Long-term Immune Persistence of GSK Biologicals' Combined Hepatitis A & B Vaccine Injected According to a 0,1,6 Mth Schedule in Healthy Adults

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00289770
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arms: 3
• Duration (Months): 1.6
• Patients Per Site Per Month: 31.1

Study Details

Study Description

Brief Summary

The aim of this study is to evaluate the long-term persistence of hepatitis A and B antibodies at Years 11, 12, 13, 14 and 15 after subjects received their first dose of a 3 dose primary vaccination schedule of combined hepatitis A/hepatitis B vaccine. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

This protocol posting deals with objectives & outcome measures of the extension phase at Year 11-15.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis B; Hepatitis A	Biological: Twinrix™	Phase 3

Detailed Description

This is a long-term follow-up study at Years 11, 12, 13, 14 and 15 after primary vaccination with GSK Biologicals' hepatitis A/hepatitis B vaccine (three-dose schedule with 3 different lots). To evaluate the long-term antibody persistence, volunteers will be bled at Years 11, 12, 13, 14 and 15 after the first vaccine dose of the primary vaccination course to determine their anti-HAV and anti-HBs antibody concentrations.

No additional subjects will be recruited in the course of this extension study. If a subject has become seronegative for anti-HAV antibodies or lost anti-HBs seroprotection concentrations at the long-term blood sampling time point (i.e. Years 11, 12, 13, 14 or 15), he/ she will be offered an additional vaccine dose.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Double Blind Randomised, Comparative Study of the Immunogenicity and Reactogenicity of Three Different Lots of GlaxoSmithKline Biologicals' Combined Hepatitis A - Hepatitis B Vaccine When Administered in Healthy Adults
• Study Start Date: Nov 1, 2004
• Actual Primary Completion Date: Dec 20, 2004
• Actual Study Completion Date: Dec 20, 2004

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A Was vaccinated with Lot A in the primary study.	Biological: Twinrix™; Intramuscular injection, 3 doses
Experimental: Group B Was vaccinated with Lot B in the primary study.	Biological: Twinrix™; Intramuscular injection, 3 doses
Experimental: Group C Was vaccinated with Lot C in the primary study.	Biological: Twinrix™; Intramuscular injection, 3 doses

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Anti-hepatitis A (Anti-HAV) Antibody Concentrations Equal to or Above Cut-off Value [Years 11, 12, 13, 14 and 15]

   Cut-off value was defined as 15 milli-international units per milliliter (mIU/mL). This was considered as seropositivity.

2. Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Equal to or Above Cut-off Values [Years 11, 12, 13, 14 and 15]

   Cut-off values were defined 3.3 mIU/mL for the in-house anti-HBs assay and 6.2 mIU/mL for the ChemiLuminescence ImmunoAssay, which was also considered as seropositivity, and 10 mIU/mL.

3. Anti-HAV and Anti-HBs Antibody Concentrations [Years 11, 12, 13, 14 and 15]

   Concentrations are expressed as geometric mean concentrations (GMCs) in mIU/mL. The laboratory assay was changed from Year 13 to Year 14 to in-house ELISA and at Year 15 to CLIA for anti-HBs GMCs.Thus for the sake of bridging, blood samples corresponding to Year 14 previously tested with ELISA were re-tested with CLIA (Year 14*).

4. Anti-HBs Antibody Concentrations [at Year 11, pre-additional vaccine, after additional dose of Engerix]

   Subjects who lost seroprotective concentrations for anti-HBs (< 10 mIU/mL) at any of the LT follow-up timepoints received an additional dose of Engerix after year 15. Two subjects were eligible for this after Year 11. 3.29 in the table means a concentration of < 3.3 mIU/mL. As the concentration was calculated per subject no mean concentration was calculated and also no measure of dispersion.

5. Number of Subjects, Receiving an Additional Vaccination of Engerix, With an Anamnestic Response [30 days post additional dose of Engerix]

   Anamnestic response was assessed in subjects receiving an additional vaccine dose of Engerix. Two subjects were found eligible at Year 11 for this additional vaccine dose. Anamnestic response was defined as: post-additional vaccination anti-HBs concentration >= 10 mIU/mL in subject seronegative before additional dose. 4-fold increase post-additional dose compared to pre-additional vaccine time point.

