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Clinical Trial Results:
A phase III/IV, community-randomised, controlled study to evaluate the effectiveness of two vaccination strategies using GlaxoSmithKline Biologicals’ HPV-16/18 L1 VLP AS04 vaccine in reducing the prevalence of HPV-16/18 infection when administered intramuscularly according to a 0, 1, 6-month schedule in healthy female and male study participants aged 12 - 15 years.

Summary
EudraCT number	2007-001731-55
Trial protocol	FI
Global end of trial date	17 Dec 2014

Results information
Results version number	v3(current)
This version publication date	15 Nov 2019
First version publication date	22 May 2015
Other versions	v1 , v2
Version creation reason

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

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Trial information

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Sponsor protocol code

106636

ISRCTN number

US NCT number

NCT00534638

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline Biologicals

Sponsor organisation address

Rue de l’Institut 89, Rixensart, Belgium, B-1330

Public contact

Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com

Scientific contact

Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com

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

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

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

Yes

Analysis stage

Final

Date of interim/final analysis

14 Dec 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

17 Dec 2014

Global end of trial reached?

Yes

Global end of trial date

17 Dec 2014

Was the trial ended prematurely?

Main objective of the trial

• To demonstrate the overall (direct and indirect) effectiveness of HPV vaccine in reducing the prevalence of HPV-16/18 genital infection in females approximately 18.5 years of age, following community-based vaccination of 12-15 year-old females only (Arm B versus Arm C). • To demonstrate the overall (direct and indirect) effectiveness of HPV vaccine in reducing the prevalence of HPV-16/18 genital infection in females approximately 18.5 years of age, following community-based vaccination of 12-15 year-old females and males (Arm A versus Arm C).

Protection of trial subjects

All subjects were supervised closely for at least 30 minutes following vaccination with appropriate medical treatment readily available. Vaccines were administered by qualified and trained personnel. Vaccines/products were administered only to eligible subjects that had no contraindications to any components of the vaccines. Subjects were followed-up from the time the subject consented to participate in the study until she/he was discharged.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Oct 2007

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

7 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Finland: 34412

Worldwide total number of subjects

34412

EEA total number of subjects

34412

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

32176

Adults (18-64 years)

2236

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Immunization phase (Day 0 to Month 12) = adolescents (birth cohorts ‘92-‘95) were vaccinated with Cervarix/Engerix-B. Effectiveness evaluation phase (Visit 5) = the vaccine’s impact was assessed on female subjects aged 18.5. At Day 0, Cervarix was not licensed for males;male subjects receiving the vaccine were considered part of a Phase III trial.

Screening details

34412 subjects were enrolled in the study, out of which 2236 subjects had a subject number allocated, but did not receive a vaccine dose, and 1 subject was excluded due to non-eligibility criteria, hence 32175 subjects were vaccinated and started the study.

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

Blinding was as follows: - Study participants in Arm A communities and female study participants in Arm B communities were blinded to their treatment allocation (HPV or HBV vaccine). - Study participants (males and females) in Arm C communities and male study participants in Arm B communities were aware of their treatment allocation as they all received HBV vaccine.

Are arms mutually exclusive

Yes

Cervarix Pooled Group

Arm description

Male and female subjects vaccinated with Cervarix vaccine. The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Arm type

Experimental

Investigational medicinal product name

Cervarix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses administered by intramuscular injection into the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Engerix-B Pooled Group

Arm description

Male and female subjects vaccinated with Engerix-B vaccine. The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Arm type

Experimental

Investigational medicinal product name

Engerix-B

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses administered by intramuscular injection into the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Number of subjects in period 1 ^[1]	Cervarix Pooled Group	Engerix-B Pooled Group
Started	14837	17338
Completed	8346	5547
Not completed	6491	11791
Consent withdrawn by subject	3	4
Migrated/moved from study area	13	11
Lost to follow-up,incomplete vaccination	83	117
Unspecified	1685	902
Lost to follow-up, complete vaccination	4707	10757

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Although 34412 subjects were enrolled, only 32175 subjects were vaccinated and started the study.

Baseline characteristics

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Reporting group title

Cervarix Pooled Group

Reporting group description

Male and female subjects vaccinated with Cervarix vaccine. The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Reporting group title

