Clinical Trial Results:
Development of readouts to detect and characterise the early and adaptive immune responses in healthy, hepatitis B virus naive adults vaccinated with the hepatitis B surface antigen in combination with a GSK Biologicals’ Adjuvant System
Summary


EudraCT number 
201200134422 
Trial protocol 
BE 
Global end of trial date 
13 Jun 2016

Results information


Results version number 
v3(current) 
This version publication date 
22 Jul 2018

First version publication date 
14 Sep 2017

Other versions 
v1 , v2 
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 
116640


Additional study identifiers


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


Sponsor organisation name 
GlaxoSmithKline Biologicals


Sponsor organisation address 
Rue de l’Institut 89, Rixensart, Belgium, B1330


Public contact 
Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089904466, GSKClinicalSupportHD@gsk.com


Scientific contact 
Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089904466, GSKClinicalSupportHD@gsk.com


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
No


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? 
No


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
20 Jun 2017


Is this the analysis of the primary completion data? 
Yes


Primary completion date 
17 May 2016


Global end of trial reached? 
Yes


Global end of trial date 
13 Jun 2016


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
To detect and measure soluble mediators from the early immune response in plasma.


Protection of trial subjects 
•All vaccinated subjects were observed closely for at least 30 minutes following the administration of vaccines, with appropriate medical treatment readily available in case of a rare anaphylactic reaction. Vaccines/products were administered by qualified and trained personnel. Vaccines/placebos were administered only to eligible subjects that had no contraindications to any components of the vaccines/placebos. Subjects were followedup for up to one month for adverse events after the last vaccination/placebos administration and during the entire study period for serious adverse events.


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
25 Feb 2013


Long term followup planned 
No


Independent data monitoring committee (IDMC) involvement? 
No


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
Belgium: 81


Worldwide total number of subjects 
81


EEA total number of subjects 
81


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) 
0


Adolescents (1217 years) 
0


Adults (1864 years) 
81


From 65 to 84 years 
0


85 years and over 
0



Recruitment


Recruitment details 
The subject disposition refers to all subjects included in the Pooling of steps, with at least one vaccine administration documented.  
Preassignment


Screening details 
During the screening period the following steps occurred: blood samples withdrawals to check eligibility criteria (HBV, hepatitis C virus [HCV], human immunodeficiency virus [HIV], haematology and blood chemistry), blood collection for innate immune assays, adaptive readouts and urine samples collection  
Preassignment period milestones


Number of subjects started 
81  
Number of subjects completed 
81  
Period 1


Period 1 title 
Overall Study (overall period)


Is this the baseline period? 
Yes  
Allocation method 
Randomised  controlled


Blinding used 
Single blind  
Roles blinded 
Subject  
Blinding implementation details 
Singleblind up to Day 60 in each Step. Subjects were unblinded at the end of their Day 60 visit.


Arms


Are arms mutually exclusive 
Yes


Arm title

HBsAg/AS_1+2 Group  
Arm description 
Subjects received, during Step 1 of the study, 1 dose of Placebo vaccine at Day 30, followed by 2 doses of HBsAg/AS vaccine, at Day 0 and Day 30; or during Step 2 of the study, 2 doses of HBsAg/AS vaccine, at Day 0 and Day 30. All vaccines were administered intramuscularly into the deltoid muscle of the nondominant upper arm.  
Arm type 
Experimental  
Investigational medicinal product name 
Saline solution


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Solution for injection


Routes of administration 
Intramuscular use


Dosage and administration details 
One dose of placebo saline solution was administered intramuscularly into the deltoid region of the nondominant arm at Day 30 in Step 1 of the study.


Investigational medicinal product name 
Adjuvanted Hepatitis B surface antigen (HBsAg) candidate vaccine GSK2231392A


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Powder and solvent for suspension for injection


Routes of administration 
Intramuscular use


Dosage and administration details 
The 2 vaccine doses were administered intramuscularly into the deltoid region of the nondominant arm at Day 0 and Day 30, in both Step 1 and Step 2 of the study.


