Immunogenicity & Safety of Hepatitis A Vaccine Co-admin With a Measles/Mumps/Rubella & a Varicella Vaccine in Children

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00197015
• Collaborator: (none)
• Enrollment: 1,474
• Locations: 42
• Arms: 3
• Duration (Months): 68.1
• Patients Per Site: 35.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This is a study to evaluate the immune response and safety of GSK Biologicals 2-dose inactivated hepatitis A vaccine when administered with a measles/mumps/rubella vaccine and a varicella (chickenpox) vaccine in children as young as 15 months of age.

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

Condition or Disease	Intervention/Treatment	Phase
Hepatitis A	Biological: Havrix®; Biological: M-M-R®II; Biological: VARIVAX®	Phase 3

Detailed Description

An open, controlled comparison of Havrix™ administered alone or with MMR II and Varivax™. The three groups evaluated are: 1) Havrix™ alone, 2) Havrix™ + MMR II and Varivax™ and 3) MMR II and Varivax™ followed by Havrix™ one month later.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1474 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Immunogenicity & Safety of GSK Biologicals' Inactivated Hepatitis A Vaccine (Havrix™) Co-administered With Merck & Company, Inc. Measles-Mumps-Rubella Vaccine (M-M-RII) & Merck & Co Varicella Vaccine (VARIVAX™) to Children 15 Months of Age
• Study Start Date: Oct 6, 2003
• Actual Primary Completion Date: Jun 9, 2009
• Actual Study Completion Date: Jun 9, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: HAV Group Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Biological: Havrix®; 2 doses administered intramuscularly
Experimental: HAV+MMR+V Group Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9	Biological: Havrix®; 2 doses administered intramuscularly; Biological: M-M-R®II; 1 dose administered subcutaneously; Biological: VARIVAX®; 1 dose administered subcutaneously
Active Comparator: MMR+V→HAV Group Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Biological: Havrix®; 2 doses administered intramuscularly; Biological: M-M-R®II; 1 dose administered subcutaneously; Biological: VARIVAX®; 1 dose administered subcutaneously

Outcome Measures

Primary Outcome Measures

1. Anti-hepatitis A Virus (HAV) Antibody Concentrations in HAV and HAV+MMR+V Groups. [31 days following the second dose of Havrix®]

   Concentrations are given as geometric mean concentrations (GMCs) expressed as milli-international units per milliliter (mIU/mL).

2. Number of Subjects With Anti-hepatitis A Virus (HAV) Antibody Concentration Equal or Above the Cut-off Value in HAV and HAV+MMR+V Groups [31 days following the second dose of Havrix®]

   Anti-HAV antibody cut-off value assessed include 15 milli-international units per milliliter (mIU/mL).

3. Number of Subjects Seroconverted for Anti-measle, Anti-mumps and Anti-varicella Antibodies in HAV+MMR+V and MMR+V→HAV Groups [42 days following the administration of M-M-R®II and VARIVAX®]

   Seroconversion is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off values assessed include 150 milli-international units per milliliter (mIU/mL) for anti-measles antibodies, 28 Effective Dose 50 (ED50) for anti-mumps antibodies and 1:5 for anti-varicella antibodies.

4. Number of Subjects With Vaccine Response for Anti-rubella Antibodies in HAV+MMR+V and MMR+V→HAV Groups [42 days following administration of M-M-R®II and VARIVAX®]

   Vaccine response is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off value assessed include 10 milli-international units per milliliter (mIU/mL).

Secondary Outcome Measures

1. Anti-measles, Anti-mumps, Anti-rubella and Anti-varicella Antibody Titers in HAV+MMR+V and MMR+V→HAV Groups [42 days following the administration of M-M-R®II and VARIVAX®]

   Titers are given as geometric mean titers (GMTs).

2. Anti-hepatitis A Virus (HAV) Antibody Concentrations in HAV and HAV+MMR+V Groups [42 days following the first dose of Havrix®]

   Concentrations are given as geometric mean concentrations (GMCs).