Engerix-B Pooled Group

Reporting group description

Male and female subjects vaccinated with Engerix-B vaccine. The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Reporting group values	Cervarix Pooled Group	Engerix-B Pooled Group	Total
Number of subjects	14837	17338	32175
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age Continuous
Out of the 2236 subjects included in the Adults (18-64 years) category in Population of trial subjects section, for 554 subjects the age categorical data were missing.
Units: years
arithmetic mean (standard deviation)	14.1 ( 0.8 )	14.1 ( 0.8 )	-
Sex: Female, Male
After the database freeze, discrepancies in the gender of 10 subjects were detected, this leading to 12401 female and 2436 male subjects in the Cervarix Pooled Group, and 8111 female and 9227 male subjects in the Engerix-B Pooled Group. These 10 subjects were not part of the Immunogenicity subset, the Diary Card subset or included in the active safety follow-up up to Month 12 for SAEs. These 10 subjects did not report any AEs and did not have any sample results. The impact on the AEs and overall effectiveness analysis was limited to the number of subjects exposed and considered minor.
Units: Subjects
Female	12399	8119	20518
Male	2438	9219	11657
Race/Ethnicity, Customized
Units: Subjects
African heritage/African American	9	8	17
Asian - Central/South Asian heritage	3	4	7
Asian - East Asian heritage	8	0	8
Asian - Japanese heritage	1	1	2
Asian - South East Asian heritage	13	4	17
White - Arabic/North African heritage	31	39	70
White - Caucasian/European heritage	14669	17190	31859
Mixed origin	103	92	195

End points

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Reporting group title

Cervarix Pooled Group

Reporting group description

Male and female subjects vaccinated with Cervarix vaccine. The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Reporting group title

Engerix-B Pooled Group

Reporting group description

Male and female subjects vaccinated with Engerix-B vaccine. The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Subject analysis set title

Cervarix/Engerix-B A Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

The A group includes subjects from communities where 70% of male and female adolescents were to be vaccinated with Cervarix vaccine. To achieve a Cervarix vaccination coverage of 70%, a 9:1 ratio was used to allocate study participants to receive Cervarix vaccine versus control Engerix-B vaccine (meaning 90% of vaccinated subjects were randomized to Cervarix). Finally, subjects from A group were either vaccinated with Cervarix, Engerix-B (control vaccine), or not vaccinated (enrolled control without vaccination). Vaccines were administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Subject analysis set title

Cervarix/Engerix-B B Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

The B group includes subjects from communities where 70% of female adolescents were to be vaccinated with Cervarix vaccine. To achieve a Cervarix vaccination coverage of 70%, a 9:1 ratio was used to allocate female participants to receive Cervarix vaccine versus control Engerix-B vaccine (meaning 90% of vaccinated females were randomized to Cervarix). In this group, all male adolescents were to be vaccinated with Engerix-B control vaccine. Finally, subjects from B group were either vaccinated with Cervarix (females) or Engerix-B/not vaccinated (males and females). Vaccines were administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Subject analysis set title

Engerix-B Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

In this control group, all adolescents were to be vaccinated with Engerix-B control vaccine. Finally, subjects from this group were either vaccinated with Engerix-B or not vaccinated. The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Subject analysis set title

Cervarix/Engerix-B Pooled Group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled A and B group: This pooled group includes subjects from communities where 70% of male and female adolescents (A group) or 70% of female adolescents (B group) were to be vaccinated with Cervarix vaccine. To achieve a Cervarix vaccination coverage of 70%, a 9:1 ratio was used to allocate study participants (A group) or female participants (B group) to receive Cervarix vaccine versus control Engerix-B vaccine (meaning 90% of vaccinated subjects (A group) or vaccinated females (B group) were randomized to Cervarix). Finally, subjects from this pooled group were either vaccinated with Cervarix, Engerix-B (control vaccine), or not vaccinated (enrolled control without vaccination). Vaccines were administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Primary: Number of female subjects with overall vaccine effectiveness against genital infection with Human Papilloma Virus (HPV)-16/18 types in Cervarix/Engerix-B B Group versus Engerix-B Group and in Cervarix/Engerix-B A Group versus Engerix-B Group

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End point title

Number of female subjects with overall vaccine effectiveness against genital infection with Human Papilloma Virus (HPV)-16/18 types in Cervarix/Engerix-B B Group versus Engerix-B Group and in Cervarix/Engerix-B A Group versus Engerix-B Group

End point description

The analysis of overall effectiveness of Cervarix vaccine against genital infection with HPV-16/18 types was based on stratified Mantel-Haenszel adjusted for clustering. The overall vaccine effectiveness was computed as 1- the prevalence odd ratio in all subjects from the investigated group (prevalence rate in all subjects from the investigated group/prevalence rate in all subjects from Engerix-B Group). The analysis was performed on female study participants from the Total Enrolled cohort on effectiveness, which included all study participants who were previously enrolled in the immunization phase, and those who joined the trial at Visit 5, for whom results were available.

End point type

Primary

End point timeframe

At the time of Visit 5 (i.e. at 18.5 years of age)

End point values	Cervarix/Engerix-B A Group	Cervarix/Engerix-B B Group	Engerix-B Group
Number of subjects analysed	3629	4029	3168
Units: Participants	139	117	329

Overall efectiveness against HPV-16/18

Statistical analysis description

The analysis of the overall effectiveness of GSK’s HPV-16/18 vaccine against HPV-16/18 genital infection in Cervarix/Engerix-B B Group versus Engerix-B Group was based on stratified Mantel-Haenszel adjusted for clustering.

