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Study of a Tetravalent Dengue Vaccine in Healthy Adults in Australia

Sponsor
Sanofi Pasteur, a Sanofi Company (Industry)
Overall Status
Completed
CT.gov ID
NCT01134263
Collaborator
(none)
715
Enrollment
8
Locations
5
Arms
27.9
Actual Duration (Months)
89.4
Patients Per Site
3.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study was to demonstrate that different CYD dengue vaccine lots manufactured using the same method and in the same location but at different times produce an equivalent immunological response after 3 doses.

Primary Objective

  • To demonstrate that three different Phase III lots of CYD dengue vaccine induce an equivalent immune response in terms of post-Dose 3 geometric mean titers (GMTs) against the four parental serotypes.
Secondary Objectives:

  • To demonstrate that data from one Phase II lot and pooled data from Phase III lots of CYD dengue vaccine show an equivalent immune response in terms of post-Dose 3 GMTs against the four parental serotypes.

  • To describe the safety of the CYD dengue vaccine in all participants after each dose.

Condition or Disease Intervention/Treatment Phase
  • Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, & 4 virus
  • Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, & 4 virus
  • Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, & 4 virus
  • Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, & 4 virus
  • Biological: Placebo: NaCl 0.9%
 Phase 3

Detailed Description

All participants received 3 doses of their assigned vaccine or placebo and provided blood samples at defined timepoints for flavivirus status and immunogenicity assessment. Safety data were collected in all participants after each dose and throughout the study.

Study Design

Study Type:
Interventional
Actual Enrollment :
715 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
An observer-blind procedure was followed for the three injections with CYD dengue vaccine or placebo. Neither the observer, Investigator, Sponsor, nor the participant knew which product was administered.
Primary Purpose:
Prevention
Official Title:
Lot-to-Lot Consistency and Bridging Study of a Tetravalent Dengue Vaccine in Healthy Adults in Australia
Actual Study Start Date :
Oct 5, 2010
Actual Primary Completion Date :
Nov 1, 2012
Actual Study Completion Date :
Feb 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: CYD Dengue Vaccine Phase III Lot 1

Participants received 3 doses of CYD dengue vaccine (Phase III Lot 1), one each at Day 0 (vaccination 1),Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously.

Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, & 4 virus
0.5 ml, Subcutaneous (SC)
Other Names:
  • CYD Dengue vaccine

    		•
    Experimental: CYD Dengue vaccine - Phase III Lot 2

    Participants received 3 doses of CYD dengue vaccine (Phase III Lot 2) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously.

    Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, & 4 virus
    0.5 ml, SC
    Other Names:
  • CYD Dengue vaccine

    		•
    Experimental: CYD Dengue vaccine - Phase III Lot 3

    Participants received 3 doses of CYD dengue vaccine (Phase III Lot 3) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously.

    Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, & 4 virus
    0.5 ml, SC
    Other Names:
  • CYD Dengue vaccine

    		•
    Experimental: CYD Dengue vaccine - Phase II Lot

    Participants received 3 doses of CYD dengue vaccine (Phase II Lot) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously.

    Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, & 4 virus
    0.5 ml, Subcutaneous (SC)
    Other Names:
  • CYD Dengue vaccine

    		•
    Placebo Comparator: Placebo

    Participants received placebo matched to CYD dengue vaccine, one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously.

    Biological: Placebo: NaCl 0.9%
    0.5 ml, SC
    Other Names:
  • NaCl

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Post-Dose 3 Geometric Mean Titers (GMTs) of Antibodies Against Each of the Four Dengue Virus Serotypes Following Vaccination With Phase III Lots of CYD Dengue Vaccine [28 days post-injection 3]

      GMTs against each of the 4 serotypes (serotype 1, serotype 2, serotype 3 and serotype 4) of dengue virus strains were assessed using the plaque reduction neutralization test (PRNT) assay. The lot-to-lot consistency between 3 Phase III lots was based on the use of the two-sided 95% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots.

    Secondary Outcome Measures

    1. Geometric Mean Titers of Antibodies Against Each of the Four Dengue Virus Serotypes Following Vaccination With Pooled Phase III Lots (1, 2 or 3 )and Phase II Lot of CYD Dengue Vaccine [28 days post-Injection 3]

      GMTs against each of the 4 serotypes (serotype 1, serotype 2, serotype 3 and serotype 4) of dengue virus strains were assessed using PRNT assay. Equivalence of Phase III vaccine with Phase II vaccine was assessed by Bridging between Phase III and Phase II Lot of CYD Dengue Vaccine.

    2. Number of Participants With Solicited Injection Site Reactions After Any Vaccination [7 days post any vaccination]

      Solicited injection site reactions: Pain, Erythema, and Swelling. Pain: Grade 3: Significant; prevents daily activity. Erythema and Swelling: Grade 3: > 10 cm. Participants with Injection Site Reactions of any Grade (1, 2 or 3) and grade 3 were reported.

    3. Number of Participants With Solicited Systemic Reactions After Any Vaccination [14 days post any vaccination]

      Solicited systemic reactions: Asthenia, Fever, Headache, Malaise and Myalgia. Fever: Grade 3: >=39.0°C (>=102.1°F). Headache, malaise, myalgia and asthenia: Grade 3: significant; prevents daily activity. Participants with systemic reactions of any Grade (1, 2 or 3) and grade 3 were reported.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    • Aged 18 to 60 years on the day of inclusion.

    • Informed consent form was signed and dated.

    • Able to attend all scheduled visits and to comply with all trial procedures.

    • For a woman of childbearing potential, use of an effective method of contraception, or abstinence from at least 4 weeks prior to the first vaccination until at least 4 weeks after the last vaccination (i.e., for 14 months).

    Exclusion Criteria:

    • Known pregnancy, or a positive urine pregnancy test.

    • History of flavivirus infection or vaccination or prolonged habitation in a dengue endemic area.

    • Currently breastfeeding a child.

    • Participation in another clinical trial investigating a vaccine, drug, medical device, or medical procedure in the 4 weeks preceding the first trial vaccination.

    • Planned participation in another clinical trial during the present trial period.

    • Planned receipt of any vaccine in the 4 weeks following any trial vaccination, except for pandemic influenza vaccination.

    • Receipt of blood or blood-derived products in the past 3 months, which might interfere with assessment of the immune response.

    • Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months).

    • Self-reported seropositivity for human immunodeficiency virus (HIV).

    • Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine used in the trial or to a vaccine containing any of the same substances.

    • Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.

    • Current alcohol abuse or drug addiction that might interfere with the ability to comply with trial procedures.

    • Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere with trial conduct or completion.

    • Identified as a site employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members (i.e., immediate, husband, wife and their children, adopted or natural) of the site employees or the Investigator.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Adelaide Australia SA 5000
    2 Carina Heights Australia QLD 4152
    3 Enoggera Australia QLD 4051
    4 Heidelberg Australia VIC 3084
    5 Herston Australia QLD 4006
    6 Herston Australia QLD 4029
    7 Subiaco Australia WA 6008
    8 Westmead Australia NSW 2145

    Sponsors and Collaborators

    • Sanofi Pasteur, a Sanofi Company

    Investigators

    • Study Director: Medical Director, Sanofi Pasteur Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Sanofi Pasteur, a Sanofi Company
    ClinicalTrials.gov Identifier:
    NCT01134263
    Other Study ID Numbers:
    • CYD17
    • U1111-1114-7646
    First Posted:
    May 31, 2010
    Last Update Posted:
    Jul 24, 2019
    Last Verified:
    May 1, 2019
    Keywords provided by Sanofi Pasteur, a Sanofi Company
    Dengue Fever
    Dengue Hemorrhagic Fever
    CYD Dengue Vaccine
    Lot Consistency
    Additional relevant MeSH terms:
    Dengue
    Hemorrhagic Fevers, Viral
    Severe Dengue
    Fever
    Hyperthermia
    Vaccines

    Study Results

    Participant Flow

    Recruitment Details Study participants were enrolled from 05 October 2010 to 26 November 2010 at 8 study sites in Australia.
    Pre-assignment Detail A total of 715 participants who met all of the inclusion criteria and none of the exclusion criteria were enrolled in the study.
    Arm/Group Title CYD Dengue Vaccine Phase III Lot 1 CYD Dengue Vaccine Phase III Lot 2 CYD Dengue Vaccine Phase III Lot 3 CYD Dengue Vaccine Phase II Lot Placebo
    Arm/Group Description Participants received 3 doses of CYD dengue vaccine (Phase III Lot 1), one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 2) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 3) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase II Lot) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received placebo matched to CYD dengue vaccine, one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously.
    Period Title: Overall Study
    STARTED 164 163 163 168 57
    Received Vaccination 1 163 162 163 167 57
    Received Vaccination 2 151 152 139 154 53
    Received Vaccination 3 140 145 134 151 49
    Safety Population 163 161 164 167 57
    COMPLETED 140 143 134 149 48
    NOT COMPLETED 24 20 29 19 9

    Baseline Characteristics

    Arm/Group Title CYD Dengue Vaccine Phase III Lot 1 CYD Dengue Vaccine Phase III Lot 2 CYD Dengue Vaccine Phase III Lot 3 CYD Dengue Vaccine Phase II Lot Placebo Total
    Arm/Group Description Participants received 3 doses of CYD dengue vaccine (Phase III Lot 1), one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 2) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of 0.5 ml CYD dengue vaccine (Phase III Lot 3) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of 0.5 ml CYD dengue vaccine (Phase II Lot) one each at Day 0 (vaccination 1), 6 (vaccination 2), and 12 (vaccination 3) months, subcutaneously. Participants received placebo matched to CYD dengue vaccine, one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Total of all reporting groups
    Overall Participants 163 162 163 167 57 712
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    39.4
    (13.3)
    39.4
    (12.9)
    38.7
    (14.1)
    38.4
    (13.2)
    39.7
    (13.5)
    39.0
    (13.4)
    Sex: Female, Male (Count of Participants)
    Female
    103
    63.2%
    87
    53.7%
    84
    51.5%
    84
    50.3%
    33
    57.9%
    391
    54.9%
    Male
    60
    36.8%
    75
    46.3%
    79
    48.5%
    83
    49.7%
    24
    42.1%
    321
    45.1%

    Outcome Measures

    1. Primary Outcome
    Title Post-Dose 3 Geometric Mean Titers (GMTs) of Antibodies Against Each of the Four Dengue Virus Serotypes Following Vaccination With Phase III Lots of CYD Dengue Vaccine
    Description GMTs against each of the 4 serotypes (serotype 1, serotype 2, serotype 3 and serotype 4) of dengue virus strains were assessed using the plaque reduction neutralization test (PRNT) assay. The lot-to-lot consistency between 3 Phase III lots was based on the use of the two-sided 95% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots.
    Time Frame 28 days post-injection 3

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on Per-protocol analysis set which included participants who received at least 1 dose of the study vaccine or placebo and had no protocol deviations. Data for this outcome measure was not planned to be collected and analyzed for Phase II Lot and placebo.
    Arm/Group Title CYD Dengue Vaccine Phase III Lot 1 CYD Dengue Vaccine Phase III Lot 2 CYD Dengue Vaccine Phase III Lot 3
    Arm/Group Description Participants received 3 doses of CYD dengue vaccine (Phase III Lot 1), one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 2) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 3) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month12 (vaccination 3) , subcutaneously.
    Measure Participants 129 123 124
    Dengue Virus Serotype 1
    20.6
    18.1
    17.1
    Dengue Virus Serotype 2
    65.9
    44.1
    58.1
    Dengue Virus Serotype 3
    74.2
    65
    71.6
    Dengue Virus Serotype 4
    131.8
    94.6
    108.5
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 2
    Comments Dengue Virus Serotype 1: Phase III Lot 1 vs Lot 2
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value 0.055
    Confidence Interval (2-Sided) 95%
    -0.067 to 0.178
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 2, CYD Dengue Vaccine Phase III Lot 3
    Comments Dengue Virus Serotype 1: Phase III Lot 2 vs Lot 3
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value 0.024
    Confidence Interval (2-Sided) 95%
    -0.102 to 0.151
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 3
    Comments Dengue Virus Serotype 1: Phase III Lot 3 vs Lot 1
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value -0.080
    Confidence Interval (2-Sided) 95%
    -0.204 to 0.045
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 2
    Comments Dengue Virus Serotype 2: Phase III Lot 1 vs Lot 2
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value 0.174
    Confidence Interval (2-Sided) 95%
    0.009 to 0.340
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 2, CYD Dengue Vaccine Phase III Lot 3
    Comments Dengue Virus Serotype 2: Phase III Lot 2 vs Lot 3
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value -0.120
    Confidence Interval (2-Sided) 95%
    -0.297 to 0.056
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 3
    Comments Dengue Virus Serotype 2: Phase III Lot 3 vs Lot 1
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value -0.054
    Confidence Interval (2-Sided) 95%
    -0.225 to 0.117
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 2
    Comments Dengue Virus Serotype 3: Phase III Lot 1 vs Lot 2
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value 0.058
    Confidence Interval (2-Sided) 95%
    -0.068 to 0.184
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 2, CYD Dengue Vaccine Phase III Lot 3
    Comments Dengue Virus Serotype 3: Phase III Lot 2 vs Lot 3
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value -0.042
    Confidence Interval (2-Sided) 95%
    -0.167 to 0.082
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 3
    Comments Dengue Virus Serotype 3: Phase III Lot 3 vs Lot 1
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value -0.016
    Confidence Interval (2-Sided) 95%
    -0.144 to 0.113
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 2
    Comments Dengue Virus Serotype 4: Phase III Lot 1 vs Lot 2
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value 0.144
    Confidence Interval (2-Sided) 95%
    -0.006 to 0.295
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 2, CYD Dengue Vaccine Phase III Lot 3
    Comments Dengue Virus Serotype 4: Phase III Lot 2 vs Lot 3
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value -0.060
    Confidence Interval (2-Sided) 95%
    -0.207 to 0.088
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 3
    Comments Dengue Virus Serotype 4: Phase III Lot 3 vs Lot 1
    Type of Statistical Test Equivalence
    Comments Lot consistency for each pair of lots was demonstrated if, for each pair of lots and each serotype the lower limit of the 95% CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value -0.085
    Confidence Interval (2-Sided) 95%
    -0.242 to 0.073
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Geometric Mean Titers of Antibodies Against Each of the Four Dengue Virus Serotypes Following Vaccination With Pooled Phase III Lots (1, 2 or 3 )and Phase II Lot of CYD Dengue Vaccine
    Description GMTs against each of the 4 serotypes (serotype 1, serotype 2, serotype 3 and serotype 4) of dengue virus strains were assessed using PRNT assay. Equivalence of Phase III vaccine with Phase II vaccine was assessed by Bridging between Phase III and Phase II Lot of CYD Dengue Vaccine.
    Time Frame 28 days post-Injection 3

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on Per Protocol Analysis Set. Here, 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was not planned to be collected and analyzed for placebo.
    Arm/Group Title CYD Dengue Vaccine Pooled Phase III Lot CYD Dengue Vaccine Phase II Lot
    Arm/Group Description Participants received 3 doses of CYD dengue vaccine one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3) from any of the Phase III Lots 1, 2 or 3. Participants received 3 doses of CYD dengue vaccine (Phase II Lot) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously.
    Measure Participants 376 128
    Dengue Virus Serotype 1
    18.6
    15.1
    Dengue Virus Serotype 2
    55.4
    25.7
    Dengue Virus Serotype 3
    70.2
    83.6
    Dengue Virus Serotype 4
    110.9
    115.4
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 2
    Comments Dengue Virus Serotype 1
    Type of Statistical Test Equivalence
    Comments Equivalence between the pooled Phase III and Phase II was demonstrated if, for each serotype the lower limit of the 95%CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value 0.091
    Confidence Interval (2-Sided) 95%
    -0.009 to 0.192
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 2
    Comments Dengue Virus Serotype 2
    Type of Statistical Test Equivalence
    Comments Equivalence between the pooled Phase III and Phase II was demonstrated if, for each serotype the lower limit of the 95%CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value 0.334
    Confidence Interval (2-Sided) 95%
    0.202 to 0.466
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 2
    Comments Dengue Virus Serotype 3
    Type of Statistical Test Equivalence
    Comments Equivalence between the pooled Phase III and Phase II was demonstrated if, for each serotype the lower limit of the 95%CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value -0.076
    Confidence Interval (2-Sided) 95%
    -0.173 to 0.021
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection CYD Dengue Vaccine Phase III Lot 1, CYD Dengue Vaccine Phase III Lot 2
    Comments Dengue Virus Serotype 4
    Type of Statistical Test Equivalence
    Comments Equivalence between the pooled Phase III and Phase II was demonstrated if, for each serotype the lower limit of the 95%CI was > -0.301 and the upper limit was < 0.301.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference of Log10 GMT
    Estimated Value -0.017
    Confidence Interval (2-Sided) 95%
    -0.137 to 0.103
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Number of Participants With Solicited Injection Site Reactions After Any Vaccination
    Description Solicited injection site reactions: Pain, Erythema, and Swelling. Pain: Grade 3: Significant; prevents daily activity. Erythema and Swelling: Grade 3: > 10 cm. Participants with Injection Site Reactions of any Grade (1, 2 or 3) and grade 3 were reported.
    Time Frame 7 days post any vaccination

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on Safety Analysis Set which included all participants who received the study dose, and participants were analyzed according to the treatment received. Here, 'number analyzed' = participants with available data for each specified category.
    Arm/Group Title CYD Dengue Vaccine Phase III Lot 1 CYD Dengue Vaccine Phase III Lot 2 CYD Dengue Vaccine Phase III Lot 3 CYD Dengue Vaccine Phase II Lot Placebo
    Arm/Group Description Participants received 3 doses of 0.5 ml CYD dengue vaccine (Phase III Lot 1), one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 2) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 3) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase II Lot) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received placebo matched to CYD dengue vaccine, one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously.
    Measure Participants 163 161 164 167 57
    Pain: Any
    73
    44.8%
    74
    45.7%
    73
    44.8%
    78
    46.7%
    11
    19.3%
    Pain: Grade 3
    1
    0.6%
    1
    0.6%
    1
    0.6%
    0
    0%
    0
    0%
    Erythema: Any
    22
    13.5%
    15
    9.3%
    25
    15.3%
    24
    14.4%
    0
    0%
    Erythema: Grade 3
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Swelling: Any
    8
    4.9%
    4
    2.5%
    2
    1.2%
    5
    3%
    1
    1.8%
    Swelling: Grade 3
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4. Secondary Outcome
    Title Number of Participants With Solicited Systemic Reactions After Any Vaccination
    Description Solicited systemic reactions: Asthenia, Fever, Headache, Malaise and Myalgia. Fever: Grade 3: >=39.0°C (>=102.1°F). Headache, malaise, myalgia and asthenia: Grade 3: significant; prevents daily activity. Participants with systemic reactions of any Grade (1, 2 or 3) and grade 3 were reported.
    Time Frame 14 days post any vaccination

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on Safety Analysis Set. Here, 'number analyzed' = participants with available data for each specified category.
    Arm/Group Title CYD Dengue Vaccine Phase III Lot 1 CYD Dengue Vaccine Phase III Lot 2 CYD Dengue Vaccine Phase III Lot 3 CYD Dengue Vaccine Phase II Lot Placebo
    Arm/Group Description Participants received 3 doses of CYD dengue vaccine (Phase III Lot 1), one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 2) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 3) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase II Lot) one each at Day 0(vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received placebo matched to CYD dengue vaccine, one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously.
    Measure Participants 163 161 164 167 57
    Asthenia: Any
    49
    30.1%
    51
    31.5%
    57
    35%
    69
    41.3%
    20
    35.1%
    Asthenia: Grade 3
    3
    1.8%
    9
    5.6%
    11
    6.7%
    9
    5.4%
    2
    3.5%
    Fever: Any
    5
    3.1%
    8
    4.9%
    8
    4.9%
    5
    3%
    1
    1.8%
    Fever: Grade 3
    0
    0%
    0
    0%
    1
    0.6%
    0
    0%
    0
    0%
    Headache: Any
    100
    61.3%
    96
    59.3%
    108
    66.3%
    104
    62.3%
    28
    49.1%
    Headache: Grade 3
    8
    4.9%
    22
    13.6%
    17
    10.4%
    14
    8.4%
    4
    7%
    Malaise: Any
    72
    44.2%
    75
    46.3%
    97
    59.5%
    90
    53.9%
    26
    45.6%
    Malaise: Grade 3
    10
    6.1%
    17
    10.5%
    19
    11.7%
    13
    7.8%
    3
    5.3%
    Myalgia: Any
    70
    42.9%
    69
    42.6%
    71
    43.6%
    84
    50.3%
    21
    36.8%
    Myalgia: Grade 3
    4
    2.5%
    10
    6.2%
    11
    6.7%
    13
    7.8%
    3
    5.3%

    Adverse Events

    Time Frame Adverse event (AE) data were collected from Day 0 (post-vaccination) up to 28 days after each dose of CYD dengue vaccine or Placebo. Solicited Reaction (SR) data were collected within 7 and 14 days after each vaccination. Serious adverse event (SAE) data were collected throughout the study, up to 30 days post-vaccination 3 (up to Month 13).
    Adverse Event Reporting Description Analysis was performed on Safety Analysis Set.
    Arm/Group Title CYD Dengue Vaccine Phase III Lot 1 CYD Dengue Vaccine Phase III Lot 2 CYD Dengue Vaccine Phase III Lot 3 CYD Dengue Vaccine Phase II Lot Placebo
    Arm/Group Description Participants received 3 doses of CYD dengue vaccine (Phase III Lot 1), one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 2) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase III Lot 3) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received 3 doses of CYD dengue vaccine (Phase II Lot) one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously. Participants received placebo matched to CYD dengue vaccine, one each at Day 0 (vaccination 1), Month 6 (vaccination 2), and Month 12 (vaccination 3), subcutaneously.
    All Cause Mortality
    CYD Dengue Vaccine Phase III Lot 1 CYD Dengue Vaccine Phase III Lot 2 CYD Dengue Vaccine Phase III Lot 3 CYD Dengue Vaccine Phase II Lot Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/163 (0%) 0/161 (0%) 0/164 (0%) 0/167 (0%) 0/57 (0%)
    Serious Adverse Events
    CYD Dengue Vaccine Phase III Lot 1 CYD Dengue Vaccine Phase III Lot 2 CYD Dengue Vaccine Phase III Lot 3 CYD Dengue Vaccine Phase II Lot Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 10/163 (6.1%) 9/161 (5.6%) 5/164 (3%) 9/167 (5.4%) 1/57 (1.8%)
    Cardiac disorders
    Stress Cardiomyopathy 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Gastrointestinal disorders
    Abdominal Pain 0/163 (0%) 0 1/161 (0.6%) 1 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Inguinal Hernia 0/163 (0%) 0 0/161 (0%) 0 1/164 (0.6%) 1 0/167 (0%) 0 0/57 (0%) 0
    Pancreatitis 0/163 (0%) 0 0/161 (0%) 0 1/164 (0.6%) 1 0/167 (0%) 0 0/57 (0%) 0
    Pancreatitis Acute 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    General disorders
    Chest Pain 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 1/167 (0.6%) 1 0/57 (0%) 0
    Pyrexia 0/163 (0%) 0 0/161 (0%) 0 1/164 (0.6%) 1 0/167 (0%) 0 0/57 (0%) 0
    Hepatobiliary disorders
    Cholecystitis 0/163 (0%) 0 1/161 (0.6%) 1 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Cholelithiasis 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 1/167 (0.6%) 1 0/57 (0%) 0
    Immune system disorders
    Hypersensitivity 0/163 (0%) 0 1/161 (0.6%) 1 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Infections and infestations
    Appendicitis 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 1/167 (0.6%) 1 0/57 (0%) 0
    Bartholin's Abscess 0/163 (0%) 0 1/161 (0.6%) 1 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Cellulitis 1/163 (0.6%) 1 1/161 (0.6%) 1 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Groin Abscess 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Skin Infection 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 1/57 (1.8%) 1
    Injury, poisoning and procedural complications
    Fall 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 1/167 (0.6%) 1 0/57 (0%) 0
    Foreign Body 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 1/167 (0.6%) 1 0/57 (0%) 0
    Ligament Rupture 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Muscle Rupture 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Metabolism and nutrition disorders
    Diabetic Ketoacidosis 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Type 2 Diabetes Mellitus 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis 0/163 (0%) 0 1/161 (0.6%) 1 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Intervertebral Disc Protrusion 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Osteoarthritis 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 1/167 (0.6%) 1 0/57 (0%) 0
    Polymyalgia Rheumatica 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 1/167 (0.6%) 1 0/57 (0%) 0
    Tendonitis 0/163 (0%) 0 1/161 (0.6%) 1 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hypergammaglobulinaemia Benign Monoclonal 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Malignant Melanoma 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Malignant Melanoma In Situ 0/163 (0%) 0 1/161 (0.6%) 1 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Prostate Cancer 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 1/57 (1.8%) 1
    Nervous system disorders
    Headache 0/163 (0%) 0 1/161 (0.6%) 1 1/164 (0.6%) 1 0/167 (0%) 0 0/57 (0%) 0
    Paraesthesia 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 1/167 (0.6%) 1 0/57 (0%) 0
    Transient Ischaemic Attack 0/163 (0%) 0 0/161 (0%) 0 1/164 (0.6%) 3 0/167 (0%) 0 0/57 (0%) 0
    Psychiatric disorders
    Anxiety 0/163 (0%) 0 1/161 (0.6%) 4 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Renal and urinary disorders
    Calculus Ureteric 1/163 (0.6%) 1 0/161 (0%) 0 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Nephritis 0/163 (0%) 0 1/161 (0.6%) 1 0/164 (0%) 0 0/167 (0%) 0 0/57 (0%) 0
    Reproductive system and breast disorders
    Pelvic Pain 0/163 (0%) 0 0/161 (0%) 0 0/164 (0%) 0 1/167 (0.6%) 1 0/57 (0%) 0
    Other (Not Including Serious) Adverse Events
    CYD Dengue Vaccine Phase III Lot 1 CYD Dengue Vaccine Phase III Lot 2 CYD Dengue Vaccine Phase III Lot 3 CYD Dengue Vaccine Phase II Lot Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 136/163 (83.4%) 131/161 (81.4%) 135/164 (82.3%) 140/167 (83.8%) 41/57 (71.9%)
    Gastrointestinal disorders
    Toothache 1/163 (0.6%) 1 2/161 (1.2%) 3 4/164 (2.4%) 4 1/167 (0.6%) 4 3/57 (5.3%) 3
    General disorders
    Asthenia 49/163 (30.1%) 66 51/161 (31.7%) 72 58/164 (35.4%) 74 69/167 (41.3%) 90 20/57 (35.1%) 26
    Injection Site Erythema 22/163 (13.5%) 26 15/161 (9.3%) 20 25/164 (15.2%) 31 24/167 (14.4%) 32 0/57 (0%) 0
    Injection Site Haematoma 12/163 (7.4%) 12 9/161 (5.6%) 11 12/164 (7.3%) 13 10/167 (6%) 10 6/57 (10.5%) 6
    Injection Site Pain 73/163 (44.8%) 122 74/161 (46%) 114 73/164 (44.5%) 122 78/167 (46.7%) 122 11/57 (19.3%) 15
    Malaise 72/163 (44.2%) 110 75/161 (46.6%) 116 97/164 (59.1%) 146 90/167 (53.9%) 126 26/57 (45.6%) 43
    Pyrexia 6/163 (3.7%) 7 9/161 (5.6%) 11 9/164 (5.5%) 10 5/167 (3%) 6 1/57 (1.8%) 1
    Infections and infestations
    Nasopharyngitis 11/163 (6.7%) 13 6/161 (3.7%) 6 9/164 (5.5%) 11 8/167 (4.8%) 8 4/57 (7%) 4
    Upper Respiratory Tract Infection 13/163 (8%) 13 14/161 (8.7%) 15 16/164 (9.8%) 18 14/167 (8.4%) 15 6/57 (10.5%) 7
    Musculoskeletal and connective tissue disorders
    Myalgia 70/163 (42.9%) 100 69/161 (42.9%) 105 72/164 (43.9%) 111 84/167 (50.3%) 124 21/57 (36.8%) 30
    Nervous system disorders
    Headache 103/163 (63.2%) 188 97/161 (60.2%) 186 108/164 (65.9%) 208 104/167 (62.3%) 201 28/57 (49.1%) 61
    Reproductive system and breast disorders
    Dysmenorrhoea 7/163 (4.3%) 9 5/161 (3.1%) 9 2/164 (1.2%) 2 4/167 (2.4%) 5 3/57 (5.3%) 4
    Respiratory, thoracic and mediastinal disorders
    Cough 9/163 (5.5%) 10 3/161 (1.9%) 3 3/164 (1.8%) 3 6/167 (3.6%) 6 1/57 (1.8%) 1
    Oropharyngeal Pain 16/163 (9.8%) 17 5/161 (3.1%) 5 7/164 (4.3%) 7 12/167 (7.2%) 13 3/57 (5.3%) 3

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Sponsor must have the opportunity to review at least 60 days prior to submission for publication or presentation. If review indicates that potentially patentable subject matter would be disclosed, publication or public disclosure may be delayed for a maximum of an additional 60 days to allow for filing the necessary patent applications.

    Results Point of Contact

    Name/Title Trial Transparency Team
    Organization Sanofi Pasteur
    Phone
    Email Contact-US@sanofi.com
    Responsible Party:
    Sanofi Pasteur, a Sanofi Company
    ClinicalTrials.gov Identifier:
    NCT01134263
    Other Study ID Numbers:
    • CYD17
    • U1111-1114-7646
    First Posted:
    May 31, 2010
    Last Update Posted:
    Jul 24, 2019
    Last Verified:
    May 1, 2019