3. Number of Subjects With Anti-hepatitis A Virus (HAV) Antibody Concentration Equal or Above the Cut-off Value in HAV and HAV+MMR+V Groups [42 days following the first dose of Havrix®]

   Anti-HAV antibody cut-off value assessed include 15 milli-international units per millilitre (mIU/mL).

4. Anti-hepatitis A Virus (HAV) Antibody Concentrations in MMR+V→HAV Group [31 days following the second dose of Havrix®]

   Concentrations are given as geometric mean concentrations (GMCs).

5. Number of Subjects With Anti-hepatitis A Virus (HAV) Antibody Concentrations Above the Cut-off Value in MMR+V→HAV Group [31 days following the second dose of Havrix®]

   Anti-HAV antibody cut-off value assessed include 15 milli-international units per millilitre (mIU/mL).

6. Number of Subjects With Vaccine Response to Havrix® [31 days following the second dose of Havrix®]

   Vaccine response was defined as: 1) a detectable anti-hepatitis A virus (HAV) antibody concentration 31 days following the second dose in subjects who were initially seronegative; and 2) a 2-fold increase in anti-HAV antibody concentrations above the pre-study concentration 31 days following the second dose in subjects who were initially seropositive.

7. Number of Subjects Reporting Solicited Local Symptoms [During the 4-day period following each dose of vaccine]

   Solicited local symptoms assessed include pain, rash (local), redness and swelling.

8. Number of Subjects Reporting Solicited General Symptoms [During the 4-day period following each dose of vaccine]

   Solicited general symptoms assessed include drowsiness, fever, irritability, loss of appetite and rash (general).

9. Number of Subjects Reporting Measles, Mumps, Rubella and Varicella Specific Solicited General Adverse Events [During the 43-day period following each dose of vaccine]

   Specific adverse events assessed include papules, vesicles, crusts, parotid/salivary gland swelling and suspected signs of meningitis/febrile seizures.

10. Number of Subjects Reporting Unsolicited Adverse Events (AEs) [During the 31-day period following each dose of vaccine]

    Unsolicited AE covers any AE 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

11. Number of Subjects Reporting Serious Adverse Events (SAEs) [During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end)]

    SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject.

12. Number of Subjects Reporting New Chronic Illnesses [During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end)]

    New Chronic illnesses include autoimmune disorders, asthma, type I diabetes, allergies.

13. Number of Subjects Reporting Medically Significant Events [During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end)]

    Medically significant events include, but are not limited to, diabetes, autoimmune disease, asthma, allergies and/or conditions prompting emergency room or physician office visits that are not related to well-child care, vaccination or common acute illnesses (e.g., upper respiratory infection, otitis media, pharyngitis, gastroenteritis, injury and visits for routine physical examination).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Months to 13 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subjects whose parents/guardians are believed by the investigator to be willing to comply with the requirements of the protocol

• A male or female child 12 and 13 months of age at the time of entry into the Enrollment Phase

• Written informed consent obtained from the parents or guardian of the subject,

• Free of obvious health problems as established by medical history and history-directed physical examination before entering into the study, and

• Parents/guardian of the subject must have a telephone or be able to be contacted by telephone

Exclusion Criteria:

• Use of any investigational or non-registered drug or vaccine other than the study vaccine(s) within 42 days preceding the first dose of study vaccine, or planned use during the study period, Chronic administration (defined as more than 14 days) of immuno-suppressant or other immune-modifying drugs within six months prior to vaccination or planned administration at any time during the study period. (For corticosteroids, this will mean prednisone, or equivalent, ≥0.5 mg/kg/day. Inhaled, nasal and topical steroids are allowed.) Planned administration or administration of any vaccine not foreseen by the study protocol during the period 31 days before and 31 days after each dose of study vaccine(s).