6. Number of Subjects With Solicited Local and General Symptoms Assessed [During the 4-day follow-up period after additional vaccination with Engerix]

   Solicited local symptoms were pain, redness and swelling. Solicited general symptoms were fatigue, fever, gastrointestinal, headache.

7. Number of Subjects With Unsolicited Symptoms [During the 30-day follow-up period after additional Engerix vaccination]

   Unsolicited AE covers any AE 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.

8. Number of Subjects With Serious Adverse Events (SAEs) [During the 30-day follow-up period after additional Engerix vaccination]

   SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject

9. Number of Subjects With Serious Adverse Events (SAEs) Determined by the Investigator to Have a Causal Relationship to Primary Vaccination or Due to Lack of Vaccine Efficacy [up to Year 11, 12, 13, 14, 15]

   SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subjects who had consented to participate in the long-term follow-up studies at the previous long-term blood sampling time points

• Written informed consent will have been obtained from each subject. before the blood sampling visit of each year.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Wilrijk		Belgium	2610

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

• Van Damme P, Leroux-Roels G, Crasta P, Messier M, Jacquet JM, Van Herck K. Antibody persistence and immune memory in adults, 15 years after a three-dose schedule of a combined hepatitis A and B vaccine. J Med Virol. 2012 Jan;84(1):11-7. doi: 10.1002/jmv.22264. Epub 2011 Nov 3.
• Van Damme P, Leroux-Roels G, Law B, Diaz-Mitoma F, Desombere I, Collard F, Tornieporth N, Van Herck K. Long-term persistence of antibodies induced by vaccination and safety follow-up, with the first combined vaccine against hepatitis A and B in children and adults. J Med Virol. 2001 Sep;65(1):6-13.
• Van Herck K, Leroux-Roels G, Van Damme P, Srinivasa K, Hoet B. Ten-year antibody persistence induced by hepatitis A and B vaccine (Twinrix) in adults. Travel Med Infect Dis. 2007 May;5(3):171-5. Epub 2006 Sep 20.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00289770
• Other Study ID Numbers: 100551 (EXT Y11); 100552 (EXT Y12); 100553 (EXT Y13); 100554 (EXT Y14); 100555 (EXT Y15)
• First Posted: Feb 10, 2006
• Last Update Posted: Aug 17, 2018
• Last Verified: Sep 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: TWINRIX™ ADULT; Hepatitis A; Hepatitis B
• Additional relevant MeSH terms: Hepatitis A; Hepatitis B; Hepatitis

Study Results

Participant Flow

Pre-assignment Detail	Subjects who came back at a follow-up, did not necessarily come back at an earlier timepoint. Therefore amount of subjects who completed the previous timepoint does not always correspond with amount of subjects who entered follow-up. As Year 15 has enrolled the most subjects, baseline measures are given for Year 15, to be as complete as possible.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Period Title: Year 11
STARTED	37
COMPLETED	37
NOT COMPLETED	0
Period Title: Year 11
STARTED	40
COMPLETED	40
NOT COMPLETED	0
Period Title: Year 11
STARTED	37
COMPLETED	37
NOT COMPLETED	0
Period Title: Year 11
STARTED	43
COMPLETED	43
NOT COMPLETED	0
Period Title: Year 11
STARTED	50
COMPLETED	49
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Overall Participants	50
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	34.4 (2.66)
Sex: Female, Male (Count of Participants)
Female	39 78%
Male	11 22%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Anti-hepatitis A (Anti-HAV) Antibody Concentrations Equal to or Above Cut-off Value
Description	Cut-off value was defined as 15 milli-international units per milliliter (mIU/mL). This was considered as seropositivity.
Time Frame	Years 11, 12, 13, 14 and 15

Outcome Measure Data

Analysis Population Description

Analysis was performed on the long-term (LT) According-To-Protocol (ATP) cohort for immunogenicity, which included subjects who returned at a particular blood sampling timepoint, were in the ATP immunogenicity cohort in the primary study and for whom serology results were available for that particular timepoint.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Measure Participants	31
Year 11	25 50%
Year 12	28 56%
Year 13	23 46%
Year 14	24 48%
Year 15	31 62%

