Trial Outcomes & Findings for Long-term Persistence Study in Healthy Adults Previously Vaccinated With Twinrix Adult (NCT NCT01037114)

Results Overview

Concentrations were expressed as GMCs in mIU/mL.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

50 participants

Primary outcome timeframe

At Years 16, 17, 18, 19 and 20.

Results posted on

2019-02-01

Participant Flow

1 subject who was not able to come at Year (Y) 16 entered the study at Y17. At Y16, 1 subject was administered a challenge dose of Engerix-B vaccine and at Y18 and Y20, 2 subjects were administered a challenge dose of Havrix vaccine. None of the subjects received a challenge dose at Y17 and Y19.

Participant milestones

Participant milestones
Measure	Twinrix Group Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Year 16 STARTED	49
Year 16 COMPLETED	49
Year 16 NOT COMPLETED	0
Year 17 STARTED	48
Year 17 COMPLETED	48
Year 17 NOT COMPLETED	0
Year 18 STARTED	44
Year 18 COMPLETED	44
Year 18 NOT COMPLETED	0
Year 19 STARTED	45
Year 19 COMPLETED	45
Year 19 NOT COMPLETED	0
Year 20 STARTED	45
Year 20 COMPLETED	44
Year 20 NOT COMPLETED	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Twinrix Group Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Year 20 Others	1

Baseline Characteristics

Number of participants at year 16 are equal to the overall number of participants analyzed, which represents the highest number of participants from year 16 to year 20.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Twinrix Group n=49 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Age, Continuous	41.7 Years STANDARD_DEVIATION 5.9 • n=45 Participants • Number of participants analyzed represents all subjects who returned at the year 20 annual time point.
Sex: Female, Male Female	36 Participants n=45 Participants • Number of participants analyzed represents all subjects who returned at the year 20 annual time point.
Sex: Female, Male Male	9 Participants n=45 Participants • Number of participants analyzed represents all subjects who returned at the year 20 annual time point.

PRIMARY outcome

Timeframe: At Years 16, 17, 18, 19 and 20.

Population: The analysis was performed on the long-term according-to-protocol (LT ATP) cohort for immunogenicity which included subjects who returned at a particular blood sampling time point, who were included in the ATP analysis for the primary study and who did not receive hepatitis A or B vaccination that was not specified in the protocol.

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.

Outcome measures

Outcome measures
Measure	Twinrix Group n=28 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
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) anti-HAV >= 15 mIU/mL [at Year 16] (N=28)	28 Subjects
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) anti-HBs >= 6.2 mIU/mL [at Year 16] (N=28)	27 Subjects
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) anti-HBs >= 10 mIU/mL [at Year 16] (N=28)	27 Subjects
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) anti-HAV >= 15 mIU/mL [at Year 17] (N=27)	26 Subjects
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) anti-HBs >= 6.2 mIU/mL [at Year 17] (N=27)	25 Subjects
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) anti-HBs >= 10 mIU/mL [at Year 17] (N=27)	25 Subjects
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) anti-HAV >= 15 mIU/mL [at Year 18] (N=25)	25 Subjects
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) anti-HBs >= 6.2 mIU/mL [at Year 18] (N=25)	23 Subjects
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) anti-HBs >= 10 mIU/mL [at Year 18] (N=25)	23 Subjects
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) anti-HAV >= 15 mIU/mL [at Year 19] (N=25)	24 Subjects
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) anti-HBs >= 6.2 mIU/mL [at Year 19] (N=25)	23 Subjects
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) anti-HBs >= 10 mIU/mL [at Year 19] (N=25)	23 Subjects
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) anti-HAV >= 15 mIU/mL [at Year 20] (N=25)	24 Subjects
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) anti-HBs >= 6.2 mIU/mL [at Year 20] (N=25)	23 Subjects
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) anti-HBs >= 10 mIU/mL [at Year 20] (N=25)	23 Subjects

PRIMARY outcome

Timeframe: At Years 16, 17, 18, 19 and 20.

Population: The analysis was performed on the long-term according-to-protocol (LT ATP) cohort for immunogenicity which included subjects who returned at a particular blood sampling time point, who were included in the ATP analysis for the primary study and who did not receive hepatitis A or B vaccination that was not specified in the protocol.

Concentrations were expressed as GMCs in mIU/mL.