• Previous vaccination against hepatitis A,

• History of hepatitis A,

• Known exposure to hepatitis A,

• Previous vaccination against measles, mumps, rubella and/or varicella,

• History of measles, mumps, rubella and/or varicella,

• Known exposure to measles, mumps, rubella and/or varicella within 30 days prior to the start of the study,

• Planned chronic use of salicylates during the 6-week period following administration of the doses of study vaccine(s),

• Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection,

• A family history of congenital, hereditary or infectious immunodeficiency or parental risk factors for HIV infection,

• History of allergic disease/reactions or hypersensitivity likely to be exacerbated by any component of HavrixTM, M-M-RII or VARIVAXTM, including 2-phenoxyethanol, neomycin and gelatin,

• History of anaphylactic or anaphylactoid reactions to egg proteins,

• History of hypersensitivity/allergic reaction to latex. Note: The tip cap and the rubber plunger of the HavrixTM needleless pre-filled syringes contain dry natural latex rubber.

• Major congenital defects or serious chronic illness,

• Active untreated tuberculosis,

• History of significant blood dyscrasias

• History of any neurologic disorder (a history of febrile seizures not associated with an underlying neurological disorder does not exclude the subject)

• Acute disease at the time of vaccination

• Administration of immunoglobulins and/or any blood products within three months prior to the first dose of study vaccine or planned administration at any time during the entire study period

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Cabot	Arkansas	United States	72023
2	GSK Investigational Site	Jonesboro	Arkansas	United States	72401
3	GSK Investigational Site	North Little Rock	Arkansas	United States	72117
4	GSK Investigational Site	Huntington Beach	California	United States	92647
5	GSK Investigational Site	Oakland	California	United States	94609
6	GSK Investigational Site	Rolling Hills Estates	California	United States	90274
7	GSK Investigational Site	Norwich	Connecticut	United States	06360
8	GSK Investigational Site	Jacksonville	Florida	United States	32209
9	GSK Investigational Site	Marietta	Georgia	United States	30062
10	GSK Investigational Site	Waterloo	Iowa	United States	50702
11	GSK Investigational Site	Waukee	Iowa	United States	50263
12	GSK Investigational Site	Lexington	Kentucky	United States	40503
13	GSK Investigational Site	Bossier City	Louisiana	United States	71111
14	GSK Investigational Site	Baltimore	Maryland	United States	21201
15	GSK Investigational Site	Henderson	Nevada	United States	89015
16	GSK Investigational Site	Las Vegas	Nevada	United States	89014
17	GSK Investigational Site	Albany	New York	United States	12208
18	GSK Investigational Site	Brooklyn	New York	United States	11203
19	GSK Investigational Site	Rochester	New York	United States	14620
20	GSK Investigational Site	Syracuse	New York	United States	13210
21	GSK Investigational Site	Lumberton	North Carolina	United States	28358
22	GSK Investigational Site	Sylva	North Carolina	United States	28779
23	GSK Investigational Site	Cleveland	Ohio	United States	44109
24	GSK Investigational Site	University Heights	Ohio	United States	44118
25	GSK Investigational Site	Tulsa	Oklahoma	United States	74104
26	GSK Investigational Site	Beaver Falls	Pennsylvania	United States	15010
27	GSK Investigational Site	Norristown	Pennsylvania	United States	19401
28	GSK Investigational Site	Pittsburgh	Pennsylvania	United States	15213
29	GSK Investigational Site	Pittsburgh	Pennsylvania	United States	15241
30	GSK Investigational Site	Rydal	Pennsylvania	United States	19046
31	GSK Investigational Site	Sellersville	Pennsylvania	United States	18960
32	GSK Investigational Site	Warwick	Rhode Island	United States	02886
33	GSK Investigational Site	Bristol	Tennessee	United States	37620
34	GSK Investigational Site	Kingsport	Tennessee	United States	37660
35	GSK Investigational Site	Kingsport	Tennessee	United States	37664
36	GSK Investigational Site	Austin	Texas	United States	78758
37	GSK Investigational Site	San Antonio	Texas	United States	78205-2489
38	GSK Investigational Site	Temple	Texas	United States	76508
39	GSK Investigational Site	Layton	Utah	United States	84041
40	GSK Investigational Site	South Jordan	Utah	United States	84095
41	GSK Investigational Site	Norfolk	Virginia	United States	23510
42	GSK Investigational Site	Marshfield	Wisconsin	United States	54449

