Antibody Persistence & Immune Memory in Healthy Adults Previously Vaccinated With Twinrix Adult

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01000324
• Collaborator: (none)
• Enrollment: 44
• Location: 1
• Arm: 1
• Duration (Months): 56.6
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This study will evaluate the persistence of the immune response to HAV (Hepatitis A Virus) antigens and HBs (Hepatitis B surface) antigens in healthy adults previously vaccinated with GlaxoSmithKline (GSK) Biologicals' Twinrix Adult. The subjects will be invited for blood sampling 16, 17, 18, 19 and 20 years after vaccination to evaluate the antibody persistence. For subjects in whom low circulating antibodies are detected, the presence of immune memory against hepatitis A & B antigens will be investigated by the administration of a challenge dose of the appropriate vaccine (Havrix and/or Engerix-B) at the next planned visit.

No new subjects will be recruited during this study.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis A; Hepatitis B	Procedure: Blood sampling; Biological: Engerix-B; Biological: Havrix	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: An Open Single Centre Study to Evaluate the Long-term Antibody Persistence and Immune Memory Between 16 and 20 Years After the Primary Study HAB-028 (208127/021) in Which Healthy Adults Were Vaccinated With Twinrix Adult Following a Three-dose Schedule.
• Study Start Date: Nov 6, 2009
• Actual Primary Completion Date: Jul 25, 2014
• Actual Study Completion Date: Jul 25, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Twinrix Group Pooled group of subjects from groups 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

Procedure: Blood sampling; Blood sampling at Year 16, 17, 18, 19 and 20 and at the time of challenge dose administration and 14 days and one month after challenge dose administration (if challenge dose needed).; Biological: Engerix-B; Engerix-B will be administered to subjects who are not seroprotected against hepatitis B; Biological: Havrix; Havrix will be administered to subjects who are seronegative for anti-HAV antibodies

Outcome Measures

Primary Outcome Measures

1. Number of Subjects Seropositive for Anti-hepatitis A Virus Antibodies (Anti-HAV) and Anti-hepatitis B Surface Antigen (Anti-HBs) Antibodies and With Anti-HBs Antibody Concentrations >= 10 Milliinternational Units Per Milliliter (mIU/mL) [At Years 16, 17, 18, 19 and 20.]

   Seropositivity for anti-HAV antibodies is defined as antibody concentrations >= 15 milliinternational units per milliliter (mIU/mL). Seropositivity for anti-HBs antibodies is defined as antibody concentrations >= 6.2 mIU/mL.

2. Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) [At Years 16, 17, 18, 19 and 20.]

   Concentrations were expressed as GMCs in mIU/mL.

Secondary Outcome Measures

1. Number of Subjects With Immune Response to the Challenge Vaccine Antigen [Before, 14 days and one month after the challenge dose at Year 19.]

   None of the subjects received a challenge dose at Years 16, 17, 18 and 20 while, one subject received the challenge dose at Year 19.

2. Anti-hepatitis B Virus (Anti-HBs) Antibody Concentration [At Year 18, 14 days and 30 days post challenge dose (Year 19).]

   Concentrations are given as Geometric Mean Concentrations (GMCs) expressed as mIU/mL.

3. Number of Subjects Reporting Unsolicited Adverse Events (AE) [During the 31-day (Day 0 to 30) period after administration of the challenge dose at Year 19.]

   An unsolicited AE was defined as any AE (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as occurrence of any unsolicited symptom regardless of intensity grade or relation to vaccination.

4. Number of Subjects Reporting Serious Adverse Events (SAEs) [During the 31-day (Day 0 to 30) period after administration of the challenge dose at Year 19.]

   A serious adverse event was 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.

5. Number of Subjects Reporting Serious Adverse Events (SAEs) [Up to Year 20.]

   A serious adverse event is any untoward medical occurrence that: resulted in death, was life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, or was a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above. 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: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

All subjects must satisfy the following criteria at entry into each of the long-term follow-up visits:

• Subjects who the investigator believes that they can and will comply with the requirements of the protocol should be enrolled in the study.

