Long Term Follow-up Study at Years 2, 3, 4 and 5 Where 2 Dosing Schedules of the Combined Hepatitis A and B Vaccine Were Compared

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00197184
• Collaborator: (none)
• Enrollment: 276
• Locations: 7
• Arms: 2
• Duration (Months): 4.3
• Patients Per Site: 39.4
• Patients Per Site Per Month: 9.2

Study Details

Study Description

Brief Summary

To evaluate the persistence of anti-hepatitis A virus (HAV) and anti-hepatitis B surface antigen (HBs) antibodies up to 2, 3, 4 and 5 years after administration of the first dose of the study vaccine.

The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

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

Detailed Description

Open, randomised, self-contained, multicentric, multinational, long-term antibody persistence studies. Immune persistence was compared between subjects who received either two dose or three doses of GSK Biologicals combined hepatitis A and hepatitis B vaccine. The long-term follow-up studies involved taking blood samples at approximately 2, 3, 4 and 5 years after the primary vaccination of combined hepatitis A and B vaccine to assess antibody persistence. No additional subjects will be recruited during the long term follow-up period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 276 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Evaluate the Persistence of Immune Response of GSK Biologicals' Twinrix™ Vaccine, Administered According to a 0,6 Month Schedule and a 0,1,6 Month Schedule, in Healthy Children Aged Between 1-11 Years at the Time of First Vaccine Dose
• Study Start Date: Nov 1, 2003
• Actual Primary Completion Date: Mar 10, 2004
• Actual Study Completion Date: Mar 10, 2004

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Twinrix Junior Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).	Biological: Twinrix™ Junior; Intramuscular injection in the left deltoid, 3 doses, junior formulation in primary study.; Other Names: Combined hepatitis A and B vaccine
Active Comparator: Twinrix Adult Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Biological: Twinrix™ Adult; Intramuscular injection in the left deltoid, 2 doses, Adult formulation in primary study.; Other Names: Combined hepatitis A and B vaccine

Outcome Measures

Primary Outcome Measures

1. Anti-hepatitis A (HAV) Antibody Concentrations [Year 2 (Month 24), Year 3 (Month 36), Year 4 (Month 48) and Year 5 (Month 60)]

   Geometric mean concentration for anti-HAV antibodies expressed as Milli-International Units per milliliter (mIU/mL)

2. Anti-hepatitis B (HBs) Antibody Concentrations [Year 2 (Month 24), Year 3 (Month 36), Year 4 (Month 48) and Year 5 (Month 60)]

   Geometric mean concentration for anti-HBs antibodies expressed as Milli-International Units per milliliter (mIU/mL).

3. Anti-HAV Antibody Concentrations in Subjects Receiving the Additional Vaccine Dose. [Before and one month after additional vaccination]

   Any subjects becoming seronegative for anti-HAV antibodies (i.e. titres < 15 mIU/ml) at any long term time point, were to receive an additional vaccine dose administered between 6 to 12 months after Year 5 time point.

4. Anti-HBs Antibody Concentrations in Subjects Receiving the Additional Vaccine Dose. [Before and One month after additional vaccination]

   Subjects losing seroprotective anti-HBs antibody titres (i.e. titres < 10 mIU/ml) at any long term time point, received an Engerix challenge dose. The table presents the geometric mean concentrations for anti-HBs antibodies, expressed as Milli-International Units per milliliter (mIU/mL).

Secondary Outcome Measures

1. Number of Subjects Reporting Serious Adverse Events (SAEs) Determined by the Investigator to Have a Causal Relationship to Primary Vaccination or Due to Lack of Vaccine Efficacy. [From last study visit of the primary study up to Year 5 long term follow-up]

   A serious adverse event (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 Receiving an Additional Vaccine Dose and Reporting Solicited Local Symptoms [during the 4-day follow-up period after additional vaccination]

   Solicited local symptoms assessed include pain, redness and swelling at the vaccine injection site. Any= regardless of intensity grade; Grade 3 Pain= spontaneously painful

3. Number of Subjects Receiving an Additional Vaccine Dose and Reporting Solicited General Symptoms. [During the 4-day follow-up period after additional vaccination]

   Solicited general symptoms assessed include fatigue, fever, gastrointestinal symptoms and headache. Any= regardless of intensity grade or relationship to vaccination; grade 3= prevented normal activity; Related= considered by the investigator to be causally related to the vaccination

4. Number of Subjects Receiving an Additional Vaccine Dose and Reporting Unsolicited Adverse Events (AEs). [During the 30-day follow-up period after additional vaccination.]

   An Adverse Event 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.

