Long-Term Immune Persistence of GSK Biologicals' Combined Hepatitis A & B Vaccine Injected According to a 0,1,6 Month Schedule

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00289718
• Collaborator: (none)
• Enrollment: 51
• Location: 1
• Arm: 1
• Duration (Months): 4
• Patients Per Site Per Month: 12.8

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 years after subjects received their first dose of a 3 dose 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 to 15.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis B; Hepatitis A	Biological: Twinrix™ adult	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, 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 during the course of this long-term 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: 51 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Long-Term Persistence Follow-up Study to Evaluate the Immune Persistence of GSK Biologicals' Combined Hepatitis A / Hepatitis B Vaccine in Healthy Adult Volunteers
• Study Start Date: Nov 1, 2004
• Actual Primary Completion Date: Mar 2, 2005
• Actual Study Completion Date: Mar 2, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Twinrix Group Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up.	Biological: Twinrix™ adult; Intramuscular administration

Outcome Measures

Primary Outcome Measures

1. Anti-hepatitis A Virus (Anti-HAV) Antibody Concentration [At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination]

   Concentrations given as geometric mean concentration (GMC) expressed as milli-international unit per millilitre (mIU/mL).

2. Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms. [During the 4-day (Day 0-3) follow-up period after additional HBV vaccination]

   Solicited local symptoms assessed include pain, redness and swelling. Any was defined as occurrence of the specified solicited local symptom regardless of its intensity. Grade 3 pain was defined as pain that prevented normal everyday activities. Grade 3 swelling was greater than 100 millimeters (mm) i.e. >100mm.

3. Number of Subjects Seropositive for Anti-HAV Antibodies [At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination]

   A seropositive subject was defined as a vaccinated subject who had a anti-HAV antibody titres ≥ 33 mIU/ml.

4. Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentration [At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination]

   Concentrations given as GMC expressed as mIU/mL. NOTE: There was a change of assay kit at Year 15 time-point, thus for the sake of bridging, blood samples corresponding to Year 14 were re-tested with ChemiLuminescence ImmunoAssay (CLIA). From Year 11 to Year 14, anti-HBs antibody concentrations were tested with ELISA with cut-off of 3.3 mIU/mL while, Year 14* onwards, anti-HBs antibody concentrations were tested with the CLIA with cut-off of 6.2 mIU/mL.

5. Number of Subjects Seropositive for Anti-HB Antibodies [At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination]

   A seropositive subject was defined as a vaccinated subject who had anti-HB antibody titres ≥ 1 mIU/mL. NOTE: There was a change of assay kit at Year 15 time-point, thus for the sake of bridging, blood samples corresponding to Year 14 were re-tested with ChemiLuminescence ImmunoAssay (CLIA)

6. Number of Subjects Seroprotected for Anti-HBs Antibodies. [At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination]

   A seroprotected subject was defined as a subjects with the anti-HBs titres ≥ 10 mIU/mL. NOTE: There was a change of assay kit at Year 15 time-point, thus for the sake of bridging, blood samples corresponding to Year 14 were re-tested with ChemiLuminescence ImmunoAssay (CLIA)

7. Number of Subjects Reporting Serious Adverse Events (SAE) [During the follow-up period after additional vaccination (minimum 30 days)]

   A SAE was defined as any untoward medical occurrence that: resulted in death, was life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was 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.

8. Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentration [Before the additional dose and 1 month after the additional dose]

   Concentrations given as GMC expressed as mIU/mL. If a subject became seronegative (< 10 mIU/mL) at any of the long-term blood sampling timepoint, he/she was offered an additional vaccine dose.

9. Number of Subjects Reporting Any Solicited General Symptoms. [During the 4-day (Day 0-3) follow-up period after additional HBV vaccination]

   Solicited general symptoms assessed included fatigue, headache, malaise, nausea, vomiting and fever. Any was defined as any solicited general symptom reported irrespective of intensity and relationship to vaccination.

10. Number of Subjects Reporting Unsolicited Adverse Events (AE) [During the 30-day follow-up period after additional vaccination]

    An AE 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.

11. Number of Subjects Reporting Serious Adverse Events (SAEs) [At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination]

    A SAE was defined as any untoward medical occurrence that: resulted in death, was life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was 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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects participating in this study should have received three-dose primary vaccination with combined hepatitis A/hepatitis B vaccine in the primary study.