Comparison groups

Cervarix/Engerix-B B Group v Engerix-B Group

Number of subjects included in analysis

7197

Analysis specification

Pre-specified

Analysis type

P-value

= 0.004 ^[1]

Method

Cochran-Mantel-Haenszel

Parameter type

Vaccine effectiveness percentage

Point estimate

49.6

Confidence interval

level

95%

sides

2-sided

lower limit

20.1

upper limit

68.2

Notes
[1] - An objective was reached if the 2-sided p-value associated to the objective was below 5%.

Overall efectiveness against HPV-16/18

Statistical analysis description

The analysis of the overall effectiveness of GSK’s HPV-16/18 vaccine against HPV-16/18 genital infection in Cervarix/Engerix-B A Group versus Engerix-B Group was based on stratified Mantel-Haenszel adjusted for clustering.

Comparison groups

Cervarix/Engerix-B A Group v Engerix-B Group

Number of subjects included in analysis

6797

Analysis specification

Pre-specified

Analysis type

P-value

= 0.232 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Vaccine effectiveness percentage

Point estimate

23.8

Confidence interval

level

95%

sides

2-sided

lower limit

-19

upper limit

51.1

Notes
[2] - An objective was reached if the 2-sided p-value associated to the objective was below 5%.

Secondary: Number of female subjects with overall vaccine effectiveness against genital infection with HPV-16/18 types in Cervarix/Engerix-B A Group versus Cervarix/Engerix-B B Group

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End point title

Number of female subjects with overall vaccine effectiveness against genital infection with HPV-16/18 types in Cervarix/Engerix-B A Group versus Cervarix/Engerix-B B Group

End point description

The analysis of overall effectiveness of Cervarix vaccine against genital infection with HPV-16/18 types was based on stratified Mantel-Haenszel adjusted for clustering. The overall vaccine effectiveness was computed as 1- the prevalence odd ratio in all subjects from the investigated group (prevalence rate in all subjects from the Cervarix/Engerix-B A Group/prevalence rate in all subjects from Engerix-B Group). Note: As per Protocol and as the confirmatory objectives were not met, only exploratory interpretation could be performed for what concerns this secondary outcome measure. The analysis was performed on female study participants from the Total Enrolled cohort on effectiveness, which included all study participants who were previously enrolled in the immunization phase, and those who joined the trial at Visit 5, for whom results were available.

End point type

Secondary

End point timeframe

At the time of Visit 5 (i.e. at 18.5 years of age)

End point values	Cervarix/Engerix-B A Group	Cervarix/Engerix-B B Group
Number of subjects analysed	3629	4029
Units: Participants	139	117

Overall efectiveness against HPV-16/18

Statistical analysis description

The analysis of the overall effectiveness of GSK’s HPV-16/18 vaccine against HPV-16/18 genital infection in Cervarix/Engerix-B A Group versus Cervarix/Engerix-B B was based on stratified Mantel-Haenszel adjusted for clustering.

Comparison groups

Cervarix/Engerix-B A Group v Cervarix/Engerix-B B Group

Number of subjects included in analysis

7658

Analysis specification

Pre-specified

Analysis type

P-value

= 0.069 ^[3]

Method

Cochran-Mantel-Haenszel

Parameter type

Vaccine effectiveness percentage

Point estimate

-52.2

Confidence interval

level

95%

sides

2-sided

lower limit

-139.4

upper limit

3.3

Notes
[3] - An objective was reached if the 2-sided p-value associated to the objective was below 5%.

Secondary: Number of female subjects with overall vaccine effectiveness against genital oncogenic infection with specific HPV types

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End point title

Number of female subjects with overall vaccine effectiveness against genital oncogenic infection with specific HPV types

End point description

The analysis of overall effectiveness of Cervarix vaccine against genital infection with specific HPV types (16, 18, 31/45, 31/33/45, 31/33/45/51, 31/33/45/51/52, 31/33/35/39/45/51/52/56/58/59/66/68, 16/18/31/33/35/39/45/51/52/56/58/59/66/68, 6, 11, 6/11, 6/11/53/74) was based on stratified Mantel-Haenszel adjusted for clustering. The effectiveness was computed as 1- the prevalence odd ratio in all subjects from the investigated group (prevalence rate in all subjects from the investigated group/prevalence rate in all subjects from Engerix-B Group). The analysis was performed on female study participants from the Total Enrolled cohort on effectiveness, which included all study participants who were previously enrolled in the immunization phase, and those who joined the trial at Visit 5, for whom results were available.

