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 

Results information


Results version number 
v1 
This version publication date 
19 May 2016

First version publication date 
19 May 2016

Other versions 
v2 
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 
2, avenue Pont Pasteur, Lyon Cedex 07, France, F69367


Public contact 
Director, Clinical Development,
Sanofi Pasteur Thailand, Sanofi Pasteur SA, 66 2264 8813, Danaya.chansinghakul@sanofipasteur.com


Scientific contact 
Director, Clinical Development,
Sanofi Pasteur Thailand, Sanofi Pasteur SA, 66 2264 8813, Danaya.chansinghakul@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 
Interim


Date of interim/final analysis 
05 Feb 2015


Is this the analysis of the primary completion data? 
Yes


Primary completion date 
29 Sep 2014


Global end of trial reached? 
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 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 
Subject, Investigator, Monitor, Assessor  
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) until the second year of the followup study. 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 
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


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





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 Collected During the Year 1 and Year 2 Passive Surveillance 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).


End point type 
Primary


End point timeframe 
Year 1 and Year 2 postvaccination




Statistical analysis title 
Relative risk; Year 1; Any of the 4 Serotypes  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 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 
1.006


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.47  
upper limit 
2.3  
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; Year 1; Serotype 1  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 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 
0.503


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.12  
upper limit 
2.19  
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; Year 1; Serotype 2  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 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  
Method 

Parameter type 
Relative Risk  
Point estimate 
2.138


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7  
upper limit 
8.73  
Statistical analysis title 
Relative risk; Year 1; Serotype 3  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 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 ^{[3]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.503


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
39.49  
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; Year 1; Serotype 4  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 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 ^{[4]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0  
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; Year 1; Unserotyped  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 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 ^{[5]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
2.68  
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; Year 2; Any of the 4 Serotypes  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 2 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  
Method 

Parameter type 
Relative risk of annual incidence rate  
Point estimate 
0.473


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.22  
upper limit 
1  
Statistical analysis title 
Relative risk; Year 2; Serotype 1  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 2 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 ^{[6]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.671


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.11  
upper limit 
4.58  
Notes [6]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative risk; Year 2; Serotype 2  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 2 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 ^{[7]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.335


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.07  
upper limit 
1.41  
Notes [7]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative risk; Year 2; Serotype 3  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 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 ^{[8]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
1.006


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.21  
upper limit 
6.22  
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; Year 2; Serotype 4  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 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 ^{[9]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.252


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.02  
upper limit 
1.76  
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; Year 2; Unserotyped  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 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 ^{[10]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.62  
Notes [10]  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 During Year I and Year 2 Passive Surveillance Following Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study ^{[11]}  
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.


End point type 
Primary


End point timeframe 
Year 1 and Year 2 postvaccination


Notes [11]  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 During the Year I and Year 2 Passive Surveillance 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).


End point type 
Primary


End point timeframe 
Year 1 and Year 2 postvaccination




Statistical analysis title 
Relative Risk; Yr 1; 4 to 5 years; Any Serotype  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 1 Any of the 4 Serotypes (4 to 5 years) 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 ^{[12]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
2.443


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.27  
upper limit 
115.54  
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; Year 1; 6 to 11 years; Any Serotype  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 Any of the 4 Serotypes (6 to 11 years) 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 ^{[13]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.861


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.37  
upper limit 
2.1  
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; Year 1; 4 to 5 years; Serotype 1  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 1 Serotype 1 (4 to 5 years) 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 ^{[14]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0  
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; Year 1; 6 to 11 years; Serotype 1  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 1 Serotype 1 (6 to 11 years) 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 ^{[15]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.304


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.05  
upper limit 
1.56  
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; Year 1; 4 to 5 years; Serotype 2  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 1 Serotype 2 (4 to 5 years) 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 ^{[16]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0  
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; Year 1; 6 to 11 years; Serotype 2  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 Serotype 2 (6 to 11 years) 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 ^{[17]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
1.646


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.51  
upper limit 
6.93  
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; Year 1; 4 to 5 years; Serotype 3  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 Serotype 3 (4 to 5 year) 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 ^{[18]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0  
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; Year 1; 6 to 11 years; Serotype 3  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 1 Serotype 3 (6 to 11 years) 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 ^{[19]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.506


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
39.75  
Notes [19]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 1; 4 to 5 years; Serotype 4  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 Serotype 4 (4 to 5 years) 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 ^{[20]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0  
Notes [20]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 1; 6 to 11 years; Serotype 4  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 Serotype 4 (6 to 11 years) 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 ^{[21]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0  
Notes [21]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 1; 4 to 5 years; Unserotyped  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 1 Unserotyped (4 to 5 years) 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 ^{[22]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.05  
Notes [22]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 1; 6 to 11 years; Unserotyped  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 1 Unserotyped (6 to 11 years) 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 ^{[23]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.75  
Notes [23]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 2; 4 to 5 years; Any Serotype  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Any of the 4 Serotypes (4 to 5 years) 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 
0.814


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.16  
upper limit 
5.24  
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; Year 2; 6 to 11 years; Any Serotype  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Any of the 4 Serotypes (6 to 11 years) 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 
0.398


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.16  
upper limit 
0.94  
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; Year 2; 4 to 5 years; Serotype 1  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Serotype 1 (4 to 5 years) 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 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0  
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; Year 2; 6 to 11 years; Serotype 1  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 2 Serotype 1 (6 to 11 years) 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


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
1.23  
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; Year 2; 4 to 5 years; Serotype 2  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 2 Serotype 2 (4 to 5 years) 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


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.05  
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; Year 2; 6 to 11 years; Serotype 2  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Serotype 2 (6 to 11 years) 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 
0.405


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.08  
upper limit 
1.88  
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; Year 2; 4 to 5 years; Serotype 3  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Serotype 3 (4 to 5 years) 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 
0.489


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.01  
upper limit 
38.35  
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; Year 2; 6 to 11 years; Serotype 3  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 2 Serotype 3 (6 to 11 years) between the CYD Dengue vaccine group and the Control group.


