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Immunogenicity and Safety of Japanese Encephalitis Vaccine When Given With Measles-Mumps-Rubella (MMR) Vaccine

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ClinicalTrials.gov Identifier: NCT02880865
Recruitment Status : Completed
First Posted : August 26, 2016
Results First Posted : September 18, 2020
Last Update Posted : October 14, 2020
Sponsor:
Collaborators:
Research Institute for Tropical Medicine,
Syneos Health
DF/Net Research, Inc.
Information provided by (Responsible Party):
PATH

Tracking Information
First Submitted Date  ICMJE August 17, 2016
First Posted Date  ICMJE August 26, 2016
Results First Submitted Date  ICMJE August 27, 2020
Results First Posted Date  ICMJE September 18, 2020
Last Update Posted Date October 14, 2020
Actual Study Start Date  ICMJE October 13, 2016
Actual Primary Completion Date May 19, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 27, 2020)
  • Percentage of Participants With Measles Seropositivity 56 Days Post-vaccination [ Time Frame: 56 days after MMR dose 1 vaccination (Day 56) ]
    Measles immunogenicity was assessed by the percentage of participants with demonstrated seropositivity for measles at 56 days post-vaccination. Seropositivity was defined by a concentration of ≥ 120 mIU/mL of anti-measles neutralizing antibody titer, as measured by the plaque reduction neutralization test (PRNT) (dilution converted to concentration using the 3rd International Standard Reference serum).
  • Percentage of Participants With Rubella Seropositivity 56 Days Post-vaccination [ Time Frame: 56 days after MMR dose 1 vaccination (Day 56) ]
    Rubella immunogenicity was assessed by the percentage of participants with demonstrated seropositivity for rubella at 56 days post-vaccination. Seropositivity was defined as antirubella immunoglobulin G (IgG) concentration of ≥ 10 IU/mL (corresponding to an optical density ratio ≥ 1.10) using a commercial IgG enzyme-linked immunosorbent assay (ELISA).
Original Primary Outcome Measures  ICMJE
 (submitted: August 22, 2016)
  • Measles seropositivity rate [ Time Frame: 56 days after MMR vaccination ]
  • Rubella seropositivity rate [ Time Frame: 56 days after MMR vaccination ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 27, 2020)
  • Percentage of Participants With Mumps Seropositivity 56 Days Post-vaccination [ Time Frame: 56 days after MMR dose 1 vaccination (Day 56) ]
    Mumps immunogenicity was assessed by the percentage of participants with demonstrated seropositivity for mumps at 56 days post-vaccination. Seropositivity was defined as an optical density ratio ≥ 1.10 using a commercial ELISA.
  • Geometric Mean Concentration (GMC) for Anti-measles Neutralizing Antibody Concentration at 56 Days Post-vaccination [ Time Frame: 56 days after MMR dose 1 vaccination (Day 56) ]
    Anti-measles neutralizing antibody concentration was measured by the plaque reduction neutralization test (PRNT).
  • GMC for Anti-rubella IgG Antibody Concentration at 56 Days Post-vaccination [ Time Frame: 56 days after MMR dose 1 vaccination (Day 56) ]
    Anti-rubella immunoglobulin G (IgG) concentration was measured using a commercial IgG enzyme-linked immunosorbent assay (ELISA).
  • Seroconversion Rate for Measles 56 Days Post-vaccination [ Time Frame: 56 days after MMR dose 1 vaccination (Day 56) ]
    The seroconversion rate for measles at 56 days post-vaccination was defined as the percentage of participants with a change in serostatus from negative to positive 56 days after vaccination or a four-fold rise in concentration 56 days after vaccination if seropositive for measles at baseline. Seropositivity was defined by a concentration of ≥ 120 mIU/mL of anti-measles neutralizing antibody titer, as measured by the plaque reduction neutralization test (PRNT).
  • Seroconversion Rate for Mumps 56 Days Post-vaccination [ Time Frame: 56 days after MMR dose 1 vaccination (Day 56) ]
    The seroconversion rate for mumps at 56 days post-vaccination was defined as the percentage of participants with a change in serostatus from negative to positive 56 days after vaccination. Seropositivity was defined as an optical density ratio ≥ 1.10, measured using a commercial ELISA. Participants with equivocal serostatus at baseline are counted as non-responders.