• Written informed consent will be 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	Gent		Belgium	9000

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: NCT00289718
• Other Study ID Numbers: 100556 (Y11); 100557 (Y12); 100558 (Y13); 100559 (Y14); 100560 (Y15)
• First Posted: Feb 10, 2006
• Last Update Posted: Feb 15, 2018
• Last Verified: Nov 1, 2016

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

Study Results

Participant Flow

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up
Period Title: Overall Study
STARTED	51
COMPLETED	51
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up
Overall Participants	51
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.4 (5.65)
Sex: Female, Male (Count of Participants)
Female	41 80.4%
Male	10 19.6%

Outcome Measures

1. Primary Outcome

Title	Anti-hepatitis A Virus (Anti-HAV) Antibody Concentration
Description	Concentrations given as geometric mean concentration (GMC) expressed as milli-international unit per millilitre (mIU/mL).
Time Frame	At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term According-to-Protocol (LT-ATP) cohort for immunogenicity, on subjects with available data for the defined timepoint

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up
Measure Participants	33
Year 11 (N=33)	369.1
Year 12 (N=33)	323.5
Year 13 (N=32)	293.7
Year 14 (N=30)	298.2
Year 15 (N=29)	274.4

2. Primary Outcome

Title	Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms.
Description	Solicited local symptoms assessed include pain, redness and swelling. Any was defined as occurrence of the specified solicited local symptom regardless of its intensity. Grade 3 pain was defined as pain that prevented normal everyday activities. Grade 3 swelling was greater than 100 millimeters (mm) i.e. >100mm.
Time Frame	During the 4-day (Day 0-3) follow-up period after additional HBV vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort, on subjects who received an additional vaccine dose. Only 1 subject received an additional dose.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A) in the primary study.
Measure Participants	1
Pain	1
Redness	0
Swelling	0

3. Primary Outcome

Title	Number of Subjects Seropositive for Anti-HAV Antibodies
Description	A seropositive subject was defined as a vaccinated subject who had a anti-HAV antibody titres ≥ 33 mIU/ml.
Time Frame	At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term According-to-Protocol (LT-ATP) cohort for immunogenicity, on subjects with available data for the defined timepoint

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up
Measure Participants	33
Year 11 (N=33)	33
Year 12 (N=33)	33
Year 13 (N=32)	32
Year 14 (N=30)	30
Year 15 (N=29)	29

4. Primary Outcome

Title	Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentration
Description	Concentrations given as GMC expressed as mIU/mL. NOTE: There was a change of assay kit at Year 15 time-point, thus for the sake of bridging, blood samples corresponding to Year 14 were re-tested with ChemiLuminescence ImmunoAssay (CLIA). From Year 11 to Year 14, anti-HBs antibody concentrations were tested with ELISA with cut-off of 3.3 mIU/mL while, Year 14* onwards, anti-HBs antibody concentrations were tested with the CLIA with cut-off of 6.2 mIU/mL.
Time Frame	At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term According-to-Protocol (LT-ATP) cohort for immunogenicity, on subjects with available data for the defined timepoint

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up
Measure Participants	33
Year 11 (N=33)	123.6
Year 12 (N=33)	150.3
Year 13 (N=32)	77.8
Year 14 (N=30)	71.7
Year 14* (N=28)	95.3
Year 15 (N=29)	79.2

5. Primary Outcome

Title	Number of Subjects Seropositive for Anti-HB Antibodies
Description	A seropositive subject was defined as a vaccinated subject who had anti-HB antibody titres ≥ 1 mIU/mL. NOTE: There was a change of assay kit at Year 15 time-point, thus for the sake of bridging, blood samples corresponding to Year 14 were re-tested with ChemiLuminescence ImmunoAssay (CLIA)
Time Frame	At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term According-to-Protocol (LT-ATP) cohort for immunogenicity, on subjects with available data for the defined timepoint

Arm/Group Title	TWINRIX GROUP
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up
Measure Participants	33
YEAR 11 (N=33)	33
YEAR 12 (N=33)	33
YEAR 13 (N=32)	32
YEAR 14 (N=30)	29
Year 14* (N=28)	27
YEAR 15 (N=29)	28

6. Primary Outcome

Title	Number of Subjects Seroprotected for Anti-HBs Antibodies.
Description	A seroprotected subject was defined as a subjects with the anti-HBs titres ≥ 10 mIU/mL. NOTE: There was a change of assay kit at Year 15 time-point, thus for the sake of bridging, blood samples corresponding to Year 14 were re-tested with ChemiLuminescence ImmunoAssay (CLIA)
Time Frame	At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term According-to-Protocol (LT-ATP) cohort for immunogenicity, on subjects with available data for the defined timepoint

Arm/Group Title	TWINRIX GROUP
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up
Measure Participants	33
YEAR 11 (N=33)	33
YEAR 12 (N=33)	32
YEAR 13 (N=32)	32
YEAR 14 (N=30)	29
Year 14* (N=28)	27
YEAR 15 (N=29)	28

7. Primary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAE)
Description	A SAE was defined as any untoward medical occurrence that: resulted in death, was life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was 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.
Time Frame	During the follow-up period after additional vaccination (minimum 30 days)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort, on subjects who received an additional vaccine dose. Only 1 subject received an additional dose.

Arm/Group Title	Twinrix Group (Lot A)	Twinrix Group (Lot B)
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A) in the primary study.	Subjects who received 2 doses of Twinrix™ (lot B) in the primary study.
Measure Participants	1	1
Number [subjects]	0	1

8. Primary Outcome

Title	Anti-Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentration
Description	Concentrations given as GMC expressed as mIU/mL. If a subject became seronegative (< 10 mIU/mL) at any of the long-term blood sampling timepoint, he/she was offered an additional vaccine dose.
Time Frame	Before the additional dose and 1 month after the additional dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort, on subjects who received an additional vaccine dose. Only 1 subject received an additional dose.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up
Measure Participants	1
before additional dose at Year 12	9.7
1 month after additional dose at Year 12	NA
before additional dose at Year 13	9.5
1 month after additional dose at Year 13	15022.3

9. Primary Outcome

Title	Number of Subjects Reporting Any Solicited General Symptoms.
Description	Solicited general symptoms assessed included fatigue, headache, malaise, nausea, vomiting and fever. Any was defined as any solicited general symptom reported irrespective of intensity and relationship to vaccination.
Time Frame	During the 4-day (Day 0-3) follow-up period after additional HBV vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort, on subjects who received an additional vaccine dose. Only 1 subject received an additional dose.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A) in the primary study.
Measure Participants	1
Any Fatigue	0
Any Headache	0
Any Malaise	0
Any Nausea	0
Any Vomiting	0
Any Fever	0

10. Primary Outcome

Title	Number of Subjects Reporting Unsolicited Adverse Events (AE)
Description	An AE 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.
Time Frame	During the 30-day follow-up period after additional vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort, on subjects who received an additional vaccine dose. Only 1 subject received an additional dose.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A) in the primary study.
Measure Participants	1
Number [subjects]	1

11. Primary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs)
Description	A SAE was defined as any untoward medical occurrence that: resulted in death, was life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was 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.
Time Frame	At Years 11, 12, 13, 14, and 15 after the first vaccine dose of the 3-dose primary vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the LT Total Cohort that included all subjects who returned at a specified follow-up study and who belonged to the Total Cohort of the primary vaccination course.

Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up
Measure Participants	51
Number [Subjects]	0

Adverse Events

Time Frame	Serious Adverse Events (SAEs):Up to Year 15 and after additional HBV vaccination;Solicited local and general symptoms:During the 4-day follow-up period post additional dose;Unsolicited AEs:During the 30-day follow-up period post additional dose.
Adverse Event Reporting Description	Safety results were reported for subjects who received an additional vaccine dose. Only one subject received an additional dose
Arm/Group Title	Twinrix Group
Arm/Group Description	Subjects who received 2 doses of Twinrix™ (lot A, B or C) in the primary study. As lot to lot consistency was assessed during the primary study, the 3 groups (lot A, B or C) were pooled into the Twinrix Group for data analyses during the long term follow-up
All Cause Mortality
	Twinrix Group
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Twinrix Group
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Musculoskeletal and connective tissue disorders
Hallux valgus	1/1 (100%)
Other (Not Including Serious) Adverse Events
	Twinrix Group
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
General disorders
Pain	1/1 (100%)
Infections and infestations
Nasopharyngitis	1/1 (100%)

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.