Long-Term Immune Persistence of GlaxoSmithKline Biologicals' Inactivated Hepatitis A Vaccine, Injected According to 0, 6-month Schedule

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00289757
• Collaborator: (none)
• Enrollment: 78
• Location: 1
• Arm: 1
• Duration (Months): 110
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The aim of this study is to evaluate the long-term persistence of hepatitis A antibodies at 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 years after subjects received their first dose of a 2 dose vaccination schedule of hepatitis A vaccine.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis A	Biological: Havrix™	Phase 4

Detailed Description

This is a long-term follow-up study at Years 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 after primary vaccination with GSK Biologicals' hepatitis A vaccine (two-dose schedule). To evaluate the long-term antibody persistence, volunteers will donate a blood sample at Years 11, 12, 13, 14,15, 16, 17, 18, 19 and 20 after the first vaccine dose of the primary vaccination course to determine their anti-hepatitis A (anti-HAV) antibody concentrations If a subject has become seronegative for anti-HAV antibodies during any of the long-term blood sampling time point (i.e. Years 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 years), he/ she will be offered an additional vaccine dose. A blood sample will be taken on the day of the additional vaccination, 14 days and one month after additional vaccination to evaluate the immune response following this vaccination.

The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007 and to include an extended follow up period up to Year 20 after primary vaccination.

The study has 10 phases (100576, 100577, 100578, 100579, 100580, 111028, 111029, 111030, 111031, 111032).

Study Design

• Study Type: Interventional
• Actual Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Double-blind, Randomized Study to Evaluate the Immunogenicity and Reactogenicity of Three Different Lots of GlaxoSmithKline Biologicals' Inactivated Hepatitis A Vaccine Containing 1440 EL.U of Antigen Per mL and Injected According to a 0, 6 Month Schedule in Healthy Adult Subjects
• Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Havrix Group Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up.	Biological: Havrix™; 2 doses at 6 months interval

Outcome Measures

Primary Outcome Measures

1. Anti-hepatitis A Virus (Anti-HAV) Antibody Concentration [At Years 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 after the first vaccine dose of the 2-dose primary vaccination]

   Concentrations given as geometric mean concentration (GMC) expressed as milli-international unit per millilitre (mIU/mL). The laboratory assay was changed at Year 11, thus the blood samples were with both the old and the new assay for the sake of bridging.

2. Anti-hepatitis A Virus (Anti-HAV) Antibody Concentration [Before the additional dose, 14 days and 30 days after the additional dose]

   Concentrations given as GMC expressed as mIU/mL.

3. Number of Seropositive Subjects for Anti-HAV Antibodies. [From Year 11 to Year 20]

   Seropositivity for anti-HAV antibodies defined as antibody concentrations ≥ 15 mIU/mL for Year 11 to Year 20 time points. The laboratory assay was changed at Year 11, thus the blood samples were with both the old and the new assay for the sake of bridging.

Secondary Outcome Measures

1. Number of Subjects Reporting Serious Adverse Events (SAE) Assessed by the Investigators as Related to Vaccination or to Study Procedures or Lack of Efficacy [Years 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 after the first vaccine dose of the 2-dose primary vaccination]

   An 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

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

   Solicited local symptoms assessed include pain, redness and swelling. Grade 3 pain = symptom that prevented normal activities. Grade 3 redness and swelling = redness or swelling above 30 mm and persisting more than 24 hours. Any = incidence of a particular symptom regardless of intensity.

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

   Solicited general symptoms assessed included fatigue, fever, gastrointestinal symptoms, and headache.

4. Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Adverse Events (AE) [During the 30-day follow-up period after additional vaccination (for subjects who received the additional vaccine dose between Year 11 and 15)]

   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. Grade AE = produced significant impairment of functioning or incapacitation and was a definite hazard to the subject's health. Related AE = assessed by the investigator as related to the study vaccination.

5. Number of Subjects Reporting Serious Adverse Events (SAE) [During the follow-up period after additional vaccination up to Year 20]

   An 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 29 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subjects who had received at least one dose of the study vaccine in the primary study

• Written informed consent will have been obtained from the subjects 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