• A male or female who received the complete primary vaccination course in the primary study Hepatitis A and B vaccine (HAB), HAB-028 (208127/021).

• Written informed consent obtained from the subject.

All subjects must satisfy the following criteria at entry into the challenge dose phase:

• Subjects who the investigator believes that they can and will comply with the requirements of the protocol.

• A male or female who received the complete primary vaccination course in the primary study HAB-028 (208127/021).

• Written informed consent obtained from the subject.

• Subjects who participated in the long-term follow-up (LTFU) phase of the HAB-028 (208127/021) study and for whom the antibody concentrations were below the cut-off at the last available follow-up time-point.

• Female subjects of non-childbearing potential may be enrolled in the study.

• Female subjects of childbearing potential may be enrolled in the study, if the subject:

• has practiced adequate contraception for 30 days prior to vaccination, and

• has a negative pregnancy test on the day of vaccination, and

• has agreed to continue adequate contraception for two months after the administration of the challenge dose.

Exclusion Criteria:

The following criteria should be checked before entry into each of the long-term follow-up visits. If any exclusion criterion applies, the subject must not be included in the study:

• Use of any investigational or non-registered product within 30 days prior to blood sampling.

• Administration of a hepatitis A, hepatitis B or combined hepatitis A and B vaccine outside the study procedures, since the primary study HAB-028 (208127/021).

• History of hepatitis A or hepatitis B infection since the primary study HAB-028 (208127/021).

• Administration of hepatitis A or hepatitis B immunoglobulins and/or any blood products within three months prior to blood sampling.

The following criteria should be checked before the challenge dose is administered. If any apply, the subject must not be included in the challenge dose phase:

• Use of any investigational or non-registered product within 30 days prior to study start or planned use during the study.

• Administration of a hepatitis A, hepatitis B or combined hepatitis A and B vaccine between the last LTFU visit and the challenge dose visit.

• History of hepatitis A or hepatitis B infection between the last LTFU visit and the challenge dose visit.

• History of anaphylactic reactions following the administration of vaccines.

• History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.

• Acute disease and/or fever at the time of enrolment.

• Pregnant or lactating female.

• Female planning to become pregnant or planning to discontinue contraceptive precautions.

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

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01000324
• Other Study ID Numbers: 112267
• First Posted: Oct 23, 2009
• Last Update Posted: Sep 4, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: Hepatitis A; Hepatitis B
• Additional relevant MeSH terms: Hepatitis A; Hepatitis B; Hepatitis

Study Results

Participant Flow

Recruitment Details	Subjects who entered the study at Years 16, 17, 18, 19 and 20 time points were subjects who completed the primary study and who returned for blood sampling at the considered time point. At Year 19 time point, one subject was given a challenge dose of Engerix.

Arm/Group Title	Twinrix Group
Arm/Group Description	Pooled group of subjects from groups 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 16
STARTED	40
COMPLETED	40
NOT COMPLETED	0
Period Title: Year 16
STARTED	32
COMPLETED	32
NOT COMPLETED	0
Period Title: Year 16
STARTED	29
COMPLETED	29
NOT COMPLETED	0
Period Title: Year 16
STARTED	28
COMPLETED	28
NOT COMPLETED	0
Period Title: Year 16
STARTED	28
COMPLETED	28
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Twinrix Group
Arm/Group Description	Pooled group of subjects from groups 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	40
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	35.5 (2.87)
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	36.3 (1.52)
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	37.7 (3.25)
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	38.8 (3.31)
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.6 (1.4)
Sex: Female, Male (Count of Participants)
Female	29 72.5%
Male	11 27.5%
Sex: Female, Male (Count of Participants)
Female	25 62.5%
Male	7 17.5%
Sex: Female, Male (Count of Participants)
Female	22 55%
Male	7 17.5%
Sex: Female, Male (Count of Participants)
Female	21 52.5%
Male	7 17.5%
Sex: Female, Male (Count of Participants)
Female	23 57.5%
Male	5 12.5%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects Seropositive for Anti-hepatitis A Virus Antibodies (Anti-HAV) and Anti-hepatitis B Surface Antigen (Anti-HBs) Antibodies and With Anti-HBs Antibody Concentrations >= 10 Milliinternational Units Per Milliliter (mIU/mL)
Description	Seropositivity for anti-HAV antibodies is defined as antibody concentrations >= 15 milliinternational units per milliliter (mIU/mL). Seropositivity for anti-HBs antibodies is defined as antibody concentrations >= 6.2 mIU/mL.
Time Frame	At Years 16, 17, 18, 19 and 20.