2. Primary Outcome

Title	Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Equal to or Above Cut-off Values
Description	Cut-off values were defined 3.3 mIU/mL for the in-house anti-HBs assay and 6.2 mIU/mL for the ChemiLuminescence ImmunoAssay, which was also considered as seropositivity, and 10 mIU/mL.
Time Frame	Years 11, 12, 13, 14 and 15

Outcome Measure Data

Analysis Population Description

Analysis was performed on the long-term (LT) According-To-Protocol (ATP) cohort for immunogenicity, which included subjects who returned at a particular blood sampling timepoint, were in the ATP immunogenicity cohort in the primary study and for whom serology results were available for that particular timepoint.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Measure Participants	31
Year 11 3.3 mIU/mL	23 46%
Year 12 3.3 mIU/mL	25 50%
Year 13 3.3 mIU/mL	20 40%
Year 14 3.3 mIU/mL	21 42%
Year 14 6.2 mIU/mL	21 42%
Year 15 6.2 mIU/mL	28 56%
Year 11 10 mIU/mL	23 46%
Year 12 10 mIU/mL	25 50%
Year 13 10 mIU/mL	20 40%
Year 14 10 mIU/mL	21 42%
Year 15 10 mIU/mL	28 56%

3. Primary Outcome

Title	Anti-HAV and Anti-HBs Antibody Concentrations
Description	Concentrations are expressed as geometric mean concentrations (GMCs) in mIU/mL. The laboratory assay was changed from Year 13 to Year 14 to in-house ELISA and at Year 15 to CLIA for anti-HBs GMCs.Thus for the sake of bridging, blood samples corresponding to Year 14 previously tested with ELISA were re-tested with CLIA (Year 14*).
Time Frame	Years 11, 12, 13, 14 and 15

Outcome Measure Data

Analysis Population Description

Analysis was performed on the long-term (LT) According-To-Protocol (ATP) cohort for immunogenicity, which included subjects who returned at a particular blood sampling timepoint, were in the ATP immunogenicity cohort in the primary study and for whom serology results were available for that particular timepoint.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Measure Participants	31
Year 11 anti-HAV	680.3
Year 12 anti-HAV	602.7
Year 13 anti-HAV	601.5
Year 14 anti-HAV	524.7
Year 15 anti-HAV	610.7
Year 11 anti-HBs	458.9
Year 12 anti-HBs	475.8
Year 13 anti-HBs	163.3
Year 14 anti-HBs	149.1
Year 14* anti-HBs	242.8
Year 15 anti-HBs	210.9

4. Primary Outcome

Title	Anti-HBs Antibody Concentrations
Description	Subjects who lost seroprotective concentrations for anti-HBs (< 10 mIU/mL) at any of the LT follow-up timepoints received an additional dose of Engerix after year 15. Two subjects were eligible for this after Year 11. 3.29 in the table means a concentration of < 3.3 mIU/mL. As the concentration was calculated per subject no mean concentration was calculated and also no measure of dispersion.
Time Frame	at Year 11, pre-additional vaccine, after additional dose of Engerix

Outcome Measure Data

Analysis Population Description

Analysis was performed on the long-term (LT) Total Vaccinated Cohort in subjects who were eligible for an additional dose. This included all subjects who had received at least one dose of the study vaccine in the primary study and who returned for the blood sampling timepoint and who had serology results for anti-HAV and anti-HBs available.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Measure Participants	2
subject 1 Year 11	3.29
subject 2 Year 11	3.29
subject 1 before additional dose	3.29
subject 2 before additional dose	14.5
subject 1 after additional dose	6548.1
subject 2 after additional dose	554.0

5. Primary Outcome

Title	Number of Subjects, Receiving an Additional Vaccination of Engerix, With an Anamnestic Response
Description	Anamnestic response was assessed in subjects receiving an additional vaccine dose of Engerix. Two subjects were found eligible at Year 11 for this additional vaccine dose. Anamnestic response was defined as: post-additional vaccination anti-HBs concentration >= 10 mIU/mL in subject seronegative before additional dose. 4-fold increase post-additional dose compared to pre-additional vaccine time point.
Time Frame	30 days post additional dose of Engerix