• Desombere I et al. (2000) Long-term persistence of cellular immunity towards hepatitis A vaccine (HAV) following HAV vaccination. J Antiviral Therapy. 5: 7.
• Van Damme P et al. (1998) Long-term immunogenicity of a high potency inactivated hepatitis A vaccine. J Hepatol. 28 (suppl.1): 113.
• Van Damme P, Matheï C, Thoelen S, Meheus A, Safary A, André FE. Single dose inactivated hepatitis A vaccine: rationale and clinical assessment of the safety and immunogenicity. J Med Virol. 1994 Dec;44(4):435-41.
• Van Herck K et al. (2000) Model-based estimates of long-term persistence of vaccine-induced hepatitis A antibodies. J Antiviral Therapy. 5:3-4.
• Van Herck K, Crasta PD, Messier M, Hardt K, Van Damme P. Seventeen-year antibody persistence in adults primed with two doses of an inactivated hepatitis A vaccine. Hum Vaccin Immunother. 2012 Mar;8(3):323-7. doi: 10.4161/hv.18617. Epub 2012 Feb 13.
• Van Herck K, Jacquet JM, Van Damme P. Antibody persistence and immune memory in healthy adults following vaccination with a two-dose inactivated hepatitis A vaccine: long-term follow-up at 15 years. J Med Virol. 2011 Nov;83(11):1885-91. doi: 10.1002/jmv.22200. Epub 2011 Aug 23.
• Van Herck K, Van Damme P. Inactivated hepatitis A vaccine-induced antibodies: follow-up and estimates of long-term persistence. J Med Virol. 2001 Jan;63(1):1-7.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00289757
• Other Study ID Numbers: 100576 (Y11); 100577 (Y12); 100578 (Y13); 100579 (Y14); 100580 (Y15); 111028 (Y16); 111029 (Y17); 111030 (Y18); 111031 (Y19); 111032 (Y20)
• First Posted: Feb 10, 2006
• Last Update Posted: Jul 23, 2018
• Last Verified: Sep 1, 2016

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

Study Results

Participant Flow

Recruitment Details	Participant Flow and Baseline measures are given for the Month 192 (Year 16) time point in order to account for all subjects participating in this long-term follow-up study. Note that not all subjects returned and participated in each of the intermediate follow-up time points.
Pre-assignment Detail	The Long-Term (LT) Total Cohort included all subjects who returned for the follow-up and who belonged to the Total Cohort in the primary study.The Long Term According-to-Protocol (LT-ATP) cohort for immunogenicity included subjects who returned for the follow-up and who were included in the ATP cohort for immunogenicity of the primary study.

Arm/Group Title	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
Period Title: Overall Study
STARTED	78
COMPLETED	78
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
Overall Participants	78
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.3 (7.00)
Sex: Female, Male (Count of Participants)
Female	56 71.8%
Male	22 28.2%

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). The laboratory assay was changed at Year 11, thus the blood samples were with both the old and the new assay for the sake of bridging.
Time Frame	At Years 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 after the first vaccine dose of the 2-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	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
Measure Participants	53
Year 11 Old Assay Method (N=43)	593.6
Year 11 New Assay Method (N=46)	297.4
Year 12 (N=42)	363.2
Year 13 (N=50)	287.7
Year 14 (N=46)	270.4
Year 15 (N=41)	290.3
Year 16 (N=53)	242.3
Year 17 (N=45)	277.9
Year 18 (N=37)	301.7
Year 19 (N=26)	226.5
Year 20 (N=34)	311.8

2. Primary Outcome

Title	Anti-hepatitis A Virus (Anti-HAV) Antibody Concentration
Description	Concentrations given as GMC expressed as mIU/mL.
Time Frame	Before the additional dose, 14 days and 30 days after the additional dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort, only on subjects who received an additional vaccine dose during the current long-term follow-up study. If a subject became seronegative (< 15 mIU/mL) at any of the long-term blood sampling timepoint, he/she was offered an additional vaccine dose.

Arm/Group Title	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
Measure Participants	2
Subject 1 (pre-additional dose)	23
Subject 1 (14 days post-additional dose)	702
Subject 1 (30 days post-additional dose)	836
Subject 2 (pre-additional dose)	24
Subject 2 (14 days post-additional dose)	6107
Subject 2 (30 days post-additional dose)	5939

3. Primary Outcome

Title	Number of Seropositive Subjects for Anti-HAV Antibodies.
Description	Seropositivity for anti-HAV antibodies defined as antibody concentrations ≥ 15 mIU/mL for Year 11 to Year 20 time points. The laboratory assay was changed at Year 11, thus the blood samples were with both the old and the new assay for the sake of bridging.
Time Frame	From Year 11 to Year 20

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	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
Measure Participants	53
Year 11 Old Assay Method (N=43)	43
Year 11 New Assay Method (N=46)	46
Year 12 (N=42)	42
Year 13 (N=50)	50
Year 14 (N=46)	46
Year 15 (N=41)	41
Year 16 (N=53)	53
Year 17 (N=45)	45
Year 18 (N=37)	37
Year 19 (N=26)	26
Year 20 (N=34)	34

4. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAE) Assessed by the Investigators as Related to Vaccination or to Study Procedures or Lack of Efficacy
Description	An 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
Time Frame	Years 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 after the first vaccine dose of the 2-dose primary vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort which included all subjects who returned to the follow-up study and who had received at least 1 dose of the vaccine in the primary study.