Comparison groups 
Control Group v CYD Dengue Vaccine Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[31]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
1.266


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.21  
upper limit 
13.29  
Notes [31]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 2; 4 to 5 years; Serotype 4  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Serotype 4 (4 to 5 years) 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 ^{[32]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0  
Notes [32]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 2; 6 to 11 years; Serotype 4  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 2 Serotype 4 (6 to 11 years) 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 ^{[33]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.253


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.02  
upper limit 
1.77  
Notes [33]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 2; 4 to 5 years; Unserotyped  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Unserotyped (4 to 5 years) 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 ^{[34]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.05  
Notes [34]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 2; 6 to 11 years; Unserotyped  
Statistical analysis description 
Relative risk analysis of the annual incidence rate at Year 2 Unserotyped (6 to 11 years) 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 ^{[35]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0  
Notes [35]  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 During Year I and Year 2 Passive Surveillance After Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study ^{[36]}  
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.


End point type 
Primary


End point timeframe 
Year 1 and Year 2 postvaccination


Notes [36]  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 Collected During the Year I and Year 2 Passive Surveillance After Vaccination with Either CYD Dengue Vaccine or a Placebo in a Previous Study ^{[37]}  
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).


End point type 
Primary


End point timeframe 
Year 1 and Year 2 postvaccination


Notes [37]  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 Collected During the Year I and Year 2 Passive Surveillance After Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study ^{[38]}  
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.


End point type 
Primary


End point timeframe 
Year 1 and Year 2 postvaccination


Notes [38]  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 Occurring During the Year I and Year 2 Passive Surveillance After Vaccination with CYD Dengue Vaccine or Placebo in a Previous Study ^{[39]}  
End point description 
Quantified viremia was defined as ≥ lower limit of quantitation (log10 pfu/mL).


End point type 
Primary


End point timeframe 
Year 1, Year 2, and entire period postvaccination at each of the following time points: Anytime, 03 days, 47 days, 07 days, After 7 days.


Notes [39]  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 Year I and Year 2 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).


End point type 
Primary


End point timeframe 
Year 1 and Year 2 postvaccination




Statistical analysis title 
Relative Risk; Year 2; Any serotype; Any grade  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Any of the 4 Serotypes Any grade between the CYD Dengue vaccine group and the Control group.
The RR was not calculated for Year 1 and is reported for only those serotypes and grades calculated in Year 2.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[40]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0.252


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
4.83  
Notes [40]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 2; Any serotype; Grade I  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Any of the 4 Serotypes Grade I between the CYD Dengue vaccine group and the Control group.
The RR was not calculated for Year 1 and is reported for only those serotypes and grades calculated in Year 2.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[41]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
2.68  
Notes [41]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 2; Serotype 2; Any grade  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Serotype 2 Any grade between the CYD Dengue vaccine group and the Control group.
The RR was not calculated for Year 1 and is reported for only those serotypes and grades calculated in Year 2.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[42]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.62  
Notes [42]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 2; Serotype 2; Grade I  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Serotype 2 Grade I between the CYD Dengue vaccine group and the Control group.
The RR was not calculated for Year 1 and is reported for only those serotypes and grades calculated in Year 2.


Comparison groups 
Control Group v CYD Dengue Vaccine Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[43]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.62  
Notes [43]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 2; Serotype 4; Any grade  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Serotype 4 Any grade between the CYD Dengue vaccine group and the Control group.
The RR was not calculated for Year 1 and is reported for only those serotypes and grades calculated in Year 2.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[44]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.62  
Notes [44]  The 95% confidence interval of the relative risk is calculated using the Exact method described by Breslow and Day. 

Statistical analysis title 
Relative Risk; Year 2; Serotype 4; Grade I  
Statistical analysis description 
Relative risk (RR) analysis of the annual incidence rate at Year 2 Serotype 4 Grade I between the CYD Dengue vaccine group and the Control group.
The RR was not calculated for Year 1 and is reported for only those serotypes and grades calculated in Year 2.


Comparison groups 
CYD Dengue Vaccine Group v Control Group


Number of subjects included in analysis 
3203


Analysis specification 
Prespecified


Analysis type 
other ^{[45]}  
Method 

Parameter type 
Relative Risk  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
19.62  
Notes [45]  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 Collected In Year I and Year 2 Passive Surveillance After Previous Vaccination with CYD Dengue Vaccine or Placebo ^{[46]}  
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 patients, 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.


End point type 
Primary


End point timeframe 
Year 1 and Year 2 postvaccination


Notes [46]  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 
This study involved a passive surveillance of hospitalized dengue cases in subjects that participated in a previous study. No vaccine were administered in the study and adverse event data were also not collected.


Assessment type 
Nonsystematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
10


Frequency threshold for reporting nonserious adverse events: 5%  
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 adverse event data were also not collected. 


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 