Arm title

EngerixB_1+2 Group  
Arm description 
Subjects received, during Step 1 of the study, 1 dose of Placebo vaccine at Day 30 followed by 3 doses of Engerix™B vaccine at Day 0, Day 30 and Day 180; or during Step 2 of the study, 3 doses of Engerix™B vaccine at Day 0, Day 30 and Day 180. All vaccine were administered intramuscularly into the deltoid muscle of the nondominant upper arm.  
Arm type 
Active comparator  
Investigational medicinal product name 
Saline solution


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Solution for injection


Routes of administration 
Intramuscular use


Dosage and administration details 
One dose of placebo saline solution was administered intramuscularly into the deltoid region of the nondominant arm at Day 30 in Step 1 of the study.


Investigational medicinal product name 
EngerixB


Investigational medicinal product code 

Other name 
HBsAg/Alum


Pharmaceutical forms 
Suspension for injection


Routes of administration 
Intramuscular use


Dosage and administration details 
The 3 doses of active comparator were administered intramuscularly into the deltoid region of the nondominant arm at Day 0, Day 30 and Day 180, in both Step 1 and Step 2 of the study.





Baseline characteristics reporting groups


Reporting group title 
HBsAg/AS_1+2 Group


Reporting group description 
Subjects received, during Step 1 of the study, 1 dose of Placebo vaccine at Day 30, followed by 2 doses of HBsAg/AS vaccine, at Day 0 and Day 30; or during Step 2 of the study, 2 doses of HBsAg/AS vaccine, at Day 0 and Day 30. All vaccines were administered intramuscularly into the deltoid muscle of the nondominant upper arm.  
Reporting group title 
EngerixB_1+2 Group


Reporting group description 
Subjects received, during Step 1 of the study, 1 dose of Placebo vaccine at Day 30 followed by 3 doses of Engerix™B vaccine at Day 0, Day 30 and Day 180; or during Step 2 of the study, 3 doses of Engerix™B vaccine at Day 0, Day 30 and Day 180. All vaccine were administered intramuscularly into the deltoid muscle of the nondominant upper arm.  



End points reporting groups


Reporting group title 
HBsAg/AS_1+2 Group


Reporting group description 
Subjects received, during Step 1 of the study, 1 dose of Placebo vaccine at Day 30, followed by 2 doses of HBsAg/AS vaccine, at Day 0 and Day 30; or during Step 2 of the study, 2 doses of HBsAg/AS vaccine, at Day 0 and Day 30. All vaccines were administered intramuscularly into the deltoid muscle of the nondominant upper arm.  
Reporting group title 
EngerixB_1+2 Group


Reporting group description 
Subjects received, during Step 1 of the study, 1 dose of Placebo vaccine at Day 30 followed by 3 doses of Engerix™B vaccine at Day 0, Day 30 and Day 180; or during Step 2 of the study, 3 doses of Engerix™B vaccine at Day 0, Day 30 and Day 180. All vaccine were administered intramuscularly into the deltoid muscle of the nondominant upper arm.  
Subject analysis set title 
hbsag/as_1 group


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Subjects received, during Step 1 of the study, 1 dose of Placebo vaccine at Day 30, followed by 2 doses of HBsAg/AS vaccine, at Day 0 and Day 30. All vaccines were administered intramuscularly into the deltoid muscle of the nondominant upper arm.


Subject analysis set title 
engerixb_1 group


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Subjects received, during Step 1 of the study, 1 dose of Placebo vaccine at Day 30 followed by 3 doses of Engerix™B vaccine at Day 0, Day 30 and Day 180. All vaccine were administered intramuscularly into the deltoid muscle of the nondominant upper arm.


Subject analysis set title 
hbsag/as_2 group


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Subjects received, during Step 2 of the study, 2 doses of HBsAg/AS vaccine, at Day 0 and Day 30. All vaccines were administered intramuscularly into the deltoid muscle of the nondominant upper arm


Subject analysis set title 
engerixb_2 group


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Subjects received, during Step 2 of the study, 3 doses of Engerix™B vaccine at Day 0, Day 30 and Day 180. All vaccine were administered intramuscularly into the deltoid muscle of the nondominant upper arm.