Arm/Group Title	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
Measure Participants	78
Year 11 (N=64)	0
Year 12 (N=60)	0
Year 13 (N=71)	0
Year 14 (N=66)	0
Year 15 (N=63)	0
Year 16 (N=78)	0
Year 17 (N=63)	0
Year 18 (N=52)	0
Year 19 (N=45)	0
Year 20 (N=50)	0

5. Secondary Outcome

Title	Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms
Description	Solicited local symptoms assessed include pain, redness and swelling. Grade 3 pain = symptom that prevented normal activities. Grade 3 redness and swelling = redness or swelling above 30 mm and persisting more than 24 hours. Any = incidence of a particular symptom regardless of intensity.
Time Frame	During the 4-day (Day 0-3) follow-up period after additional vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort, only on subjects who received an additional vaccine dose during the current long-term follow-up study. If a subject became seronegative (< 15 mIU/mL) at any of the long-term blood sampling timepoint, he/she was offered an additional vaccine dose.

Arm/Group Title	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
Measure Participants	2
Any Pain	1
Any Redness	0
Any Swelling	0
Grade 3 Pain	0
Grade 3 Redness > 30 mm	0
Grade 3 Swelling > 30 mm	0

6. Secondary Outcome

Title	Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms
Description	Solicited general symptoms assessed included fatigue, fever, gastrointestinal symptoms, and headache.
Time Frame	During the 4-day (Day 0-3) follow-up period after additional vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort, only on subjects who received an additional vaccine dose during the current long-term follow-up study. If a subject became seronegative (< 15 mIU/mL) at any of the long-term blood sampling timepoint, he/she was offered an additional vaccine dose.

Arm/Group Title	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
Measure Participants	2
Any, Grade 3 and Related Fatigue	0
Any, Grade 3 and Related Fever	0
Any, Grade 3 and Related Gastrointestinal	0
Any, Grade 3 and Related Headache	0

7. Secondary Outcome

Title	Number of Subjects Reporting Any, Grade 3 and Related 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. Grade AE = produced significant impairment of functioning or incapacitation and was a definite hazard to the subject's health. Related AE = assessed by the investigator as related to the study vaccination.
Time Frame	During the 30-day follow-up period after additional vaccination (for subjects who received the additional vaccine dose between Year 11 and 15)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort, only on subjects who received an additional vaccine dose during the current long-term follow-up study. If a subject became seronegative (< 15 mIU/mL) at any of the long-term blood sampling timepoint, he/she was offered an additional vaccine dose.

Arm/Group Title	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
Measure Participants	2
Any AE(s)	1
Grade 3 AE(s)	0
AE(s) Related	0

8. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAE)
Description	An 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.
Time Frame	During the follow-up period after additional vaccination up to Year 20

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term Total cohort, only on subjects who received an additional vaccine dose during the current long-term follow-up study. If a subject became seronegative (< 15 mIU/mL) at any of the long-term blood sampling timepoint, he/she was offered an additional vaccine dose.

Arm/Group Title	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
Measure Participants	2
Number [Subjects]	0

Adverse Events

Time Frame	Until year 20 for SAEs and within 4-days after additional vaccination for other AEs. During the 30-day (Day 0 to Day 29) follow-up period after additional vaccination.
Adverse Event Reporting Description	Analyses were performed on the Long-Term (LT) Total Cohort including subjects who returned for the follow-up and who belonged to the Total Cohort in the primary study. For the other AEs only subjects receiving an additional dose were included. Therefore the number of subjects at risk is not consistent with the LT Total Cohort.
Arm/Group Title	Havrix Group
Arm/Group Description	Subjects who received 2 doses of Havrix™ (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 Havrix Group for data analyses during the long term follow-up
All Cause Mortality
	Havrix Group
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Havrix Group
	Affected / at Risk (%)	# Events
Total	0/78 (0%)
Other (Not Including Serious) Adverse Events
	Havrix Group
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
General disorders
Pain	1/2 (50%)
Infections and infestations
Influenza like illness	1/2 (50%)

Limitations/Caveats

[Not Specified]

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.