Outcome measures

Outcome measures
Measure	Twinrix Group n=28 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) anti-HAV [at Year 16] (N=28)	262.5 mIU/mL Interval 189.9 to 362.9
Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) anti-HBs [at Year 16] (N=28)	79.9 mIU/mL Interval 45.2 to 141.0
Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) anti-HAV [at Year 17] (N=27)	369.4 mIU/mL Interval 257.9 to 529.1
Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) anti-HBs [at Year 17] (N=27)	71.7 mIU/mL Interval 39.6 to 129.8
Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) anti-HAV [at Year 18] (N=25)	237.7 mIU/mL Interval 163.7 to 345.4
Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) anti-HBs [at Year 18] (N=25)	61.3 mIU/mL Interval 36.8 to 102.3
Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) anti-HAV [at Year 19] (N=25)	234.3 mIU/mL Interval 159.0 to 345.5
Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) anti-HBs [at Year 19] (N=25)	59.7 mIU/mL Interval 35.1 to 101.4
Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) anti-HAV [at Year 20] (N=25)	229.3 mIU/mL Interval 157.1 to 334.6
Anti-HAV and Anti-HBs Geometric Mean Concentrations (GMCs) anti-HBs [at Year 20] (N=25)	57.7 mIU/mL Interval 33.6 to 99.1

SECONDARY outcome

Timeframe: Before, 14 days and one month (30 days) after the challenge dose of Engerix-B.

Population: The analysis was performed on the long-term according-to-protocol (LT ATP) cohort for immunogenicity which included subjects who returned at the blood sampling time point for whom results were available and who received a challenge dose of Engerix-B vaccine because their anti-HBs antibody concentrations were \< 10 mIU/mL.

Concentration was given in mIU/mL. Only 1 subject was eligible for the challenge dose of Engerix-B at the Year 16 time point. Therefore the values for this subject are given without a measure of dispersion.

Outcome measures

Outcome measures
Measure	Twinrix Group n=1 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Anti-HBs Concentrations After the Challenge Dose of Engerix-B before challenge dose at Year 16	7.86 mIU/mL
Anti-HBs Concentrations After the Challenge Dose of Engerix-B 14 days after challenge dose at Year 16	50640.0 mIU/mL
Anti-HBs Concentrations After the Challenge Dose of Engerix-B 1 month (Day 30) after challenge dose at Year 16	31442.0 mIU/mL

SECONDARY outcome

Timeframe: Before, 14 days and one month (30 days) after the challenge dose of Havrix.

Population: The analysis was performed on the long-term according-to-protocol (LT ATP) cohort for immunogenicity which included subjects who returned at the blood sampling time point for whom results were available and who received a challenge dose of Havrix vaccine because their anti-HAV antibody concentrations were \< 15 mIU/mL.

Concentration was given in mIU/mL. Only 2 subjects were eligible for the challenge dose of Havrix, one at Year 18 and another at Year 20 time point. Therefore the values for these subject are given without a measure of dispersion.

Outcome measures

Outcome measures
Measure	Twinrix Group n=2 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Anti-HAV Concentrations After the Challenge Dose of Havrix before challenge dose at Year 18	25 mIU/mL
Anti-HAV Concentrations After the Challenge Dose of Havrix 14 days after challenge dose at Year 18	3421 mIU/mL
Anti-HAV Concentrations After the Challenge Dose of Havrix 1 month (Day 30) after challenge dose at Year 18	3389 mIU/mL
Anti-HAV Concentrations After the Challenge Dose of Havrix before challenge dose at Year 20	19 mIU/mL
Anti-HAV Concentrations After the Challenge Dose of Havrix 14 days after challenge dose at Year 20	1096 mIU/mL
Anti-HAV Concentrations After the Challenge Dose of Havrix 1 month (Day 30) after challenge dose at Year 20	1060 mIU/mL

SECONDARY outcome

Timeframe: 30 days after the challenge dose of Engerix-B.

Population: The analysis was performed on the long-term according-to-protocol (LT ATP) cohort for immunogenicity which included subjects who returned at the blood sampling time point for whom results were available and who received a challenge dose of Engerix-B vaccine because their anti-HBs antibody concentrations were \< 10 mIU/mL.

At Year 16 only 1 subject was eligible for the challenge dose of Engerix-B. Anti-HBs anamnestic response to the challenge dose was defined as: * Anti-HBs antibody concentrations \>= 10 mIU/mL at one month post-challenge dose in subjects seronegative at the pre-challenge time point. * At least a 4-fold increase in anti-HBs antibody concentrations, at one month post-challenge dose in subjects seropositive at the pre-challenge time point.