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

• Rinderknecht S, Michaels MG, Blatter M, Gaglani M, Andrews W, Abughali N, Chandreshekaran V, Trofa AF. Immunogenicity and safety of an inactivated hepatitis A vaccine when coadministered with measles-mumps-rubella and varicella vaccines in children less than 2 years of age. Pediatr Infect Dis J. 2011 Oct;30(10):e179-85. doi: 10.1097/INF.0b013e31822256a5.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00197015
• Other Study ID Numbers: 208109/231
• First Posted: Sep 20, 2005
• Last Update Posted: Jul 31, 2018
• Last Verified: Oct 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Hepatitis A; Chickenpox; Rubella; Hepatitis

Study Results

Participant Flow

Pre-assignment Detail	While the total numbers of subjects enrolled in the study was 1474, the total number of subjects that entered the study was 1241. The remaining subjects received a subject number but no vaccine dose and were therefore excluded from the analysis and group assignment.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Period Title: Overall Study
STARTED	324	455	462
COMPLETED	274	366	385
NOT COMPLETED	50	89	77

Baseline Characteristics

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group	Total
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9	Total of all reporting groups
Overall Participants	324	455	462	1241
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	15.0 (0.27)	15.0 (0.22)	15.0 (0.25)	15.0 (0.25)
Sex: Female, Male (Count of Participants)
Female	154 47.5%	208 45.7%	232 50.2%	594 47.9%
Male	170 52.5%	247 54.3%	230 49.8%	647 52.1%

Outcome Measures

1. Primary Outcome

Title	Anti-hepatitis A Virus (HAV) Antibody Concentrations in HAV and HAV+MMR+V Groups.
Description	Concentrations are given as geometric mean concentrations (GMCs) expressed as milli-international units per milliliter (mIU/mL).
Time Frame	31 days following the second dose of Havrix®

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results from HAV and HAV+MMR+V Groups.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	206	0	286
Geometric Mean (95% Confidence Interval) [mIU/mL]	1390.4	1895.2

2. Primary Outcome

Title	Number of Subjects With Anti-hepatitis A Virus (HAV) Antibody Concentration Equal or Above the Cut-off Value in HAV and HAV+MMR+V Groups
Description	Anti-HAV antibody cut-off value assessed include 15 milli-international units per milliliter (mIU/mL).
Time Frame	31 days following the second dose of Havrix®

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results from HAV and HAV+MMR+V groups.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	206	0	286
Count of Participants [Participants]	204 63%	285 62.6%

3. Primary Outcome

Title	Number of Subjects Seroconverted for Anti-measle, Anti-mumps and Anti-varicella Antibodies in HAV+MMR+V and MMR+V→HAV Groups
Description	Seroconversion is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off values assessed include 150 milli-international units per milliliter (mIU/mL) for anti-measles antibodies, 28 Effective Dose 50 (ED50) for anti-mumps antibodies and 1:5 for anti-varicella antibodies.
Time Frame	42 days following the administration of M-M-R®II and VARIVAX®

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results from HAV+MMR+V and MMR+V→HAV groups.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	0	250	268
Anti-measles	247 76.2%	267 58.7%
Anti-mumps	193 59.6%	207 45.5%
Anti-varicella	168 51.9%	187 41.1%

4. Primary Outcome

Title	Number of Subjects With Vaccine Response for Anti-rubella Antibodies in HAV+MMR+V and MMR+V→HAV Groups
Description	Vaccine response is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off value assessed include 10 milli-international units per milliliter (mIU/mL).
Time Frame	42 days following administration of M-M-R®II and VARIVAX®

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results from HAV+MMR+V and MMR+V→HAV groups.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	0	247	271
Count of Participants [Participants]	246 75.9%	270 59.3%

5. Secondary Outcome

Title	Anti-measles, Anti-mumps, Anti-rubella and Anti-varicella Antibody Titers in HAV+MMR+V and MMR+V→HAV Groups
Description	Titers are given as geometric mean titers (GMTs).
Time Frame	42 days following the administration of M-M-R®II and VARIVAX®

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results from HAV+MMR+V and MMR+V→HAV groups.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	0	269	304
Anti-measles	3218.3	3136.3
Anti-rubella	88.3	76.0
Anti-varicella	281.7	286.9
Anti-mumps	215.7	170.3

6. Secondary Outcome

Title	Anti-hepatitis A Virus (HAV) Antibody Concentrations in HAV and HAV+MMR+V Groups
Description	Concentrations are given as geometric mean concentrations (GMCs).
Time Frame	42 days following the first dose of Havrix®

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results from HAV and HAV+MMR+V groups.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	228	0	306
Geometric Mean (95% Confidence Interval) [milli-international units per milliliter]	43.1	43.5

7. Secondary Outcome

Title	Number of Subjects With Anti-hepatitis A Virus (HAV) Antibody Concentration Equal or Above the Cut-off Value in HAV and HAV+MMR+V Groups
Description	Anti-HAV antibody cut-off value assessed include 15 milli-international units per millilitre (mIU/mL).
Time Frame	42 days following the first dose of Havrix®

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results from HAV and HAV+MMR+V groups.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	228	0	306
Count of Participants [Participants]	194 59.9%	276 60.7%

8. Secondary Outcome

Title	Anti-hepatitis A Virus (HAV) Antibody Concentrations in MMR+V→HAV Group
Description	Concentrations are given as geometric mean concentrations (GMCs).
Time Frame	31 days following the second dose of Havrix®

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results from MMR+V→HAV Group.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	0	237	0
Geometric Mean (95% Confidence Interval) [milli-international units per milliliter]	1770.3

9. Secondary Outcome

Title	Number of Subjects With Anti-hepatitis A Virus (HAV) Antibody Concentrations Above the Cut-off Value in MMR+V→HAV Group
Description	Anti-HAV antibody cut-off value assessed include 15 milli-international units per millilitre (mIU/mL).
Time Frame	31 days following the second dose of Havrix®

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results from MMR+V→HAV Group.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	0	237	0
Count of Participants [Participants]	237 73.1%

10. Secondary Outcome

Title	Number of Subjects With Vaccine Response to Havrix®
Description	Vaccine response was defined as: 1) a detectable anti-hepatitis A virus (HAV) antibody concentration 31 days following the second dose in subjects who were initially seronegative; and 2) a 2-fold increase in anti-HAV antibody concentrations above the pre-study concentration 31 days following the second dose in subjects who were initially seropositive.
Time Frame	31 days following the second dose of Havrix®

Outcome Measure Data

Analysis Population Description

Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	194	224	259
Count of Participants [Participants]	192 59.3%	224 49.2%	257 55.6%

11. Secondary Outcome

Title	Number of Subjects Reporting Solicited Local Symptoms
Description	Solicited local symptoms assessed include pain, rash (local), redness and swelling.
Time Frame	During the 4-day period following each dose of vaccine

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total Vaccinated cohort, on subjects with available data.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	304	411	419
Pain	103 31.8%	162 35.6%	187 40.5%
Rash (local)	0 0%	3 0.7%	4 0.9%
Redness	97 29.9%	149 32.7%	151 32.7%
Swelling	45 13.9%	70 15.4%	82 17.7%

12. Secondary Outcome

Title	Number of Subjects Reporting Solicited General Symptoms
Description	Solicited general symptoms assessed include drowsiness, fever, irritability, loss of appetite and rash (general).
Time Frame	During the 4-day period following each dose of vaccine