5. Number of Subjects Receiving an Additional Vaccine Dose and Reporting Any Serious Adverse Events [At least one month after additional vaccination]

   A serious adverse event (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: 3 Years to 13 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Participation in primary study

• Written informed consent obtained before each long term follow up visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	North Adelaide	South Australia	Australia	5006
2	GSK Investigational Site	Carlton	Victoria	Australia	3053
3	GSK Investigational Site	Bruxelles		Belgium	1200
4	GSK Investigational Site	Barcelona		Spain	08042
5	GSK Investigational Site	Blanes (Girona)		Spain	17300
6	GSK Investigational Site	Cerdanyola Del Vallés / Barcelona		Spain	08290
7	GSK Investigational Site	Valencia		Spain	46024

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

• Marshall H, Nolan T, Díez Domingo J, Rombo L, Sokal EM, Marès J, Casanovas JM, Kuriyakose S, Leyssen M, Jacquet JM. Long-term (5-year) antibody persistence following two- and three-dose regimens of a combined hepatitis A and B vaccine in children aged 1-11 years. Vaccine. 2010 Jun 17;28(27):4411-5. doi: 10.1016/j.vaccine.2010.04.040. Epub 2010 Apr 29.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00197184
• Other Study ID Numbers: 208127/132 (EXT Y2); 208127/133 (EXT Y3); 208127/134 (EXT Y4); 208127/137 (EXT Y5); NCT00787449
• First Posted: Sep 20, 2005
• Last Update Posted: Aug 20, 2018
• Last Verified: Oct 1, 2016

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

Study Results

Participant Flow

Arm/Group Title	Twinrix Adult	Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
Period Title: Overall Study
STARTED	139	137
COMPLETED	139	137
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Twinrix Adult	Twinrix Junior	Total
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).	Total of all reporting groups
Overall Participants	139	137	276
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.6 (2.97)	11.2 (3.11)	11.4 (3.04)
Sex: Female, Male (Count of Participants)
Female	59 42.4%	64 46.7%	123 44.6%
Male	80 57.6%	73 53.3%	153 55.4%

Outcome Measures

1. Primary Outcome

Title	Anti-hepatitis A (HAV) Antibody Concentrations
Description	Geometric mean concentration for anti-HAV antibodies expressed as Milli-International Units per milliliter (mIU/mL)
Time Frame	Year 2 (Month 24), Year 3 (Month 36), Year 4 (Month 48) and Year 5 (Month 60)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term According to Protocol cohort for analysis of immunogenicity (LT ATP immunogenicity cohort) which included all subjects that complied with the protocol and for whom data concerning immunogenicity endpoint measures were available for the particular time point measured.

Arm/Group Title	Twinrix Adult	Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
Measure Participants	129	119
At year 2	1122.2	1377.8
At year 3	998.6	1347.1
At year 4	737.5	915.9
At year 5	576.8	698.4

2. Primary Outcome

Title	Anti-hepatitis B (HBs) Antibody Concentrations
Description	Geometric mean concentration for anti-HBs antibodies expressed as Milli-International Units per milliliter (mIU/mL).
Time Frame	Year 2 (Month 24), Year 3 (Month 36), Year 4 (Month 48) and Year 5 (Month 60)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Long Term According to Protocol cohort for analysis of immunogenicity (LT ATP immunogenicity cohort) which included all subjects that complied with the protocol and for whom data concerning immunogenicity endpoint measures were available for the particular time point measured.

Arm/Group Title	Twinrix Adult	Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
Measure Participants	129	119
At year 2	479.9	830.6
At year 3	325.1	695.1
At year 4	270.2	519.7
At year 5	150.2	283.7

3. Primary Outcome

Title	Anti-HAV Antibody Concentrations in Subjects Receiving the Additional Vaccine Dose.
Description	Any subjects becoming seronegative for anti-HAV antibodies (i.e. titres < 15 mIU/ml) at any long term time point, were to receive an additional vaccine dose administered between 6 to 12 months after Year 5 time point.
Time Frame	Before and one month after additional vaccination

Outcome Measure Data

Analysis Population Description

None of the subjects became seronegative for anti-HAV antibodies during the Year 2 to Year 5 long term follow-up. Hence none of the subjects received an additional Havrix dose.

Arm/Group Title	Twinrix Adult	Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
Measure Participants	0	0

4. Primary Outcome

Title	Anti-HBs Antibody Concentrations in Subjects Receiving the Additional Vaccine Dose.
Description	Subjects losing seroprotective anti-HBs antibody titres (i.e. titres < 10 mIU/ml) at any long term time point, received an Engerix challenge dose. The table presents the geometric mean concentrations for anti-HBs antibodies, expressed as Milli-International Units per milliliter (mIU/mL).
Time Frame	Before and One month after additional vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total vaccinated cohort for the challenge dose, including all subjects who received an additional vaccine dose between 6 to 12 months after year 5.