End point title 
Concentrations of cytokines and chemokines  Step 1 ^{[1]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
At Day 30 prior to product administration


Notes [1]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines and chemokines concentrations  Step 1 ^{[2]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postplacebo at Day 30 plus 1.5 Hours


Notes [2]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines and chemokines in Step 1 ^{[3]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postplacebo at Day 30 plus 3 Hours


Notes [3]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines and chemokines during Step 1 ^{[4]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postplacebo at Day 30 plus 6 Hours


Notes [4]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines/chemokines  Step 1 ^{[5]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postplacebo at Day 30 plus 9 Hours


Notes [5]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines/chemokines in Step 1 ^{[6]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postplacebo at Day 30 plus 12 Hours


Notes [6]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines/chemokines during Step 1 ^{[7]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postplacebo at Day 30 plus 18 Hours


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines and chemokines concentrations in Step 1 ^{[8]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postplacebo at Day 29


Notes [8]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines and chemokines concetrations during Step 1 ^{[9]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postplacebo at Day 28


Notes [9]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines/chemokines concentrations in Step 1 ^{[10]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postplacebo at Day 27


Notes [10]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines and chemokines concentrations during Step 1 ^{[11]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postplacebo at Day 23


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines and chemokines  study Step 1 ^{[12]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Predose1 at Day 0


Notes [12]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines and chemokines in Step 1 of study ^{[13]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose1 at Day 0 plus 1.5 Hours


Notes [13]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines and chemokines during Step 1 of study ^{[14]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose1 at Day 0 plus 6 Hours


Notes [14]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines and chemokines concentrations  study Step 1 ^{[15]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose1 at Day 0 plus 12 Hours


Notes [15]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines and chemokines concentrations in Step 1 of study ^{[16]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose1 at Day 0 plus 18 Hours


Notes [16]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines and chemokines concentrations during Step 1 of study ^{[17]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose1 at Day 1


Notes [17]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines/chemokines concentrations  study Step 1 ^{[18]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose1 at Day 2


Notes [18]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines/chemokines concentrations in Step 1 of study ^{[19]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose1 at Day 7


Notes [19]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines/chemokines concentrations during Step 1 of study ^{[20]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose1 at Day 30


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Plasma concentrations of cytokines and chemokines  Step 1 ^{[21]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 30 plus 1.5 Hours


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Plasma concentrations of cytokines and chemokines  study Step 1 ^{[22]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 30 plus 3 Hours


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Plasma concentrations of cytokines and chemokines in Step 1 of study ^{[23]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 30 plus 6 hours


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Plasma concentrations of cytokines and chemokines during Step 1 of study ^{[24]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 30 plus 9 Hours


Notes [24]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Plasma concentrations of cytokines/chemokines during Step 1 of study ^{[25]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 30 plus 12 Hours


Notes [25]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Plasma concentrations of cytokines/chemokines  Step 1 of study ^{[26]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 30 plus 18 Hours


Notes [26]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Plasma concentrations of cytokines/chemokines in Step 1 of study ^{[27]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 31


Notes [27]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of plasma cytokines and chemokines  Step 1 ^{[28]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 32


Notes [28]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of plasma cytokines and chemokines in Step 1 ^{[29]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 33


Notes [29]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of plasma cytokines and chemokines during Step 1 ^{[30]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 37


Notes [30]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines and chemokines  Step 2 ^{[31]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.


End point type 
Primary


End point timeframe 
Predose 1 at Day 0


Notes [31]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Cytokines and chemokines concentrations  Step 2 ^{[32]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma. The analysis was performed only on the HBsAg/AS_2 Group.


End point type 
Primary


End point timeframe 
Postdose 1 at Day 1


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines and chemokines during Step 2 ^{[33]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma. The analysis was performed only on the HBsAg/AS_2 Group.


End point type 
Primary


End point timeframe 
Postdose 1 at Day 30


Notes [33]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines and chemokines in Step 2 ^{[34]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma. The analysis was performed only on the HBsAg/AS_2 Group.


End point type 
Primary


End point timeframe 
Postdose2 at Day 30 plus 6 Hours


Notes [34]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines/chemokines  Step 2 ^{[35]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma. The analysis was performed only on the HBsAg/AS_2 Group.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 31


Notes [35]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines/chemokines in Step 2 ^{[36]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma. The analysis was performed only on the HBsAg/AS_2 Group.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 37


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Concentrations of cytokines/chemokines during Step 2 ^{[37]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma. The analysis was performed only on the EngerixB_2 Group.


