-HBs antibody concentrations < 10 mIU/ml at the long-term blood sampling time-point (i.e. Year 2, 3, 4 or 5) and who received the challenge dose (administered 6 to 12 months after the Year 5 time-point).
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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 |
10 Sep 2001
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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: 229
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Country: Number of subjects enrolled |
Belgium: 61
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Country: Number of subjects enrolled |
Spain: 110
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Country: Number of subjects enrolled |
Sweden: 110
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Worldwide total number of subjects |
510
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EEA total number of subjects |
281
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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) |
100
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Children (2-11 years) |
410
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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 |
- | |||||||||
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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. | |||||||||
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Period 1
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Period 1 title |
Year 2 - Year 5 (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Twinrix Adult Y2-Y5 | |||||||||
Arm description |
Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation). | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Twinrix Adult
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Intramuscular injection in the left deltoid, 2 doses, Adult formulation in primary study.
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Arm title
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Twinrix Junior Y2-Y5 | |||||||||
Arm description |
Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation). | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Twinrix Junior
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Intramuscular injection in the left deltoid, 3 doses, junior formulation in primary study.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The worldwide enrollment is from the Primary study 208127/120 and the number of subjects reported in the baseline period is from follow-up phase studies (208127/132 TO 208127/137) which started and completed the Study. |
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Baseline characteristics reporting groups
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Reporting group title |
Twinrix Adult Y2-Y5
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Reporting group description |
Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Twinrix Junior Y2-Y5
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Reporting group description |
Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Twinrix Adult Y2-Y5
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Reporting group description |
Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation). | ||
Reporting group title |
Twinrix Junior Y2-Y5
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Reporting group description |
Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation). | ||
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End point title |
Anti-hepatitis A (HAV) antibody concentrations [1] | ||||||||||||||||||||||||
End point description |
Geometric mean concentration for anti-HAV antibodies expressed as Milli-International Units per milliliter (mIU/mL)
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End point type |
Primary
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End point timeframe |
Year 2 (Month 24), Year 3 (Month 36), Year 4 (Month 48) and Year 5 (Month 60)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Anti-hepatitis B (HBs) antibody concentrations [2] | ||||||||||||||||||||||||
End point description |
Geometric mean concentration for anti-HBs antibodies expressed as Milli-International Units per milliliter (mIU/mL).
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End point type |
Primary
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End point timeframe |
Year 2 (Month 24), Year 3 (Month 36), Year 4 (Month 48) and Year 5 (Month 60)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Anti-HAV antibody concentrations in subjects receiving the additional vaccine dose. [3] | ||||||||||||
End point description |
Any subjects becoming seronegative for anti-HAV antibodies (i.e. titres < 15 mIU/ml) at any long term time point, were to receive an additional vaccine dose administered between 6 to 12 months after Year 5 time point.
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End point type |
Primary
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End point timeframe |
Before and one month after additional vaccination
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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| Notes [4] - No subjects became seronegative for anti-HAV antibodies. [5] - No subjects became seronegative for anti-HAV antibodies. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Anti-HBs antibody concentrations in subjects receiving the additional vaccine dose. [6] | ||||||||||||||||||
End point description |
Subjects losing seroprotective anti-HBs antibody titres (i.e. titres < 10 mIU/ml) at any long term time point, received an Engerix challenge dose. The table presents the geometric mean concentrations for anti-HBs antibodies, expressed as Milli-International Units per milliliter (mIU/mL).
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End point type |
Primary
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End point timeframe |
Before and One month after additional vaccination
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of subjects reporting Serious Adverse Events (SAEs) determined by the investigator to have a causal relationship to primary vaccination or due to lack of vaccine efficacy. | ||||||||||||
End point description |
A serious adverse event (SAE) is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
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End point type |
Secondary
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End point timeframe |
From last study visit of the primary study up to Year 5 long term follow-up
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of subjects receiving an additional vaccine dose and reporting solicited local symptoms | |||||||||||||||||||||||||||
End point description |
Solicited local symptoms assessed include pain, redness and swelling at the vaccine injection site. Any= regardless of intensity grade; Grade 3 Pain= spontaneously painful
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End point type |
Secondary
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End point timeframe |
during the 4-day follow-up period after additional vaccination
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Number of subjects receiving an additional vaccine dose and reporting solicited general symptoms. | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Solicited general symptoms assessed include fatigue, fever, gastrointestinal symptoms and headache. Any= regardless of intensity grade or relationship to vaccination; grade 3= prevented normal activity; Related= considered by the investigator to be causally related to the vaccination
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End point type |
Secondary
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End point timeframe |
During the 4-day follow-up period after additional vaccination
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of subjects receiving an additional vaccine dose and reporting unsolicited adverse events (AEs). | ||||||||||||
End point description |
An Adverse Event is 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.
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End point type |
Secondary
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End point timeframe |
During the 30-day follow-up period after additional vaccination.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of subjects receiving an additional vaccine dose and reporting any Serious Adverse Events | ||||||||||||
End point description |
A serious adverse event (SAE) is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
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End point type |
Secondary
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End point timeframe |
At least one month 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 (Day 0-3) follow-up period after the additional vaccination. Unsolicited AEs: During the 31-day (Day 0-30) period after the additional vaccination; SAEs: During the entire study period
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Adverse event reporting additional description |
The number of occurrences reported for solicited symptoms, adverse events, and serious adverse events were not available for posting. The number of subjects affected by each specific event was indicated as the number of occurrences.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
7.1
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Reporting groups
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Reporting group title |
Twinrix Adult
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Reporting group description |
Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Twinrix Junior
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Reporting group description |
Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Notes [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: There were less subjects enrolled in the follow-up phase of the study than in the primary phase. [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: There were less subjects enrolled in the follow-up phase of the study than in the primary phase. [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: There were less subjects enrolled in the follow-up phase of the study than in the primary phase. [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: There were less subjects enrolled in the follow-up phase of the study than in the primary phase. [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: There were less subjects enrolled in the follow-up phase of the study than in the primary phase. [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: There were less subjects enrolled in the follow-up phase of the study than in the primary phase. [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: There were less subjects enrolled in the follow-up phase of the study than in the primary phase. [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: There were less subjects enrolled in the follow-up phase of the study than in the primary phase. |
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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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24 Jul 2001 |
• To account for the competitive enrolment that is to be used for this study, extra randomization numbers and vaccine supplies will be needed at the study centres.
• The study site in The Netherlands under Professor R.A. Coutinho and the study site in Croatia under Professor Berislav Borčić will now not be used and, in consequence, can be deleted from the study protocol. To replace these two sites, a new study site in Belgium has been incorporated (UCL, Brussels under Dr Etienne Sokal).
• Anne Howard has been appointed as the Australian Study Monitor for this project, replacing Serge De Bartolo, therefore, her contact details are now included.
• Inmaculada Nuñez Arias has been appointed as one of the Spanish Study Monitors for this project, replacing Sandra Sistiaga, therefore, her contact details are now included.
• The section of the title pages requiring the signatures of the Principal Investigators has been deleted due to its redundancy in the modified protocol. |
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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 | |||