  • Seroconversion Rate for Rubella 56 Days Post-vaccination [ Time Frame: 56 days after MMR dose 1 vaccination (Day 56) ]
    The seroconversion rate for rubella at 56 days post-vaccination was defined as the percentage of participants with a change in serostatus from negative to positive 56 days after vaccination or a four-fold rise in concentration 56 days after vaccination if seropositive for rubella at baseline. Seropositivity is defined as a post-vaccination concentration of ≥ 10 IU/mL measured using a commercial ELISA.
  • Percentage of Participants With Japanese Encephalitis Seropositivity 28 Days Post-vaccination [ Time Frame: 28 days after CD-JEV vaccination (Day 28 for Group 1 and Day 84 for Group 2) ]
    Japanese encephalitis (JE) immunogenicity was assessed by the percentage of participants with demonstrated seropositivity 28 days after CD-JEV vaccination. Seropositivity was defined as an anti-JE serum neutralizing antibody titer of ≥ 1:10, as measured by JE PRNT-50.
  • Geometric Mean Titer (GMT) for Serum Neutralizing Antibody Titer to JE Virus at 28 Days Post-vaccination [ Time Frame: 28 days after CD-JEV vaccination (Day 28 for Group 1 and Day 84 for Group 2) ]
    Anti-JE serum neutralizing antibody titer was measured using JE PRNT-50.
  • Number of Participants With Immediate Reactions Within 30 Minutes of Each Vaccination [ Time Frame: 30 minutes following each study vaccination ]
    Participants were observed for 30 minutes after each vaccination for immediate reactions. Immediate reactions included both local (injection site) and systemic reactions. MMR vaccine was injected on left upper thigh and CD-JEV was injected on right upper thigh. Serious reactions were those meeting one of the following conditions:
    • Death.
    • Life threatening
    • Required inpatient hospitalization or prolongation of existing hospitalization.
    • Resulted in a persistent or significant disability or incapacity.
    • Important medical events that, based upon appropriate medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed above.
  • Number of Participants With Solicited Local and Systemic Reactions Within 14 Days of Each Vaccination [ Time Frame: 30 minutes through 14 days following each vaccination ]
    Reactogenicity post-vaccination was assessed from 30 minutes through 14 days following vaccination. Parents used a structured reactogenicity diary card to record the following solicited (pre-listed) local and system reactions. Local reactions (at injection site):
    • Ecchymosis (bruising)
    • Erythema (redness)
    • Edema (swelling)
    • Induration (hardness)
    • Pain/tenderness
    Systemic reactions:
    • Fever
    • Rash
    • Cough
    • Runny nose
    • Change in eating habits
    • Diarrhea
    • Sleepiness
    • Irritability
    • Unusual crying
    • Vomiting
  • Number of Participants With Solicited Local Reactions Within 14 Days of Each Vaccination by Maximum Severity [ Time Frame: 30 minutes through 14 days following each vaccination ]
    Parents recorded local reactions on a diary card. Local ecchymosis, erythema, edema, and induration were graded as follows: Grade 1: ≤2.5 cm in diameter. Grade 2: >2.5 cm in diameter with 50% of surface area of extremity segment involved. Grade 3: ≥50% surface area of extremity segment involved OR ulceration OR secondary infection OR phlebitis OR sterile abscess OR drainage. Grade 4: potentially life-threatening (e.g., abscess, exfoliative dermatitis, necrosis involving dermis or deeper tissue). Injection site pain/tenderness (pain without touching or tenderness when the area is touched) were graded as follows: Grade 1: pain/tenderness causing no or minimal limitation of use of limb. Grade 2: pain/tenderness causing greater than minimal limitation of use of limb. Grade 3: pain/tenderness causing inability to perform usual social and functional activities. Grade 4: pain/tenderness causing inability to perform basic self-care OR hospitalization indicated.
  • Number of Participants With Systemic Reactions Within 14 Days of Each Vaccination by Maximum Severity [ Time Frame: 30 minutes through 14 days following each vaccination ]
    Parents recorded systemic reactions on a diary card. Fever was recorded and graded as follows (axillary temperature): Grade 1: 37.5°C to 37.9°C Grade 2: 38.0°C to 38.4°C Grade 3: 38.5°C to 40.0°C Grade 4: >40.0°C Rash, cough, runny nose, change in eating habits, diarrhea, sleepiness, irritability, unusual crying, vomiting, and any other unsolicited reaction occurring from 30 minutes through 14 days post vaccination were graded as follows: Grade 1: symptoms causing no or minimal interference with usual social and functional activities. Grade 2: symptoms causing greater than minimal interference with usual social and functional activities. Grade 3: symptoms causing inability to perform usual social and functional activities with intervention or hospitalization indicated. Grade 4: symptoms causing inability to perform basic self-care functions OR medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death.