Outcome Measure Data

Analysis Population Description

Analysis was performed on the long-term (LT) Total Vaccinated Cohort in subjects who were eligible for an additional dose. This included all subjects who had received at least one dose of the study vaccine in the primary study and who returned for the blood sampling timepoint and who had serology results for anti-HAV and anti-HBs available.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Measure Participants	2
Count of Participants [Participants]	2 4%

6. Primary Outcome

Title	Number of Subjects With Solicited Local and General Symptoms Assessed
Description	Solicited local symptoms were pain, redness and swelling. Solicited general symptoms were fatigue, fever, gastrointestinal, headache.
Time Frame	During the 4-day follow-up period after additional vaccination with Engerix

Outcome Measure Data

Analysis Population Description

Analysis was performed on the long-term (LT) Total Vaccinated Cohort in subjects who were eligible for an additional dose. This included all subjects who had received at least one dose of the study vaccine in the primary study and who returned for the blood sampling timepoint and who had serology results for anti-HAV and anti-HBs available.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Measure Participants	2
Pain	0 0%
Redness	0 0%
Swelling	0 0%
Fatigue	1 2%
Fever	0 0%
Gastrointestinal	1 2%
Headache	0 0%

7. Primary Outcome

Title	Number of Subjects With Unsolicited Symptoms
Description	Unsolicited AE covers any AE 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.
Time Frame	During the 30-day follow-up period after additional Engerix vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the long-term (LT) Total Vaccinated Cohort in subjects who were eligible for an additional dose. This included all subjects who had received at least one dose of the study vaccine in the primary study and who returned for the blood sampling timepoint and who had serology results for anti-HAV and anti-HBs available.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Measure Participants	2
Count of Participants [Participants]	1 2%

8. Primary Outcome

Title	Number of Subjects With Serious Adverse Events (SAEs)
Description	SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject
Time Frame	During the 30-day follow-up period after additional Engerix vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the long-term (LT) Total Vaccinated Cohort in subjects who were eligible for an additional dose. This included all subjects who had received at least one dose of the study vaccine in the primary study and who returned for the blood sampling timepoint and who had serology results for anti-HAV and anti-HBs available.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Measure Participants	2
Count of Participants [Participants]	0 0%

9. Primary Outcome

Title	Number of Subjects With Serious Adverse Events (SAEs) Determined by the Investigator to Have a Causal Relationship to Primary Vaccination or Due to Lack of Vaccine Efficacy
Description	SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject.
Time Frame	up to Year 11, 12, 13, 14, 15

Outcome Measure Data

Analysis Population Description

Analysis was performed on the long-term (LT) Total Vaccinated Cohort, this included all subjects who had received at least one dose of the study vaccine in the primary study and who returned for the blood sampling time-point and who had serology results for anti-HAV and anti-HBs available.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
Measure Participants	50
Year 11	0 0%
Year 12	0 0%
Year 13	0 0%
Year 14	0 0%
Year 15	0 0%

Adverse Events

Time Frame	SAEs were collected up to Year 15. Other adverse events were collected within 4-days after additional vaccination (solicited) and 30-days after additional vaccination (unsolicited).
Adverse Event Reporting Description	As the number of subjects differs for SAEs at the different timepoints the maximum number has been taken for the amount of subjects at risk.
Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who were vaccinated with either Lot 1, Lot 2 or Lot 3 of Twinrix in the primary study according to a 0, 1, 6-Month schedule
All Cause Mortality
	Twinrix Group
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Twinrix Group
	Affected / at Risk (%)	# Events
Total	0/50 (0%)
Other (Not Including Serious) Adverse Events
	Twinrix Group
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
Eye disorders
Heaviness sensation above eyes	1/2 (50%)
General disorders
Fatigue	1/2 (50%)
Gastrointestinal	1/2 (50%)

Limitations/Caveats

A decrease in the specificity of the anti-HB ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following complete retesting and reanalysis.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.