End point type

Secondary

End point timeframe

At the time of Visit 5 (i.e. at 18.5 years of age)

End point values	Cervarix/Engerix-B A Group	Cervarix/Engerix-B B Group	Engerix-B Group
Number of subjects analysed	3629	4029	3168
Units: Participants
HPV-16	88	85	227
HPV-18	62	41	134
HPV-31/45	97	93	182
HPV-31/33/45	175	173	271
HPV-31/33/45/51	449	450	441
HPV-31/33/45/51/52	563	585	532
HPV-31/33/35/39/45/51/52/56/58/59/66/68	923	961	776
HPV-16/18/31/33/35/39/45/51/52/56/58/59/66/68	965	999	883
HPV-6	192	183	139
HPV-11	39	32	34
HPV-6/11	221	204	165
HPV-6/11/53/74	403	381	307

No statistical analyses for this end point

Secondary: Number of female subjects with total vaccine effectiveness against oropharyngeal infection with HPV-16/18 types

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End point title

Number of female subjects with total vaccine effectiveness against oropharyngeal infection with HPV-16/18 types

End point description

The analysis of total effectiveness of Cervarix vaccine against oropharyngeal infection with HPV-16/18 types was based on stratified Mantel-Haenszel adjusted for clustering. The effectiveness was computed as 1- the prevalence odd ratio in Cervarix vaccinated subjects from the investigated group (prevalence rate in Cervarix vaccinated subjects from the investigated group/prevalence rate in all subjects from Engerix-B Group). The analysis was performed on female study participants from the Total Enrolled cohort on effectiveness, which included all study participants who were previously enrolled in the immunization phase, and those who joined the trial at Visit 5, for whom results were available.

End point type

Secondary

End point timeframe

At the time of Visit 5 (i.e. at 18.5 years of age)

End point values	Engerix-B Group	Cervarix/Engerix-B Pooled Group
Number of subjects analysed	1679	3192
Units: Participants	27	9

No statistical analyses for this end point

Secondary: Number of female subjects with total vaccine effectiveness against oropharyngeal oncogenic infection with specific HPV types

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End point title

Number of female subjects with total vaccine effectiveness against oropharyngeal oncogenic infection with specific HPV types

End point description

The analysis of total effectiveness of Cervarix vaccine against oropharyngeal infection with specific HPV types (16, 18, 31/45, 31/33/45, 31/33/45/51, 31/33/45/51/52, 31/33/35/39/45/51/52/56/58/59/66/68, 16/18/31/33/35/39/45/51/52/56/58/59/66/68, 6, 11, 6/11, 6/11/53/74) was based on stratified Mantel-Haenszel adjusted for clustering. The effectiveness was computed as 1- the prevalence odd ratio in all Cervarix vaccinated subjects from the investigated group (prevalence rate in all Cervarix vaccinated subjects from the investigated group/prevalence rate in all subjects from Engerix-B Group). The analysis was performed on female study participants from the Total Enrolled cohort on effectiveness, which included all study participants who were previously enrolled in the immunization phase, and those who joined the trial at Visit 5, for whom results were available.

End point type

Secondary

End point timeframe

At the time of Visit 5 (at 18.5 years of age)

End point values	Engerix-B Group	Cervarix/Engerix-B Pooled Group
Number of subjects analysed	1679	3192
Units: Participants
HPV-16	19	6
HPV-18	10	4
HPV-31/45	9	3
HPV-31/33/45	16	9
HPV-31/33/45/51	42	53
HPV-31/33/45/51/52	49	63
HPV-31/33/35/39/45/51/52/56/58/59/66/68	79	129
HPV-16/18/31/33/35/39/45/51/52/56/58/59/66/68	95	136
HPV-6	27	36
HPV-11	5	5
HPV-6/11	29	41
HPV-6/11/53/74	45	72

No statistical analyses for this end point

Secondary: Number of male subjects reporting any and Grade 3 solicited local symptoms, in a subset of subjects

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End point title

Number of male subjects reporting any and Grade 3 solicited local symptoms, in a subset of subjects

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 50 millimeters (mm) of injection site. The analysis was performed on the Total vaccinated cohort (TVC) - the Diary card subset, which included a subset of male adolescents from Cervarix/Engerix-B A Group and Engerix-B Group, with at least one study vaccine administration documented, who were selected for active assessment of safety using diary cards and for whom data were available.