Outcome measures

Outcome measures
Measure	Twinrix Group n=1 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Number of Subjects With Anamnestic Response to the Challenge Dose of Engerix-B	1 Subjects

SECONDARY outcome

Timeframe: 30 days after the challenge dose of Havrix.

Population: The analysis was performed on the long-term according-to-protocol (LT ATP) cohort for immunogenicity which included subjects who returned at the blood sampling time point for whom results were available and who received a challenge dose of Havrix vaccine because their anti-HAV antibody concentrations were \< 15 mIU/mL.

Anti-HAV anamnestic response to the challenge dose was defined as: * Anti-HAV antibody concentrations ≥ 15 mIU/mL at one month post-challenge dose, in subjects seronegative at the pre-challenge time point. * At least a 2-fold increase in anti-HAV antibody concentrations one month after the challenge dose, in subjects having anti-HAV antibody concentrations ≥ 100 mIU/mL at the pre-challenge time point. * Or at least a 4-fold increase in anti-HAV antibody concentrations one month after the challenge dose, in seropositive subjects having anti-HAV antibody concentrations \< 100 mIU/mL at the pre-challenge time-point.

Outcome measures

Outcome measures
Measure	Twinrix Group n=2 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Number of Subjects With Anamnestic Response to the Challenge Dose of Havrix	2 subjects

SECONDARY outcome

Timeframe: 31 days (Days 0-30) after the challenge dose of Engerix-B and Havrix.

Population: The analysis was performed on the long-term total cohort which included subjects who returned at the blood sampling time point for whom results were available and who received a challenge dose of Engerix-B vaccine or Havrix.

At Year 16, 1 subject was administered a challenge dose of Engerix-B and at Y18 and Y20, 2 subjects were administered a challenge dose of Havrix. 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.

Outcome measures

Outcome measures
Measure	Twinrix Group n=3 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Number of Subjects Reporting Unsolicited Adverse Events (AEs)	1 Subjects

SECONDARY outcome

Timeframe: During the 31-day (Days 0-30) follow-up period after the Engerix-B challenge dose.

Population: The analysis was performed on the long-term total cohort which included subjects who returned at the blood sampling time point for whom results were available and who received a challenge dose of Engerix-B vaccine because their anti-HBs antibody concentrations were \< 10 mIU/mL.

Only 1 subject received a challenge dose at Year 16 of Engerix-B. 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.

Outcome measures

Outcome measures
Measure	Twinrix Group n=1 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Number of Subjects With Serious Adverse Events (SAEs)	0 Subjects

SECONDARY outcome

Timeframe: During the 31-day (Days 0-30) follow-up period after the Havrix challenge dose.

Population: The analysis was performed on the long-term total cohort which included subjects who returned at the blood sampling time point for whom results were available and who received a challenge dose of Havrix vaccine because their anti-HAV antibody concentrations were \< 15 mIU/mL.

One subject received a challenge dose of Havrix at Year 18 and another at Year 20. Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

Outcome measures

Outcome measures
Measure	Twinrix Group n=2 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Number of Subjects With Serious Adverse Events (SAEs)	0 subjects

SECONDARY outcome

Timeframe: Up to Year 20.

Population: The LT Total cohort included all subjects who returned at each annual time point and who belonged to the Total cohort in the primary study.

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.

Outcome measures

Outcome measures
Measure	Twinrix Group n=49 Participants Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Number of Subjects Reporting SAEs Related to Study Participation or a Concurrent GSK Medication	0 Subjects

Adverse Events

Twinrix Group

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Twinrix Group n=3 participants at risk；n=49 participants at risk Subjects who received 3 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 first long-term follow-up NCT00289718 and this long-term follow-up. A challenge dose of the Havrix or Engerix-B vaccines can be administered in this study based on serology results at each time point.
Musculoskeletal and connective tissue disorders Back pain	33.3% 1/3 • Number of events 1 • 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. As no challenge dose was administered during Years 17 and 19 time points, SAEs and other adverse events were not assessed. At Year 16, 1 subject was administered a challenge dose of Engerix-B vaccine and at Years 18 and 20, 2 subjects were administered a challenge dose of Havrix vaccine, 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.

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER