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

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

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.

Study Overview

• Status: Completed
• Conditions: Hepatitis A
• Intervention / Treatment: Biological: Havrix®; Biological: M-M-R®II; Biological: VARIVAX®

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 Type: Interventional
• Enrollment (Actual): 1474
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Cabot, Arkansas, United States, 72023
      • GSK Investigational Site
    • Jonesboro, Arkansas, United States, 72401
      • GSK Investigational Site
    • North Little Rock, Arkansas, United States, 72117
      • GSK Investigational Site
  • California
    • Huntington Beach, California, United States, 92647
      • GSK Investigational Site
    • Oakland, California, United States, 94609
      • GSK Investigational Site
    • Rolling Hills Estates, California, United States, 90274
      • GSK Investigational Site
  • Connecticut
    • Norwich, Connecticut, United States, 06360
      • GSK Investigational Site
  • Florida
    • Jacksonville, Florida, United States, 32209
      • GSK Investigational Site
  • Georgia
    • Marietta, Georgia, United States, 30062
      • GSK Investigational Site
  • Iowa
    • Waterloo, Iowa, United States, 50702
      • GSK Investigational Site
    • Waukee, Iowa, United States, 50263
      • GSK Investigational Site
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • GSK Investigational Site
  • Louisiana
    • Bossier City, Louisiana, United States, 71111
      • GSK Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • GSK Investigational Site
  • Nevada
    • Henderson, Nevada, United States, 89015
      • GSK Investigational Site
    • Las Vegas, Nevada, United States, 89014
      • GSK Investigational Site
  • New York
    • Albany, New York, United States, 12208
      • GSK Investigational Site
    • Brooklyn, New York, United States, 11203
      • GSK Investigational Site
    • Rochester, New York, United States, 14620
      • GSK Investigational Site
    • Syracuse, New York, United States, 13210
      • GSK Investigational Site
  • North Carolina
    • Lumberton, North Carolina, United States, 28358
      • GSK Investigational Site
    • Sylva, North Carolina, United States, 28779
      • GSK Investigational Site
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • GSK Investigational Site
    • University Heights, Ohio, United States, 44118
      • GSK Investigational Site
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • GSK Investigational Site
  • Pennsylvania
    • Beaver Falls, Pennsylvania, United States, 15010
      • GSK Investigational Site
    • Norristown, Pennsylvania, United States, 19401
      • GSK Investigational Site
    • Pittsburgh, Pennsylvania, United States, 15241
      • GSK Investigational Site
    • Pittsburgh, Pennsylvania, United States, 15213
      • GSK Investigational Site
    • Rydal, Pennsylvania, United States, 19046
      • GSK Investigational Site
    • Sellersville, Pennsylvania, United States, 18960
      • GSK Investigational Site
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • GSK Investigational Site
  • Tennessee
    • Bristol, Tennessee, United States, 37620
      • GSK Investigational Site
    • Kingsport, Tennessee, United States, 37660
      • GSK Investigational Site
    • Kingsport, Tennessee, United States, 37664
      • GSK Investigational Site
  • Texas
    • Austin, Texas, United States, 78758
      • GSK Investigational Site
    • San Antonio, Texas, United States, 78205-2489
      • GSK Investigational Site
    • Temple, Texas, United States, 76508
      • GSK Investigational Site
  • Utah
    • Layton, Utah, United States, 84041
      • GSK Investigational Site
    • South Jordan, Utah, United States, 84095
      • GSK Investigational Site
  • Virginia
    • Norfolk, Virginia, United States, 23510
      • GSK Investigational Site
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-hepatitis A Virus (HAV) Antibody Concentrations in HAV and HAV+MMR+V Groups.	Concentrations are given as geometric mean concentrations (GMCs) expressed as milli-international units per milliliter (mIU/mL).	31 days following the second dose of Havrix®
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	Anti-HAV antibody cut-off value assessed include 15 milli-international units per milliliter (mIU/mL).	31 days following the second dose of Havrix®
Number of Subjects Seroconverted for Anti-measle, Anti-mumps and Anti-varicella Antibodies in HAV+MMR+V and MMR+V→HAV Groups	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.	42 days following the administration of M-M-R®II and VARIVAX®
Number of Subjects With Vaccine Response for Anti-rubella Antibodies in HAV+MMR+V and MMR+V→HAV Groups	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).	42 days following administration of M-M-R®II and VARIVAX®

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-measles, Anti-mumps, Anti-rubella and Anti-varicella Antibody Titers in HAV+MMR+V and MMR+V→HAV Groups	Titers are given as geometric mean titers (GMTs).	42 days following the administration of M-M-R®II and VARIVAX®
Anti-hepatitis A Virus (HAV) Antibody Concentrations in HAV and HAV+MMR+V Groups	Concentrations are given as geometric mean concentrations (GMCs).	42 days following the first dose of Havrix®
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	Anti-HAV antibody cut-off value assessed include 15 milli-international units per millilitre (mIU/mL).	42 days following the first dose of Havrix®
Anti-hepatitis A Virus (HAV) Antibody Concentrations in MMR+V→HAV Group	Concentrations are given as geometric mean concentrations (GMCs).	31 days following the second dose of Havrix®
Number of Subjects With Anti-hepatitis A Virus (HAV) Antibody Concentrations Above the Cut-off Value in MMR+V→HAV Group	Anti-HAV antibody cut-off value assessed include 15 milli-international units per millilitre (mIU/mL).	31 days following the second dose of Havrix®
Number of Subjects With Vaccine Response to 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.	31 days following the second dose of Havrix®
Number of Subjects Reporting Solicited Local Symptoms	Solicited local symptoms assessed include pain, rash (local), redness and swelling.	During the 4-day period following each dose of vaccine
Number of Subjects Reporting Solicited General Symptoms	Solicited general symptoms assessed include drowsiness, fever, irritability, loss of appetite and rash (general).	During the 4-day period following each dose of vaccine
Number of Subjects Reporting Measles, Mumps, Rubella and Varicella Specific Solicited General Adverse Events	Specific adverse events assessed include papules, vesicles, crusts, parotid/salivary gland swelling and suspected signs of meningitis/febrile seizures.	During the 43-day period following each dose of vaccine
Number of Subjects Reporting Unsolicited Adverse Events (AEs)	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	During the 31-day period following each dose of vaccine
Number of Subjects Reporting Serious Adverse Events (SAEs)	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.	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)
Number of Subjects Reporting New Chronic Illnesses	New Chronic illnesses include autoimmune disorders, asthma, type I diabetes, allergies.	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)
Number of Subjects Reporting Medically Significant Events	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).	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)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General 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.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start: October 6, 2003
• Primary Completion (Actual): June 9, 2009
• Study Completion (Actual): June 9, 2009

Study Registration Dates

• First Submitted: September 13, 2005
• First Submitted That Met QC Criteria: September 13, 2005
• First Posted (Estimate): September 20, 2005

Study Record Updates

• Last Update Posted (Actual): July 31, 2018
• Last Update Submitted That Met QC Criteria: July 2, 2018
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Herpesviridae Infections; Varicella Zoster Virus Infection; Togaviridae Infections; Rubivirus Infections; Hepatitis; Hepatitis A; Chickenpox; Rubella
• Other Study ID Numbers: 208109/231

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Clinical Study Report
   Information identifier: 208109/231
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Informed Consent Form
   Information identifier: 208109/231
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Dataset Specification
   Information identifier: 208109/231
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Individual Participant Data Set
   Information identifier: 208109/231
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Study Protocol
   Information identifier: 208109/231
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Statistical Analysis Plan
   Information identifier: 208109/231
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register