End point type

Secondary

End point timeframe

During the 7-day post-vaccination period following each dose and across doses

End point values	Cervarix Pooled Group	Engerix-B Pooled Group
Number of subjects analysed	603	1028
Units: Participants
Any Pain, Dose 1 (N=590;1021)	463	157
Grade 3 Pain, Dose 1 (N=590;1021)	12	1
Any Redness, Dose 1 (N=590;1021)	99	90
Grade 3 Redness, Dose 1 (N=590;1021)	1	0
Any Swelling, Dose 1 (N=590;1021)	61	29
Grade 3 Swelling, Dose 1 (N=590;1021)	4	0
Any Pain, Dose 2 (N=509;935)	331	123
Grade 3 Pain, Dose 2 (N=509;935)	9	1
Any Redness, Dose 2 (N=509;935)	88	59
Grade 3 Redness, Dose 2 (N=509;935)	1	0
Any Swelling, Dose 2 (N=509;935)	66	16
Grade 3 Swelling, Dose 2 (N=509;935)	3	0
Any Pain, Dose 3 (N=491;812)	326	108
Grade 3 Pain, Dose 3 (N=491;812)	11	0
Any Redness, Dose 3 (N=491;812)	100	50
Grade 3 Redness, Dose 3 (N=491;812)	2	0
Any Swelling, Dose 3 (N=491;812)	69	18
Grade 3 Swelling, Dose 3 (N=491;812)	3	0
Any Pain, Across doses (N=603;1028)	506	251
Grade 3 Pain, Across doses (N=603;1028)	26	2
Any Redness, Across doses (N=603;1028)	169	131
Grade 3 Redness, Across doses (N=603;1028)	4	0
Any Swelling, Across doses (N=603;1028)	131	46
Grade 3 Swelling, Across doses (N=603;1028)	8	0

No statistical analyses for this end point

Secondary: Number of male subjects reporting any, Grade 3 and related to vaccination solicited general symptoms, in a subset of subjects

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End point title

Number of male subjects reporting any, Grade 3 and related to vaccination solicited general symptoms, in a subset of subjects

End point description

Assessed solicited general symptoms were arthralgia, fatigue, fever [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)], gastrointestinal symptoms (including nausea, vomiting, diarrhoea and/or abdominal pain), headache, myalgia, rash and urticaria. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever > 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination. The analysis was performed on the TVC - the Diary card subset, which included a subset of male adolescents from Cervarix/Engerix-B A Group and Engerix-B Group, with at least one study vaccine administration documented, who were selected for active assessment of safety using diary cards and for whom data were available.