  • Number of Participants With Unsolicited Adverse Events Within 28 Days of Each Vaccination [ Time Frame: 28 days following each vaccination ]
    Each adverse event (AE) was assessed for relationship to vaccine by the study clinician according to the following: Definitely Related: An adverse event or unanticipated problem clearly related to the research procedures. Possibly Related: There is a reasonable possibility that the adverse event or unanticipated problem, incident, experience, or outcome may have been caused by the procedures involved in the research. Not Related: Any adverse event or unanticipated problem clearly not related to study procedures. Related adverse events includes events that were assessed as definitely or possibly related.
  • Number of Participants With Serious Adverse Events Throughout the Study [ Time Frame: Up to 112 days ]
    A serious adverse event (SAE) was defined as an AE that met one of the following:
    • Death
    • Life threatening
    • Required inpatient hospitalization or prolongation of existing hospitalization
    • Resulted in persistent or significant disability or incapacity
    • Important medical events that, based upon appropriate medical judgment, jeopardized the participant and required medical or surgical intervention to prevent an outcomes listed above
    AEs were assessed for relationship to vaccine by the study clinician according to the following: Definitely Related: An AE or unanticipated problem clearly related to the research procedures. Possibly Related: There is a reasonable possibility that the AE or unanticipated problem, incident, experience, or outcome may have been caused by the procedures involved in the research. Not Related: Any AE or unanticipated problem clearly not related to study procedures. Related SAEs includes events that were assessed as definitely or possibly related.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 22, 2016)
  • Mumps seropositivity rate [ Time Frame: 56 days after MMR vaccination ]
  • Geometric mean neutralizing antibody concentration (GMC) [ Time Frame: 56 days after MMR vaccination ]
  • Anti-mumps Immunoglobulin G (IgG) mean index standard ratio [ Time Frame: 56 days after MMR vaccination ]
  • Anti-rubella IgG GMC [ Time Frame: 56 days after MMR vaccination ]
  • Measles, mumps, and rubella seroconversion rates [ Time Frame: 56 days after MMR vaccination ]
  • Japanese encephalitis seropositivity rate [ Time Frame: 28 days after CD-JEV vaccination ]
  • Anti-Japanese encephalitis neutralizing antibody geometric mean titers [ Time Frame: 28 days after CD-JEV vaccination ]
  • Frequency counts of immediate reactions observed following vaccination [ Time Frame: 30 minutes following each vaccination ]
  • Frequency counts of solicited local and systemic adverse events following vaccination [ Time Frame: 14 days following each vaccination ]
  • Frequency counts of unsolicited adverse events following vaccination [ Time Frame: 28 days following each vaccination ]
  • Frequency counts of serious adverse events following vaccination [ Time Frame: 112 days following first vaccination or until study end (expected to be 8 months) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Immunogenicity and Safety of Japanese Encephalitis Vaccine When Given With Measles-Mumps-Rubella (MMR) Vaccine
Official Title  ICMJE Immunogenicity and Safety of Concurrent Administration of Live, Attenuated SA 14-14-2 Japanese Encephalitis Vaccine and Measles-Mumps-Rubella Vaccine in Infants 9-12 Months of Age in the Philippines
Brief Summary This study aims to provide evidence that co-administration of measles-mumps-rubella vaccine (MMR) and live attenuated SA 14-14-2 Japanese encephalitis vaccine (CD-JEV) does not adversely affect immunogenicity or safety.
Detailed Description When incorporating a new vaccine in the Expanded Programme on Immunization (EPI), it is important to provide evidence that it can be introduced concurrently with other routine pediatric vaccines without significantly impairing the immune response to any vaccine while maximizing coverage and minimizing cost. This non-inferiority study aims to compare CD-JEV and MMR responses in a population of children in a country where MMR introduction is ongoing or planned. This information will help the ministries of health evaluate the addition of CD-JEV into routine EPI.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Encephalitis, Japanese
  • Measles
  • Mumps
  • Rubella
Intervention  ICMJE
  • Biological: Live attenuated SA 14-14-2 Japanese Encephalitis vaccine
    Single 0.5 mL dose of World Health Organization prequalified live, attenuated SA 14-14-2 JE vaccine manufactured by Chengdu Institute of Biological Products, Chengdu, China, administered by subcutaneous injection
    Other Names:
    • CD-JEV
    • CD.JEVAX®
    • RS.JEV®
  • Biological: Measles, mumps, rubella vaccine
    Single 0.5 mL dose of live, attenuated measles-mumps-rubella vaccine (Schwarz measles virus, RIT 4385 mumps strain, and Wistar RA 27/3 rubella virus) manufactured by GlaxoSmithKline, Inc., administered by subcutaneous injection.