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total Vaccinated cohort, on subjects with available data.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	304	424	411
Drowsiness	95 29.3%	179 39.3%	178 38.5%
Fever	54 16.7%	110 24.2%	80 17.3%
Irritability	144 44.4%	238 52.3%	216 46.8%
Loss of appetite	94 29%	170 37.4%	154 33.3%
Rash (general)	5 1.5%	7 1.5%	10 2.2%

13. Secondary Outcome

Title	Number of Subjects Reporting Measles, Mumps, Rubella and Varicella Specific Solicited General Adverse Events
Description	Specific adverse events assessed include papules, vesicles, crusts, parotid/salivary gland swelling and suspected signs of meningitis/febrile seizures.
Time Frame	During the 43-day period following each dose of vaccine

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total Vaccinated cohort, on subjects from MMR+V→HAV and HAV+MMR+V groups.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	0	455	462
Papules	23 7.1%	23 5.1%
Vesicles	17 5.2%	17 3.7%
Crusts	12 3.7%	12 2.6%
Parotid/salivary gland swelling	0 0%	1 0.2%
Suspected signs of meningitidis/febrile seizures	1 0.3%	2 0.4%

14. Secondary Outcome

Title	Number of Subjects Reporting Unsolicited Adverse Events (AEs)
Description	Unsolicited AE covers any AE 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
Time Frame	During the 31-day period following each dose of vaccine

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total Vaccinated cohort.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	324	455	462
Count of Participants [Participants]	186 57.4%	286 62.9%	249 53.9%

15. Secondary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs)
Description	SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject.
Time Frame	During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total Vaccinated cohort.

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	324	455	462
Active Phase	1 0.3%	6 1.3%	5 1.1%
Extended Safety Follow-up Phase	6 1.9%	6 1.3%	11 2.4%

16. Secondary Outcome

Title	Number of Subjects Reporting New Chronic Illnesses
Description	New Chronic illnesses include autoimmune disorders, asthma, type I diabetes, allergies.
Time Frame	During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total Vaccinated cohort (for the Active Phase) and the Extended Safety Follow-up cohort (for the Extended Safety Follow-up Phase).

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	324	455	462
Active Phase	0 0%	0 0%	0 0%
Extended Safety Follow-Up Phase	0 0%	0 0%	0 0%

17. Secondary Outcome

Title	Number of Subjects Reporting Medically Significant Events
Description	Medically significant events include, but are not limited to, diabetes, autoimmune disease, asthma, allergies and/or conditions prompting emergency room or physician office visits that are not related to well-child care, vaccination or common acute illnesses (e.g., upper respiratory infection, otitis media, pharyngitis, gastroenteritis, injury and visits for routine physical examination).
Time Frame	During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the Total Vaccinated cohort (for the Active Phase) and the Extended Safety Follow-up cohort (for the Extended Safety Follow-up Phase).

Arm/Group Title	HAV Group	MMR+V→HAV Group	HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)	Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)	Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
Measure Participants	324	455	462
Active Phase	0 0%	0 0%	0 0%
Extended Safety Follow-Up Phase	0 0%	0 0%	0 0%