End point type

Secondary

End point timeframe

During the 7-day post-vaccination period following each dose and across doses

End point values	Cervarix Pooled Group	Engerix-B Pooled Group
Number of subjects analysed	604	1028
Units: Participants
Any Arthralgia, Dose 1 (N=590;1021)	58	58
Grade 3 Arthralgia, Dose 1 (N=590;1021)	0	1
Related Arthralgia, Dose 1 (N=590;1021)	37	45
Any Fatigue, Dose 1 (N=590;1021)	224	301
Grade 3 Fatigue, Dose 1 (N=590;1021)	3	9
Related Fatigue, Dose 1 (N=590;1021)	156	246
Any Fever (axillary), Dose 1 (N=590;1021)	15	35
Grade 3 Fever (axillary), Dose 1 (N=590;1021)	3	4
Related Fever (axillary), Dose 1 (N=590;1021)	7	23
Any Gastrointestinal, Dose 1 (N=590;1021)	73	101
Grade 3 Gastrointestinal, Dose 1 (N=590;1021)	7	6
Related Gastrointestinal, Dose 1 (N=590;1021)	45	84
Any Headache, Dose 1 (N=590;1021)	178	255
Grade 3 Headache, Dose 1 (N=590;1021)	10	7
Related Headache, Dose 1 (N=590;1021)	108	181
Any Myalgia, Dose 1 (N=590;1021)	229	169
Grade 3 Myalgia, Dose 1 (N=590;1021)	6	2
Related Myalgia, Dose 1 (N=590;1021)	196	138
Any Rash, Dose 1 (N=590;1021)	13	17
Grade 3 Rash, Dose 1 (N=590;1021)	0	0
Related Rash, Dose 1 (N=590;1021)	5	12
Any Urticaria, Dose 1 (N=590;1021)	3	12
Grade 3 Urticaria, Dose 1 (N=590;1021)	0	0
Related Urticaria, Dose 1 (N=590;1021)	2	11
Any Arthralgia, Dose 2 (N=511;936)	41	38
Grade 3 Arthralgia, Dose 2 (N=511;936)	0	3
Related Arthralgia, Dose 2 (N=511;936)	36	33
Any Fatigue, Dose 2 (N=511;936)	136	155
Grade 3 Fatigue, Dose 2 (N=511;936)	2	7
Related Fatigue, Dose 2 (N=511;936)	100	123
Any Fever, Dose 2 (N=511;936)	19	28
Grade 3 Fever, Dose 2 (N=511;936)	1	2
Related Fever, Dose 2 (N=511;936)	11	10
Any Gastrointestinal, Dose 2 (N=511;936)	45	50
Grade 3 Gastrointestinal, Dose 2 (N=511;936)	4	5
Related Gastrointestinal, Dose 2 (N=511;936)	27	38
Any Headache, Dose 2 (N=511;936)	101	144
Grade 3 Headache, Dose 2 (N=511;936)	5	4
Related Headache, Dose 2 (N=511;936)	55	104
Any Myalgia, Dose 2 (N=511;936)	151	97
Grade 3 Myalgia, Dose 2 (N=511;936)	1	1
Related Myalgia, Dose 2 (N=511;936)	143	77
Any Rash, Dose 2 (N=511;936)	9	14
Grade 3 Rash, Dose 2 (N=511;936)	0	0
Related Rash, Dose 2 (N=511;936)	4	9
Any Urticaria, Dose 2 (N=511;936)	1	2
Grade 3 Urticaria, Dose 2 (N=511;936)	0	0
Related Urticaria, Dose 2 (N=511;936)	1	1
Any Arthralgia, Dose 3 (N=492;814)	53	33
Grade 3 Arthralgia, Dose 3 (N=492;814)	1	0
Related Arthralgia, Dose 3 (N=492;814)	41	29
Any Fatigue, Dose 3 (N=492;814)	135	141
Grade 3 Fatigue, Dose 3 (N=492;814)	4	6
Related Fatigue, Dose 3 (N=492;814)	100	116
Any Fever, Dose 3 (N=492;814)	15	27
Grade 3 Fever, Dose 3 (N=492;814)	2	3
Related Fever, Dose 3 (N=492;814)	10	24
Any Gastrointestinal, Dose 3 (N=492;814)	19	50
Grade 3 Gastrointestinal, Dose 3 (N=492;814)	0	2
Related Gastrointestinal, Dose 3 (N=492;814)	12	39
Any Headache, Dose 3 (N=492;814)	101	123
Grade 3 Headache, Dose 3 (N=492;814)	2	3
Related Headache, Dose 3 (N=492;814)	69	97
Any Myalgia, Dose 3 (N=492;814)	158	80
Grade 3 Myalgia, Dose 3 (N=492;814)	5	0
Related Myalgia, Dose 3 (N=492;814)	137	69
Any Rash, Dose 3 (N=492;814)	11	9
Grade 3 Rash, Dose 3 (N=492;814)	0	0
Related Rash, Dose 3 (N=492;814)	5	8
Any Urticaria, Dose 3 (N=492;814)	0	3
Grade 3 Urticaria, Dose 3 (N=492;814)	0	0
Related Urticaria, Dose 3 (N=492;814)	0	3
Any Arthralgia, Across doses (N=604;1028)	107	97
Grade 3 Arthralgia, Across doses (N=604;1028)	1	4
Related Arthralgia, Across doses (N=604;1028)	87	81
Any Fatigue, Across doses (N=604;1028)	291	411
Grade 3 Fatigue, Across doses (N=604;1028)	7	21
Related Fatigue, Across doses (N=604;1028)	233	351
Any Fever, Across doses (N=604;1028)	48	85
Grade 3 Fever, Across doses (N=604;1028)	6	9
Related Fever, Across doses (N=604;1028)	28	53
Any Gastrointestinal, Across doses (N=604;1028)	106	163
Grade 3 Gastrointestinal, Across doses(N=604;1028)	11	13
Related Gastrointestinal,Across doses(N=604;1028)	70	128
Any Headache, Across doses (N=604;1028)	261	371
Grade 3 Headache, Across doses (N=604;1028)	15	14
Related Headache, Across doses (N=604;1028)	176	280
Any Myalgia, Across doses (N=604;1028)	321	250
Grade 3 Myalgia, Across doses (N=604;1028)	12	3
Related Myalgia, Across doses (N=604;1028)	291	211
Any Rash, Across doses (N=604;1028)	29	33
Grade 3 Rash, Across doses (N=604;1028)	0	0
Related Rash, Across doses (N=604;1028)	14	23
Any Urticaria, Across doses (N=604;1028)	4	15
Grade 3 Urticaria, Across doses (N=604;1028)	0	0
Related Urticaria, Across doses (N=604;1028)	3	13

No statistical analyses for this end point

Secondary: Number of male subjects reporting any, Grade 3 and related to vaccination unsolicited adverse events (AEs), in a subset of subjects

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End point title

Number of male subjects reporting any, Grade 3 and related to vaccination unsolicited adverse events (AEs), in a subset of subjects

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 follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevented normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination. This analysis was performed on the TVC - the Diary Card subset, which included a subset of male adolescents from Cervarix/Engerix-B A Group and Engerix-B Group who were selected for active assessment of safety using diary cards and for whom data were available.

End point type

Secondary

End point timeframe

Within the 30-day post-vaccination period

End point values	Cervarix Pooled Group	Engerix-B Pooled Group
Number of subjects analysed	643	1047
Units: Participants
Any AEs	157	202
Grade 3 AEs	31	46
Related AEs	12	19

No statistical analyses for this end point

Secondary: Number of male subjects with urticaria/rash within 30 minutes after each vaccination dose, in a subset of subjects

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End point title

Number of male subjects with urticaria/rash within 30 minutes after each vaccination dose, in a subset of subjects

End point description

The number of subjects with urticaria/rash assessed within 30 minutes following each vaccine dose are reported. Confirmed urticaria/rash = subjects who reported urticaria/rash within the specified time frame. Not confirmed urticaria/rash = number of subjects who did not report urticaria/rash within the specified time frame. This analysis was performed on the TVC - the Diary Card subset, which included a subset of male adolescents from Cervarix/Engerix-B A Group and Engerix-B Group who were selected for active assessment of safety using diary cards and for whom data were available.

End point type

Secondary

End point timeframe

Within 30 minutes following each vaccination dose

End point values	Cervarix Pooled Group	Engerix-B Pooled Group
Number of subjects analysed	643	1047
Units: Participants
Not confirmed urticaria/rash, Dose 1 (N=643;1047)	643	1047
Confirmed urticaria/rash, Dose 1 (N=643;1047)	0	0
Not confirmed urticaria/rash, Dose 2 (N=634;1042)	634	1042
Confirmed urticaria/rash, Dose 2 (N=634;1042)	0	0
Not confirmed urticaria/rash, Dose 3 (N=631;1039)	630	1039
Confirmed urticaria/rash, Dose 3 (N=631;1039)	0	0
Missing urticaria/rash, Dose 3 (N=631;1039)	1	0

No statistical analyses for this end point

Secondary: Number of male subjects reporting medically significant conditions (MSCs), in a subset of subjects

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End point title

Number of male subjects reporting medically significant conditions (MSCs), in a subset of subjects

End point description

MSCs are defined as AEs prompting emergency room or physician visits that are not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that are not related to common diseases. Common diseases include: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections and injury. This analysis was performed on the TVC - the Diary Card subset, which included a subset of male adolescents from Cervarix/Engerix-B A Group and Engerix-B Group who were selected for active assessment of safety using diary cards and for whom data were available.

End point type

Secondary

End point timeframe

From Dose 1 (at Day 0) until Month 12

End point values	Cervarix Pooled Group	Engerix-B Pooled Group
Number of subjects analysed	643	1047
Units: Participants	47	76

No statistical analyses for this end point

Secondary: Number of male subjects reporting any serious adverse events (SAEs) and SAEs causally related to vaccination, in a subset of subjects

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End point title

Number of male subjects reporting any serious adverse events (SAEs) and SAEs causally related to vaccination, in a subset of subjects

End point description

Serious adverse events (SAEs) assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. The analysis was performed on the TVC - subset of male subjects with active follow-up Month 0-Month 12 for SAEs, which included the male subjects in the Diary Card subset and the remaining Cervarix/Engerix-B A Group male subjects for whom data were available.

End point type

Secondary

End point timeframe

From Dose 1 (at Day 0) until Month 12

End point values	Cervarix Pooled Group	Engerix-B Pooled Group
Number of subjects analysed	2436	1267
Units: Participants
Any SAEs	58	25
Related SAEs	4	1

No statistical analyses for this end point

Secondary: Number of subjects reporting SAEs assessed by the investigator as possibly related to vaccination

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End point title

Number of subjects reporting SAEs assessed by the investigator as possibly related to vaccination

End point description

Serious adverse events (SAEs) assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. The analysis was performed on the Total Vaccinated Cohort, which included all vaccinated subjects for whom data were available.

End point type

Secondary

End point timeframe

During the entire study period (from Day 0 up to Visit 5 [18.5 years of age] or up to the day before 19 years of age for subjects who did not attend Visit 5)

End point values	Cervarix Pooled Group	Engerix-B Pooled Group
Number of subjects analysed	14837	17338
Units: Participants	25	30

No statistical analyses for this end point

Secondary: Number of subjects with new onset of autoimmune diseases (NOADs), retrieved from Care Register for Social Welfare and Health Care (HILMO)

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End point title

Number of subjects with new onset of autoimmune diseases (NOADs), retrieved from Care Register for Social Welfare and Health Care (HILMO)

End point description

NOADs include colitis ulcerative, juvenile arthritis, type 1 diabetes mellitus, coeliac disease and Chron's disease, Basedow's disease, erythema nodosum VIIth nerve paralysis and psoriasis. The analysis was performed on the Total Vaccinated cohort, which included all vaccinated subjects for whom data were available.

End point type

Secondary

End point timeframe

During the entire study period (from day 0 up to Visit 5 [at 18.5 years of age] or up to the day before 19 years of age for subjects who did not attend Visit 5)

End point values	Cervarix Pooled Group	Engerix-B Pooled Group
Number of subjects analysed	14837	17338
Units: Participants	149	180

No statistical analyses for this end point

Secondary: Number of subjects reporting pregnancies and outcomes of reported pregnancies with onset during the study period, retrieved from Medical Birth Registry and HILMO

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End point title

Number of subjects reporting pregnancies and outcomes of reported pregnancies with onset during the study period, retrieved from Medical Birth Registry and HILMO

End point description

Pregnancies with onset during the study were classified by their outcome. Outcomes included live infant with no apparent congenital anomaly, elective termination with no apparent congenital anomaly, spontaneous abortion with no apparent congenital anomaly, ectopic pregnancy, stillbirth with no apparent congenital anomaly and molar pregnancy. Note: The analysis was performed based on the corrected demographical data. Please refer to the rationale provided in the Baseline characteristics section. The analysis was performed on the total number of pregnant subjects reported, part of the Total Vaccinated cohort, which included all vaccinated subjects for whom data were available.