    Other Names:
    • MMR
    • Priorix®
Study Arms  ICMJE
  • Experimental: Group 1 - MMR and CD-JEV
    Participants receiving one dose of CD-JEV vaccine and one dose of MMR vaccine concurrently at Day 0; Group 1 will also receive a second dose of MMR per the routine immunization schedule at Day 84 (12 months of age).
    Interventions:
    • Biological: Live attenuated SA 14-14-2 Japanese Encephalitis vaccine
    • Biological: Measles, mumps, rubella vaccine
  • Experimental: Group 2 - MMR then CD-JEV
    Participants receiving one dose of MMR vaccine at Day 0 and one dose of CD-JEV 56 days later. Group 2 will receive a second dose of MMR per the routine immunization schedule at Day 84 (12 months of age).
    Interventions:
    • Biological: Live attenuated SA 14-14-2 Japanese Encephalitis vaccine
    • Biological: Measles, mumps, rubella vaccine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 22, 2016)
628
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 11, 2017
Actual Primary Completion Date May 19, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 9 months to < 10 months at the time of enrollment.
  • Residence in the study area.
  • At least one parent or guardian willing to provide written informed consent.
  • Generally healthy and free of obvious health problems as established by medical history, physical examination, and clinical judgment.
  • A parent or guardian is willing to attend all planned study visits and allow home visits and phone contacts, as required by the protocol.

Exclusion Criteria:

  • Previous receipt of any measles-mumps-rubella containing vaccine.
  • Previous receipt of any Japanese encephalitis vaccine.
  • History of measles, mumps, rubella, or Japanese encephalitis infection.
  • Administration of any other vaccine within 28 days prior to administration of a study vaccine or planned vaccination of any vaccine other than catch-up doses of routine EPI vaccines or oral polio vaccine during the 28 days after study vaccination.
  • History of allergic disease or known hypersensitivity to any component of the study vaccines and/or following administration of vaccines included in the local program of immunization.
  • Use of any investigational or non-registered drug within 90 days prior to the administration of study vaccines or planned administration during the study period.
  • Administration of immunoglobulins and/or any blood products within 90 days prior to the administration of study vaccines or planned administration during the study period.
  • Chronic administration (defined as > 7 days) of immunosuppressing or other immune-modifying agents within 14 days before or after vaccination (including systemic corticosteroids equivalent to prednisone ≥ 0.5 mg/kg/day; topical and inhaled steroids are allowed).
  • Primary or acquired immunodeficiency, including human immunodeficiency virus (HIV) infection, or a family history of congenital or hereditary immunodeficiency as reported by parent.
  • Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by medical history or physical examination, which might interfere with the study objectives.
  • Severely malnourished infants as measured by World Health Organization weight-for-height tables (Z-score < -3).
  • Any condition or criterion that, in the opinion of the study physician, might compromise the well-being of the participant, compliance with study procedures, or interpretation of the outcomes of the study.
  • Acute illness at the time of enrollment defined as the presence of a moderate or severe illness with fever (axillary temperature ≥ 38.0°C) or without fever (severity determined at the discretion of the study physician). Acute illness is a temporary exclusion. Vaccination should be postponed at least 7 days after recovery. A visit for reassessment may be scheduled 7 days or more after temporary exclusion illness is resolved. Eligibility for study participation must be reassessed again at the next visit.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 9 Months to 9 Months   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Philippines
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02880865
Other Study ID Numbers  ICMJE JEV06
PHRR160822-001339 ( Registry Identifier: Philippine Health Research Registry (PHRR) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: The study team agrees that the practice of offering study results to participants in human research is fundamental to the ethical principle of respect for persons. However, the sponsor prefers to report at the aggregate level to maintain participant confidentiality and ensure results are community-based. Thus, the sponsor plans to report results at the aggregate level. The sponsor will produce a poster of the results to be placed at each health center. A community meeting may also be held to communicate the results. Aggregate results will also be posted on www.clinicaltrials.gov.
Responsible Party PATH
Study Sponsor  ICMJE PATH
Collaborators  ICMJE
  • Research Institute for Tropical Medicine,
  • Syneos Health
  • DF/Net Research, Inc.
Investigators  ICMJE
Principal Investigator: Maria Rosario Capeding, MD Research Institute for Tropical Medicine,
PRS Account PATH
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP