Clinical Trial Results:
LongTerm Safety FollowUp of Thai Children Who Were Included in an Efficacy Study of a Tetravalent Dengue Vaccine
Summary


EudraCT number 
201400173788 
Trial protocol 
Outside EU/EEA 
Global end of trial date 
19 Feb 2016

Results information


Results version number 
v2(current) 
This version publication date 
23 Aug 2018

First version publication date 
19 May 2016

Other versions 
v1 
Version creation reason 

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information


Trial identification


Sponsor protocol code 
CYD57


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT01983553  
WHO universal trial number (UTN) 
U111111277380  
Sponsors


Sponsor organisation name 
Sanofi Pasteur SA


Sponsor organisation address 
14 Espace Henry Vallée, Lyon, France, 69007


Public contact 
Trial Transparency, Sanofi Pasteur, RegistryContactUs@sanofipasteur.com


Scientific contact 
Trial Transparency, Sanofi Pasteur, RegistryContactUs@sanofipasteur.com


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
Yes


EMA paediatric investigation plan number(s) 
EMEA001201PIP0111  
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? 
Yes


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
20 Oct 2016


Is this the analysis of the primary completion data? 
No


Global end of trial reached? 
Yes


Global end of trial date 
19 Feb 2016


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
The main objective of this study is to evaluate the continuous longterm followup of hospitalized dengue and safety of subjects who received CYD dengue vaccine in study CYD23 (EudraCT No. 201400171025) including retrospective data collection (i.e., including the blood samples collected from March 05th, 2012 to September 9th, 2013) and prospective data collection from CYD57 study start (September 10th, 2013) until the end of the study, and the following activities will be performed.
1) To describe the incidence of virologicallyconfirmed hospitalized dengue cases.
2) To characterize hospitalized dengue cases.
3) To evaluate the occurrence of related and fatal serious adverse events (SAEs).


Protection of trial subjects 
Subjects were vaccinated in a previous study, CYD23. No vaccination was administered as part of this study.


Background therapy 
In study CYD23, subjects age 4 to 11 were randomized to receive 3 injections of either CYD dengue vaccine or control, 1 each at 0, 6, and 12 months. Those that received at least one injection were eligible to be included in this followup study.  
Evidence for comparator 
Not applicable  
Actual start date of recruitment 
10 Sep 2013


Long term followup planned 
Yes


Long term followup rationale 
Safety, Efficacy  
Long term followup duration 
4 Years  
Independent data monitoring committee (IDMC) involvement? 
Yes


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
Thailand: 3203


Worldwide total number of subjects 
3203


EEA total number of subjects 
0


Number of subjects enrolled per age group 

In utero 
0


Preterm newborn  gestational age < 37 wk 
0


Newborns (027 days) 
0


Infants and toddlers (28 days23 months) 
0


Children (211 years) 
3203


Adolescents (1217 years) 
0


Adults (1864 years) 
0


From 65 to 84 years 
0


85 years and over 
0



Recruitment


Recruitment details 
Study subjects were enrolled in the original study CYD23 from 10 September 2013 to 29 November 2013 at 1 clinic center in Thailand.  
Preassignment


Screening details 
Of the 3997 subjects who were treated in the original study CYD23, a total of 3203 subjects were included in the 4year safety followup CYD57 study.  
Period 1


Period 1 title 
Overall trial (overall period)


Is this the baseline period? 
Yes  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Assessor, Subject, Investigator, Monitor  
Blinding implementation details 
Subjects and site staff remained blinded to the treatment allocation in CYD23 until the end of the study (CYD57) to avoid any bias in the safety followup (detection of dengue cases). In the event of an emergency (i.e., serious adverse event), the code of CYD57 could be broken by the Investigator as explained in the codebreaking procedures described in the Operating Guidelines.


Arms


Are arms mutually exclusive 
Yes


Arm title

CYD Dengue Vaccine Group  
Arm description 
Subjects received 3 injections of CYD dengue vaccine, 1 injection each at 0, 6, and 12 months in study CYD23.  
Arm type 
Experimental  
Investigational medicinal product name 
CYD Dengue vaccine


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Powder and solvent for suspension for injection


Routes of administration 
Subcutaneous use


Dosage and administration details 
0.5 mL, subcutaneous, 1 injection each at 0, 6, and 12 months in the initial CYD23 study.


Arm title

Control Group  
Arm description 
Subjects received either Rabies vaccine (Verorab®) or placebo control as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.  
Arm type 
Active comparator  
Investigational medicinal product name 
Placebo (sodium chloride)


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Suspension for injection


Routes of administration 
Subcutaneous use


Dosage and administration details 
0.5 mL, subcutaneous, 1 injection of either Verorab or placebo as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.


Investigational medicinal product name 
Rabies vaccine (Verorab®)


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Powder and solvent for suspension for injection


Routes of administration 
Subcutaneous use


Dosage and administration details 
0.5 mL, subcutaneous, 1 injection of either Verorab or placebo as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.





Baseline characteristics reporting groups


Reporting group title 
CYD Dengue Vaccine Group


Reporting group description 
Subjects received 3 injections of CYD dengue vaccine, 1 injection each at 0, 6, and 12 months in study CYD23.  
Reporting group title 
Control Group


Reporting group description 
Subjects received either Rabies vaccine (Verorab®) or placebo control as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.  



End points reporting groups


Reporting group title 
CYD Dengue Vaccine Group


Reporting group description 
Subjects received 3 injections of CYD dengue vaccine, 1 injection each at 0, 6, and 12 months in study CYD23.  
Reporting group title 
Control Group


Reporting group description 
Subjects received either Rabies vaccine (Verorab®) or placebo control as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study. 


End point title 
Annual Incidence of Hospitalized VirologicallyConfirmed Dengue Due to Any and Each Serotype Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study  
End point description 
Annual incidence rate was defined as the cases among the number of subjects present at the beginning of each period (M) multiplied by 100 converted in annual rate (Annual incidence rate = Cases among M*100). Analysis was performed on Followup Analysis Set (FupAS) which included all subjects who were included in study CYD57.


End point type 
Primary


End point timeframe 
Year 1 to Year 4 postvaccination




Statistical analysis title 
Relative risk; Any of the 4 Serotypes  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[1]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.93


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.64  
upper limit 
1.36  
Notes [1]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative risk; Serotype 1  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 1 between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[2]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.96


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.44  
upper limit 
2.21  
Notes [2]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative risk; Serotype 2  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 2 between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[3]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
1.326


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.64  
upper limit 
2.94  
Notes [3]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative risk; Serotype 3  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 3 between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[4]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
1.056


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.48  
upper limit 
2.51  
Notes [4]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative risk; Serotype 4  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[5]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.629


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.27  
upper limit 
1.47  
Notes [5]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative risk; Unserotyped  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Unserotyped between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[6]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
1.22  
Notes [6]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 


End point title 
Number of Cases and Episodes of Hospitalized VirologicallyConfirmed Dengue Due to Any and Each Serotype Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study ^{[7]}  
End point description 
Cases were defined as the number of subjects with at least one hospitalized virologicallyconfirmed dengue episode. Episodes were defined as the number of hospitalized virologicallyconfirmed dengue episodes. Analysis was performed on FupAS.


End point type 
Primary


End point timeframe 
Year 1 to Year 4 postvaccination


Notes [7]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome. 



No statistical analyses for this end point 


End point title 
Annual Incidence of Hospitalized VirologicallyConfirmed Dengue Due to Any and Each Serotype Collected By Age Group Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study  
End point description 
Annual incidence rate was defined as the cases among the number of subjects present at the beginning of each period (M) multiplied by 100 converted in annual rate (Annual incidence rate = Cases among M*100). Analysis was performed on FupAS. Here, “n” signifies number of subjects evaluable for each specified category. Endpoint values <0.1 were rounded to 0.1.


End point type 
Primary


End point timeframe 
Year 1 to Year 4 postvaccination




Statistical analysis title 
Relative Risk; 4 to 5 years; Any Serotype  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes (4 to 5 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[8]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
1.411


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.64  
upper limit 
3.42  
Notes [8]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 6 to 11 years; Any Serotype  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[9]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.807


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.53  
upper limit 
1.25  
Notes [9]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 4 to 5 years; Serotype 1  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 1 (4 to 5 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[10]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
4.885


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7  
upper limit 
212.02  
Notes [10]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 6 to 11 years; Serotype 1  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 1 (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[11]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.557


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.21  
upper limit 
1.46  
Notes [11]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 4 to 5 years; Serotype 2  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 2 (4 to 5 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[12]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
2.931


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.36  
upper limit 
134.83  
Notes [12]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 6 to 11 years; Serotype 2  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 2 (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[13]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
1.165


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.53  
upper limit 
2.74  
Notes [13]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 4 to 5 years; Serotype 3  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 for Serotype 3 (4 to 5 year) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[14]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
1.221


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.2  
upper limit 
12.83  
Notes [14]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 6 to 11 years; Serotype 3  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 3 (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[15]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
1.013


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.41  
upper limit 
2.73  
Notes [15]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 4 to 5 years; Serotype 4  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 (4 to 5 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[16]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.977


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.21  
upper limit 
6.04  
Notes [16]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 6 to 11 years; Serotype 4  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[17]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.506


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.18  
upper limit 
1.44  
Notes [17]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 4 to 5 years; Unserotyped  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Unserotyped (4 to 5 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 525 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[18]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
2.6  
Notes [18]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; 6 to 11 years; Unserotyped  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Unserotyped (6 to 11 years) between the CYD Dengue vaccine group and the Control group. Total number of subjects analysed were 2618 instead of 3203.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[19]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.75  
Notes [19]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 


End point title 
Number of Cases and Episodes of Hospitalized VirologicallyConfirmed Dengue Due to Any and Each Serotype Collected By Age Group Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study ^{[20]}  
End point description 
Cases were defined as the number of subjects with at least one hospitalized virologicallyconfirmed dengue episode. Episodes were defined as the number of hospitalized virologicallyconfirmed dengue episodes. Analysis was performed on FupAS. Here, “n” signifies number of subjects evaluable for each specified category.


End point type 
Primary


End point timeframe 
Year 1 to Year 4 postvaccination


Notes [20]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome. 



No statistical analyses for this end point 


End point title 
Annual Incidence of Clinically Severe Hospitalized VirologicallyConfirmed Dengue Due to Any and Each Serotype Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study ^{[21]}  
End point description 
Annual incidence rate was defined as the cases among the number of subjects present at the beginning of each period (M) multiplied by 100 converted in annual rate (Annual incidence rate = Cases among M*100). Analysis was performed on FupAS. Endpoint values <0.1 were rounded to 0.1.


End point type 
Primary


End point timeframe 
Year 1 to Year 4 postvaccination


Notes [21]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome. 



No statistical analyses for this end point 


End point title 
Number of Cases and Episodes of Clinically Severe Hospitalized VirologicallyConfirmed Dengue Due to Any and Each Serotype Following Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study ^{[22]}  
End point description 
Cases were defined as the number of subjects with at least one hospitalized virologicallyconfirmed dengue episode. Episodes were defined as the number of hospitalized virologicallyconfirmed dengue episodes. Analysis was performed on FupAS.


End point type 
Primary


End point timeframe 
Year 1 to Year 4 postvaccination


Notes [22]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome. 



No statistical analyses for this end point 


End point title 
Number of Subjects with NonSerotype Specific Dengue Viremia Among Hospitalized VirologicallyConfirmed Dengue Cases Following Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study ^{[23]}  
End point description 
Quantified viremia was defined as >= lower limit of quantitation (log10 plaque forming unit [pfu]/mL). Analysis was performed on FupAS.


End point type 
Primary


End point timeframe 
Year 1 to Year 4 postvaccination at each of the following time points: Anytime, 03 days, 47 days, 07 days, After 7 days.


Notes [23]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome. 



No statistical analyses for this end point 


End point title 
Annual Incidence of Hospitalized VirologicallyConfirmed Dengue Cases Due to Any and Each Serotype and Meeting WHO 1997 Criteria Collected During Entire Passive Surveillance After Previous Vaccination with Either CYD Dengue Vaccine or Placebo  
End point description 
Annual incidence rate was defined as the cases among the number of subjects present at the beginning of each period (M) multiplied by 100 converted in annual rate (Annual incidence rate = Cases among M*100). Analysis was performed on FupAS. Endpoint values <0.1 were rounded to 0.1.


End point type 
Primary


End point timeframe 
Year 1 to Year 4 postvaccination




Statistical analysis title 
Relative Risk; Any serotype; Any grade  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes Any grade between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[24]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
1.174


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.27  
upper limit 
7.03  
Notes [24]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Any serotype; Grade I  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes Grade I between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[25]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.252


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
4.83  
Notes [25]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Any serotype; Grade II  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Any of the 4 Serotypes Grade II between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[26]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
2.012


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.2  
upper limit 
99.1  
Notes [26]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Serotype 2; Any grade  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 2 Any grade between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[27]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.503


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
39.49  
Notes [27]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Serotype 2; Grade I  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 2 Grade I between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[28]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.503


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
39.49  
Notes [28]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Serotype 4; Any grade  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 Any grade between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[29]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.252


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
4.83  
Notes [29]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Serotype 4; Grade I  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 Grade I between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[30]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.62  
Notes [30]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Serotype 4; Grade II  
Statistical analysis description 
Relative risk analysis of the annual incidence rate during Year 1 to Year 4 for Serotype 4 Grade II between the CYD Dengue vaccine group and the Control group.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[31]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.503


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
39.49  
Notes [31]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 


End point title 
Number of Cases and Episodes of Hospitalized VirologicallyConfirmed Dengue Cases Due to Any and Each Serotype and Meeting WHO 1997 Criteria Following Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study ^{[32]}  
End point description 
Cases were defined as the number of subjects with at least one hospitalized virologicallyconfirmed dengue episode meeting WHO criteria. Episodes are defined as the number of hospitalized virologicallyconfirmed dengue episodes meeting WHO criteria. Grade I: Fever accompanied by nonspecific constitutional symptoms; the only hemorrhagic manifestation is a positive tourniquet test. Grade II: Spontaneous bleeding in addition to the manifestations of Grade I subjects, usually in the form of skin and/or other hemorrhages. Grade III: Circulatory failure manifested by rapid and weak pulse, narrowing of pulse pressure (20 mmHg or less) or hypotension, with the presence of cold clammy skin and restlessness. Grade IV: Profound shock with undetectable blood pressure and pulse. Analysis was performed on FupAS.


End point type 
Primary


End point timeframe 
Year 1 to Year 4 postvaccination


Notes [32]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome. 



No statistical analyses for this end point 


Adverse events information ^{[1]}


Timeframe for reporting adverse events 
Throughout the study period (Year 1 to Year 4)


Adverse event reporting additional description 
This study involved a passive surveillance of hospitalized dengue cases and related and fatal SAEs in subjects that participated in a previous study. Nonserious adverse event data was not collected since no vaccine was administered in the present study.


Assessment type 
Systematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
10


Reporting groups


Reporting group title 
Control Group


Reporting group description 
Subjects received either Rabies vaccine (Verorab®) or placebo control as a first injection on Day 0, placebo for second and third injections at 6 and 12 months, respectively, in the original CYD23 study.  
Reporting group title 
CYD Dengue Vaccine Group


Reporting group description 
Subjects received 3 injections of CYD dengue vaccine, 1 injection each at 0, 6, and 12 months in study CYD23.  
Notes [1]  There are no nonserious adverse events recorded for these results. It is expected that there will be at least one nonserious adverse event reported. Justification: This was a longterm immunogenicity followup study of subjects who participated in the primary study. No vaccines were administered in the followup study and nonSAE data was also not collected. 



Frequency threshold for reporting nonserious adverse events: 5%  



Substantial protocol amendments (globally) 

Were there any global substantial amendments to the protocol? Yes  
Date 
Amendment 

08 Jan 2014 
Additional clarifications were added to the study objectives. 

17 Feb 2014 
Study objectives were further updated and statistical analyses were revised. 

Interruptions (globally) 

Were there any global interruptions to the trial? No  
Limitations and caveats 

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.  
None reported  
Online references 

http://www.ncbi.nlm.nih.gov/pubmed/22975340 