Outcome Measure Data

Analysis Population Description

The analysis was performed on the Long-Term (LT) According-to-Protocol (ATP) cohort for analysis of immunogenicity. They were included in the ATP analysis for the primary study, did not receive hepatitis A or B (hep A/B) vaccination that was not specified in the protocol and were not eliminated for abnormal increase of antibody concentrations.

Arm/Group Title	Twinrix Group
Arm/Group Description	Pooled group of subjects from groups 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	23
Anti-HAV >=15 mIU/mL [at Year 16] (N=23)	23
anti-HBs >= 6.2 mIU/mL [at Year 16] (N=23)	20
anti-HBs >= 10 mIU/mL [at Year 16] (N=23)	20
anti-HAV >= 15 mIU/mL [at Year 17] (N=19)	19
anti-HBs >= 6.2 mIU/mL [at Year 17] (N=19)	17
anti-HBs >= 10 mIU/mL [at Year 17] (N=19)	17
anti-HAV >= 15 mIU/mL [at Year 18] (N=10)	10
anti-HBs >= 6.2 mIU/mL [at Year 18] (N=10)	9
anti-HBs >= 10 mIU/mL [at Year 18] (N=10)	9
anti-HAV >= 15 mIU/mL [at Year 19] (N=17)	17
anti-HBs >= 6.2 mIU/mL [at Year 19] (N=18)	17
anti-HBs >= 10 mIU/mL [at Year 19] (N=18)	17
anti-HAV >= 15 mIU/mL [at Year 20] (N=18)	18
anti-HBs >= 6.2 mIU/mL [at Year 20] (N=18)	17
anti-HBs >= 10 mIU/mL [at Year 20] (N=18)	17

2. Primary Outcome

Title	Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs)
Description	Concentrations were expressed as GMCs in mIU/mL.
Time Frame	At Years 16, 17, 18, 19 and 20.

Outcome Measure Data

Analysis Population Description

The analysis was performed on the Long-Term (LT) According-to-Protocol (ATP) cohort for analysis of immunogenicity.They were included in the ATP analysis for the primary study, did not receive hepatitis A or B vaccination that was not specified in the protocol and were not eliminated for abnormal increase of antibody concentrations.

Arm/Group Title	Twinrix Group
Arm/Group Description	Pooled group of subjects from groups 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	23
anti-HAV [at Year 16] (N=23)	614.2
anti-HBs [at Year 16] (N=23)	138.7
anti-HAV [at Year 17] (N=19)	479.2
anti-HBs [at Year 17] (N=19)	165.1
anti-HAV [at Year 18] (N=10)	653.2
anti-HBs [at Year 18] (N=10)	278.3
anti-HAV [at Year 19] (N=17)	728.7
anti-HBs [at Year 19] (N=18)	198.4
anti-HAV [at Year 20] (N=18)	511.9
anti-HBs [at Year 20] (N=18)	195.8

3. Secondary Outcome

Title	Number of Subjects With Immune Response to the Challenge Vaccine Antigen
Description	None of the subjects received a challenge dose at Years 16, 17, 18 and 20 while, one subject received the challenge dose at Year 19.
Time Frame	Before, 14 days and one month after the challenge dose at Year 19.