Arm/Group Title	Twinrix Adult	Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
Measure Participants	11	5
Before vaccination	4.9	2.4
Post vaccination	521.3	509.7

5. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs) Determined by the Investigator to Have a Causal Relationship to Primary Vaccination or Due to Lack of Vaccine Efficacy.
Description	A serious adverse event (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	From last study visit of the primary study up to Year 5 long term follow-up

Outcome Measure Data

Analysis Population Description

The analysis was performed on the Long term Total vaccinated cohort wich included all subjects who returned at a specified follow-up study

Arm/Group Title	Twinrix Adult	Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
Measure Participants	139	137
Count of Participants [Participants]	0 0%	0 0%

6. Secondary Outcome

Title	Number of Subjects Receiving an Additional Vaccine Dose and Reporting Solicited Local Symptoms
Description	Solicited local symptoms assessed include pain, redness and swelling at the vaccine injection site. Any= regardless of intensity grade; Grade 3 Pain= spontaneously painful
Time Frame	during the 4-day follow-up period after additional vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total vaccinated cohort for the challenge dose, including all subjects who received an additional vaccine dose between 6 to 12 months after year 5.

Arm/Group Title	Twinrix Adult	Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
Measure Participants	11	5
Pain, any	6 4.3%	0 0%
Pain, grade 3	0 0%	0 0%
Redness, any	1 0.7%	0 0%
Redness, >20mm	0 0%	0 0%
Swelling, any	0 0%	0 0%
Swelling, >20mm	0 0%	0 0%

7. Secondary Outcome

Title	Number of Subjects Receiving an Additional Vaccine Dose and Reporting Solicited General Symptoms.
Description	Solicited general symptoms assessed include fatigue, fever, gastrointestinal symptoms and headache. Any= regardless of intensity grade or relationship to vaccination; grade 3= prevented normal activity; Related= considered by the investigator to be causally related to the vaccination
Time Frame	During the 4-day follow-up period after additional vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total vaccinated cohort for the challenge dose, including all subjects who received an additional vaccine dose between 6 to 12 months after year 5.

Arm/Group Title	Twinrix Adult	Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
Measure Participants	11	5
Fatigue, any	3 2.2%	0 0%
Fatigue, grade 3	0 0%	0 0%
Fatigue, related	3 2.2%	0 0%
Fever (axillary), ≥37°C	0 0%	0 0%
Fever (axillary), >39.5°C	0 0%	0 0%
Fever (axillary), related	0 0%	0 0%
Gastrointestinal, any	2 1.4%	0 0%
Gastrointestinal, grade 3	0 0%	0 0%
Gastrointestinal, related	2 1.4%	0 0%
Headache, any	4 2.9%	0 0%
Headache, grade 3	0 0%	0 0%
Headache, related	4 2.9%	0 0%

8. Secondary Outcome

Title	Number of Subjects Receiving an Additional Vaccine Dose and Reporting Unsolicited Adverse Events (AEs).
Description	An Adverse Event 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 Total vaccinated cohort for the challenge dose, including all subjects who received an additional vaccine dose between 6 to 12 months after year 5.

Arm/Group Title	Twinrix Adult	Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
Measure Participants	11	5
Count of Participants [Participants]	2 1.4%	0 0%

9. Secondary Outcome

Title	Number of Subjects Receiving an Additional Vaccine Dose and Reporting Any Serious Adverse Events
Description	A serious adverse event (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	At least one month after additional vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total vaccinated cohort for the challenge dose, including all subjects who received an additional vaccine dose between 6 to 12 months after year 5.

Arm/Group Title	Twinrix Adult	Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).	Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
Measure Participants	11	5
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	Solicited symtoms: During the 4-day (Day 0-3) follow-up period after the additional vaccination. Unsolicited AEs: During the 31-day (Day 0-30) period after the additional vaccination; SAEs: During the entire study period
Adverse Event Reporting Description	Solicited and unsolicited symptoms were collected on the Total vaccinated cohort for the challenge dose for subjects who received the additional vaccine dose after the Year 5; SAEs were collected on the Long term Total vaccinated cohort throughout the study period.
Arm/Group Title	Twinrix Adult		Twinrix Junior
Arm/Group Description	Subjects previously received 2 doses of combined hepatitis A / hepatitis B vaccine (adult formulation).		Subjects previously received 3 doses of combined hepatitis A / hepatitis B vaccine (junior formulation).
All Cause Mortality
	Twinrix Adult		Twinrix Junior
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Twinrix Adult		Twinrix Junior
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/139 (0%)		0/137 (0%)
Other (Not Including Serious) Adverse Events
	Twinrix Adult		Twinrix Junior
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/11 (63.6%)		0/5 (0%)
General disorders
Redness at the injection site	1/11 (9.1%)		0/5 (0%)
Pain at the injection site	6/11 (54.5%)		0/5 (0%)
Fatigue	3/11 (27.3%)		0/5 (0%)
Gastrointestinal disorder	2/11 (18.2%)		0/5 (0%)
Headache	4/11 (36.4%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/11 (9.1%)		0/5 (0%)
Nervous system disorders
Syncope vasovagal	1/11 (9.1%)		0/5 (0%)
Reproductive system and breast disorders
Balanitis	1/11 (9.1%)		0/5 (0%)

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.