Adverse Events

Adverse Event Reporting Description	Events collected by systematic assessment are reported for subjects with a symptom diary card available. Events collected by non-systematic method are reported for the Total Vaccinated Cohort
Arm/Group Title	HAV Group		MMR+V→HAV Group		HAV+MMR+V Group
Arm/Group Description	Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9)		Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5)		Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9
All Cause Mortality
	HAV Group		MMR+V→HAV Group		HAV+MMR+V Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	HAV Group		MMR+V→HAV Group		HAV+MMR+V Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/324 (2.2%)		12/455 (2.6%)		16/462 (3.5%)
Gastrointestinal disorders
Constipation	0/324 (0%)		1/455 (0.2%)		0/462 (0%)
Ileus	0/324 (0%)		1/455 (0.2%)		0/462 (0%)
General disorders
Sudden death	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Infections and infestations
Bronchiolitis	0/324 (0%)		1/455 (0.2%)		1/462 (0.2%)
Bronchitis	0/324 (0%)		1/455 (0.2%)		1/462 (0.2%)
Bronchitis viral	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Cellulitis	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Gastroenteritis viral	0/324 (0%)		1/455 (0.2%)		0/462 (0%)
Gastroenteritis	1/324 (0.3%)		0/455 (0%)		1/462 (0.2%)
Respiratory syncytial virus bronchiolitis	1/324 (0.3%)		1/455 (0.2%)		0/462 (0%)
Gastroenteritis rotavirus	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Groin abscess	1/324 (0.3%)		0/455 (0%)		0/462 (0%)
Localised infection	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Otitis media	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Otitis media chronic	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Pneumonia	0/324 (0%)		1/455 (0.2%)		0/462 (0%)
Subcutaneous abscess	0/324 (0%)		1/455 (0.2%)		0/462 (0%)
Viral infection	0/324 (0%)		1/455 (0.2%)		0/462 (0%)
Injury, poisoning and procedural complications
Burns second degree	0/324 (0%)		1/455 (0.2%)		0/462 (0%)
Chemical poisoning	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Humerus fracture	0/324 (0%)		1/455 (0.2%)		0/462 (0%)
Accidental overdose	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Animal bite	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Subdural haematoma	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Metabolism and nutrition disorders
Dehydratation	2/324 (0.6%)		1/455 (0.2%)		2/462 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukaemia	1/324 (0.3%)		0/455 (0%)		0/462 (0%)
Nervous system disorders
Mental retardation	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Autism	1/324 (0.3%)		0/455 (0%)		1/462 (0.2%)
Convulsion	1/324 (0.3%)		0/455 (0%)		0/462 (0%)
Psychiatric disorders
Breathing-related sleep disorder	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Respiratory, thoracic and mediastinal disorders
Adenoidal hypertrophy	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Asthma	0/324 (0%)		0/455 (0%)		1/462 (0.2%)
Other (Not Including Serious) Adverse Events
	HAV Group		MMR+V→HAV Group		HAV+MMR+V Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	251/324 (77.5%)		366/455 (80.4%)		363/462 (78.6%)
Gastrointestinal disorders
Diarrhoea	16/324 (4.9%)		39/455 (8.6%)		22/462 (4.8%)
Teething	25/324 (7.7%)		24/455 (5.3%)		19/462 (4.1%)
Vomiting	14/324 (4.3%)		30/455 (6.6%)		12/462 (2.6%)
General disorders
Pyrexia	34/324 (10.5%)		68/455 (14.9%)		56/462 (12.1%)
Papules	0/0 (NaN)		23/455 (5.1%)		23/462 (5%)
Drowsiness	95/304 (31.3%)		179/411 (43.6%)		178/424 (42%)
Fever	54/304 (17.8%)		110/411 (26.8%)		80/424 (18.9%)
Irritability	144/304 (47.4%)		238/411 (57.9%)		216/424 (50.9%)
Loss of appetite	94/304 (30.9%)		170/411 (41.4%)		154/424 (36.3%)
Pain	103/304 (33.9%)		162/411 (39.4%)		187/419 (44.6%)
Redness	97/304 (31.9%)		149/411 (36.3%)		151/419 (36%)
Swelling	45/304 (14.8%)		70/411 (17%)		82/419 (19.6%)
Infections and infestations
Otitis media	35/324 (10.8%)		79/455 (17.4%)		65/462 (14.1%)
Upper respiratory tract infection	31/324 (9.6%)		64/455 (14.1%)		58/462 (12.6%)
Nasopharyngitis	19/324 (5.9%)		19/455 (4.2%)		19/462 (4.1%)
Respiratory, thoracic and mediastinal disorders
Cough	21/324 (6.5%)		20/455 (4.4%)		23/462 (5%)
Rhinorrhoea	20/324 (6.2%)		22/455 (4.8%)		17/462 (3.7%)

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.