Outcome Measure Data

Analysis Population Description

The analysis was performed on LT Total cohort that included all subjects who returned at each annual time point and who belonged to the Total Vaccinated cohort in the primary study.

Arm/Group Title	Twinrix Group
Arm/Group Description	Pooled group of subjects from groups 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	1
Number [Subjects]	1

4. Secondary Outcome

Title	Anti-hepatitis B Virus (Anti-HBs) Antibody Concentration
Description	Concentrations are given as Geometric Mean Concentrations (GMCs) expressed as mIU/mL.
Time Frame	At Year 18, 14 days and 30 days post challenge dose (Year 19).

Outcome Measure Data

Analysis Population Description

The analysis was performed on LT Total cohort that included all subjects who returned at each annual time point and who belonged to the Total Vaccinated cohort in the primary study.

Arm/Group Title	Twinrix Group
Arm/Group Description	Pooled group of subjects from groups 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	1
[Subject 1; at year 18]	13.26
[Subject 1; 14 days post challenge dose]	21926.00
[Subject 1; 30 days post challenge dose]	12736.00

5. Secondary Outcome

Title	Number of Subjects Reporting Unsolicited Adverse Events (AE)
Description	An unsolicited AE was defined as any AE (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as occurrence of any unsolicited symptom regardless of intensity grade or relation to vaccination.
Time Frame	During the 31-day (Day 0 to 30) period after administration of the challenge dose at Year 19.

Outcome Measure Data

Analysis Population Description

The analysis was performed on LT Total cohort that included all subjects who returned at each annual time point and who belonged to the Total Vaccinated cohort in the primary study

Arm/Group Title	Twinrix Group
Arm/Group Description	Pooled group of subjects from groups 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	1
Number [Subjects]	1

6. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs)
Description	A serious adverse event was 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 31-day (Day 0 to 30) period after administration of the challenge dose at Year 19.

Outcome Measure Data

Analysis Population Description

The analysis was performed on LT Total cohort that included all subjects who returned at each annual time point and who belonged to the Total Vaccinated cohort in the primary study.

Arm/Group Title	Twinrix Group
Arm/Group Description	Pooled group of subjects from groups 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	1
Number [Subjects]	0

7. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs)
Description	A serious adverse event is any untoward medical occurrence that: resulted in death, was life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, or was a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above. 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	Up to Year 20.

Outcome Measure Data

Analysis Population Description

The analysis was performed on LT Total cohort that included all subjects who returned at each annual time point and who belonged to the Total Vaccinated cohort in the primary study.

Arm/Group Title	Twinrix Group
Arm/Group Description	Pooled group of subjects from groups 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	40
Number [Subjects]	0

Adverse Events

Time Frame	SAEs: During the 31-day (Days 0 to 30) follow-up period after the challenge dose and from the beginning of the long term follow-up to Year 20; Unsolicited symptoms: During the 31-day (Days 0 to 30) follow-up period after the challenge dose.
Adverse Event Reporting Description	As no challenge dose was administered during Years 16, 17, 18 and 20 time points, SAEs and other adverse events were not assessed. 1 subject received the challenge dose at Year 19 for whom the SAEs and other adverse events were assessed during the 31 day period post challenge dose. SAEs were also collected for the entire safety follow-up.
Arm/Group Title	Twinrix Group
Arm/Group Description	Pooled group of subjects from groups 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	0/40 (0%)
Serious Adverse Events
	Twinrix Group
	Affected / at Risk (%)	# Events
Total	0/40 (0%)
Other (Not Including Serious) Adverse Events
	Twinrix Group
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Musculoskeletal and connective tissue disorders
Musculoskeletal stiffness	1/1 (100%)	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/1 (100%)	1

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 partial or complete retesting/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.