End point type 
Primary


End point timeframe 
Postdose 2 at Day 180


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Plasma concentrations of cytokines and chemokines  study Step 2 ^{[38]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.The analysis was performed only on theEngerixB_2 Group.


End point type 
Primary


End point timeframe 
Postdose2 at Day 30 plus 6 Hours


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Plasma concentrations of cytokines and chemokines in Step 2 of study ^{[39]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma. The analysis was performed only on the EngerixB_2 Group.


End point type 
Primary


End point timeframe 
Postdose 3 at Day 180 plus 6 Hours


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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
Plasma concentrations of cytokines and chemokines during Step 2 of study ^{[40]}  
End point description 
Cytokines and chemokines analysed were Eselectin, granulocyte macrophage colonystimulating factor (GMCSF), interferonγ (IFNγ), interleukin10 (IL10), IL18, IL2, IL3, IL4, IL5, IL6, IL6r, IL7, IL8, IFNγinducible protein (IP10), monocyte chemoattractant protein1 (MCP1), MCP2, MCP4, monokine induced by IFNγ (MIG), macrophage inflammatory protein1 alpha (MIP1 alpha), MIP1 beta, MIP3alpha, MPIF1, tumor necrosis factoralpha (TNFalpha) and TNFbeta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma. The analysis was performed only on the EngerixB_2 Group.


End point type 
Primary


End point timeframe 
Postdose 3 at Day 187


Notes [40]  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: The scope of this primary end point was descriptive, no statistical hypothesis test was performed. 



No statistical analyses for this end point 


End point title 
AntiHepatitis B surface (antiHBs) antibody concentrations in serum  Step 1  
End point description 
AntiHBs antibody concentrations in serum were measured by Chemi Luminiscence Immuno Assay (CLIA). Concentrations were presented as geometric mean concentrations, in milliInternational Units per milliliter (mIU/mL).


End point type 
Secondary


End point timeframe 
At Day 0 (PRE) and Day 60 (D60) postvaccination




No statistical analyses for this end point 


End point title 
Number of subjects with any and grade 3 solicited local symptoms  Step 1  
End point description 
Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site.


End point type 
Secondary


End point timeframe 
During the 7day (Days 06) postplacebo (PP) and postvaccination period following each vaccine dose (D1 and D2) and across doses




No statistical analyses for this end point 


End point title 
Number of subjects with any, grade 3 and related solicited general symptoms  Step 1  
End point description 
Assessed solicited general symptoms were fatigue, gastrointestinal symptoms [nausea, vomiting, diarrhoea and /or abdominal pain], headache, malaise, myalgia, shivering and temperature [defined as oral temperature equal to or above (≥) 37.5 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever > 39.5 °C. Related = symptom assessed by the investigator as related to the vaccination


End point type 
Secondary


End point timeframe 
During the 7day (Days 06) postplacebo (PP) and postvaccination period following each vaccine dose (D1 and D2) and across doses




No statistical analyses for this end point 


End point title 
Number of subjects with solicited symptoms, as assessed by the investigator/study nurse  
End point description 
Assessed solicited symptoms were fever [defined as oral temperature equal to or above (≥) 37.5 degrees Celsius (°C)], pain, redness [spreading beyond 20 millimeters (mm) of injection site], induration [spreading beyond 20 millimeters (mm) of injection site], swelling [spreading beyond 20 millimeters (mm) of injection site] and muscle stiffness.


End point type 
Secondary


End point timeframe 
Up to 4 days postplacebo/vaccine administration.




No statistical analyses for this end point 


End point title 
Number of subjects with any unsolicited adverse events (AEs)  Step 1  
End point description 
An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of followup for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination.


End point type 
Secondary


End point timeframe 
Within the 28day (Days 027) postplacebo (PP) and postproduct administration period.




No statistical analyses for this end point 


End point title 
Number of subjects with serious adverse events (SAEs)  Step 1  
End point description 
Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.


End point type 
Secondary


End point timeframe 
From Day 0 up to Day 60 for the HBsAg/AS_1 Group and from Day 0 up to Day 210 for the Engerix B_1 Group




No statistical analyses for this end point 


End point title 
Number of subjects with any potential immunemediated disorders (pIMDs)  Step 1  
End point description 
PIMD(s) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.


End point type 
Secondary


End point timeframe 
From Day 0 up to Day 60 for the HBsAg/AS_1 Group and from Day 0 up to Day 210 for the Engerix B_1 Group




No statistical analyses for this end point 


End point title 
Number of subjects with any new medical conditions requiring medical attention (MAEs)  Step 1  
End point description 
MAEs were defined as events for which the subject received medical attention defined as hospitalization, an emergency room visit, or a visit to or from medical personnel (medical doctor) for any reason. Any MAE(s) = Occurrence of any MAE(s) regardless of intensity grade or relation to vaccination. Analysis of intensity and relationship to vaccination of MAEs was not performed.


End point type 
Secondary


End point timeframe 
From Day 0 up to Day 60 for the HBsAg/AS_1 Group and from Day 0 up to Day 210 for the Engerix B_1 Group




Notes [41]  Step 1 completion for the HBsAg/AS_1 Group was reached at Day 60 

No statistical analyses for this end point 


End point title 
Levels of Alanine aminotransferase (ALT) in blood samples  Step 1  
End point description 
Biochemical laboratory parameters assessed included ALT levels. ALT concentrations were expressed in units per liter (U/L). ALT levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 


End point title 
Levels of Aspartate aminotransferase (AST) in blood samples  Step 1  
End point description 
Biochemical laboratory parameters assessed included AST levels. AST concentrations were expressed in units per liter (U/L). AST levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 


End point title 
Levels of Basophils in blood samples  Step 1  
End point description 
Haematological laboratory parameters assessed included basophil levels. Basophil levels were expressed in billion cells per liter (billion cells/L). Basophil levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 


End point title 
Levels of total Bilirubin in blood samples  Step 1  
End point description 
Biochemical laboratory parameters assessed included total bilirubin levels. Bilirubin concentrations were expressed in milligrams per deciliter (mG/dL). Bilirubin levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 


End point title 
Levels of serum Creatinine in blood samples  Step 1  
End point description 
Biochemical laboratory parameters assessed included creatinine levels. Creatinine concentrations were expressed in milligrams per deciliter (mg/dL). Creatinine levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 


End point title 
Levels of Creatinine phosphokinase (CPK) in blood samples  Step 1  
End point description 
Biochemical laboratory parameters assessed included CPK levels. CPK concentrations were expressed in milligrams per deciliter (mg/dL). CPK levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 


End point title 
Levels of creactive protein (CRP) in blood samples  Step 1  
End point description 
Biochemical laboratory parameters assessed included CRP levels. CRP concentrations were expressed in milligrams per liter (mg/L). CRP levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 


End point title 
Levels of Eosinophils in blood samples  Step 1  
End point description 
Haematological laboratory parameters assessed included eosinophil levels. Eosinophil levels were expressed in billion cells per liter (billion cells/L). Eosinophil levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 


End point title 
Levels of Haemoglobin in blood samples  Step 1  
End point description 
Haematological laboratory parameters assessed included haemoglobin levels, expressed in gram per deciliter (d/dL). Haemoglobin levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 


End point title 
Levels of Lactate dehydrogenase (LDH) in blood samples  Step 1  
End point description 
Biochemical laboratory parameters assessed included LDH levels, expressed in units per liter (U/L). LDH levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 


End point title 
Levels of Lymphocytes in blood samples  Step 1  
End point description 
Haematological laboratory parameters assessed included lymphocyte levels. Lymphocyte levels were expressed in billion cells per liter (billion cells/L). Lymphocyte levels were assessed at different time points (plus 6, 12 and 18 hours  H6, H12, H18) on Day 0 and Day 30.


End point type 
Secondary


End point timeframe 
At Day 0, Day 0 H6, Day 0 H12, Day 0 H18, Day 1, Day 7, Day 30, Day 30 H6, Day 30 H12, Day 30 H18, Day 31, Day 37 and Day 60




No statistical analyses for this end point 
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