End point type

Secondary

End point timeframe

During the entire study period (from Day 0 up to Visit 5 [at 18.5 years of age] or up to the day before 19 years of age for subjects who did not attend Visit 5)

End point values	Cervarix Pooled Group	Engerix-B Pooled Group
Number of subjects analysed	777	567
Units: Participants
Live infant with no apparent anomaly	254	183
Elective termination with no apparent anomaly	454	332
Ectopic pregnancy	5	5
Spontaneous abortion with no apparent anomaly	62	45
Stillbirth with no apparent congenital anomaly	0	1
Molar pregnancy	2	1

No statistical analyses for this end point

Secondary: Number of subjects with HPV-16 and HPV-18 antibody concentrations equal to or above the cut-off values, by gender, in a subset of subjects

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End point title

Number of subjects with HPV-16 and HPV-18 antibody concentrations equal to or above the cut-off values, by gender, in a subset of subjects ^[4]

End point description

The antibody concentrations against HPV-16 and HPV-18 were determined by Enzyme-linked immunosorbent assay (ELISA). The cut-off of the assay was 8 ELISA units per milliliter (EL.U/mL) for anti-HPV-16 and 7 EL.U/mL for anti-HPV-18 at Visits 1 and 4 and 19 EL.U/mL for HPV-16 and 18 EL.U/mL for HPV-18 at Visit 5. The analysis was performed on the ATP cohort for immunogenicity-Immunogenicity subset, which comprised the same male study subjects from the Cervarix/Engerix-B A Group included in the Diary Card subset, plus approximately 1500 female study subjects from the same Cervarix/Engerix-B A Group, with assay results available at the considered time point.

End point type

Secondary

End point timeframe

At the time of Visit 1 (at Day 0), Visit 4 (at Month 7) and Visit 5 (at 18.5 years of age)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results were only assessed in a subset of subjects.

End point values	Cervarix Pooled Group
Number of subjects analysed	1163
Units: Participants
anti-HPV-16 ≥ 8 EL.U/mL, males (Day 0) (N=536)	40
anti-HPV-16 ≥ 8 EL.U/mL, males (Month 7) (N=536)	536
anti-HPV-16 ≥ 19 EL.U/mL, males (18.5Y) (N=217)	217
anti-HPV-16 ≥ 8 EL.U/mL, females (Day 0) (N=1163)	86
anti-HPV-16 ≥ 8 EL.U/mL,females (Month 7) (N=1163)	1163
anti-HPV-16 ≥ 19 EL.U/mL, females (18.5Y) (N=688)	688
anti-HPV-18 ≥ 7 EL.U/mL, males (Day 0) (N=535)	31
anti-HPV-18 ≥ 7 EL.U/mL, males (Month 7) (N=535)	535
anti-HPV-18 ≥ 18 EL.U/mL, males (18.5Y) (N=217)	217
anti-HPV-18 ≥ 7 EL.U/mL, females (Day 0) (N=1160)	84
anti-HPV-18 ≥ 7 EL.U/mL,females (Month 7) (N=1160)	1160
anti-HPV-18 ≥ 18 EL.U/mL, females (18.5Y) (N=686)	685

No statistical analyses for this end point

Secondary: Anti-HPV-16 and anti-HPV-18 antibody concentrations, by gender, in a subset of subjects

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End point title

Anti-HPV-16 and anti-HPV-18 antibody concentrations, by gender, in a subset of subjects ^[5]

End point description

End point type

Secondary

End point timeframe

At the time of Visit 1 (Day 0), Visit 4 (at Month 7) and at the time of Visit 5 (18.5 years of age)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The results were only assessed in a subset of subjects.

End point values	Cervarix Pooled Group
Number of subjects analysed	1163
Units: EL.U/mL
geometric mean (confidence interval 95%)
anti-HPV-16 ≥ 8 EL.U/mL, males (Day 0) (N=536)	4.5 (4.3 to 4.6)
anti-HPV-16 ≥ 8 EL.U/mL, males (Month 7) (N=536)	23959.1 (22301.0 to 25740.4)
anti-HPV-16 ≥ 19 EL.U/mL, males (18.5Y) (N=217)	2759.5 (2432.1 to 3130.9)
anti-HPV-16 ≥ 8 EL.U/mL, females (Day 0) (N=1163)	4.5 (4.4 to 4.6)
anti-HPV-16 ≥ 8 EL.U/mL,females (Month 7) (N=1163)	21327.2 (20338.9 to 22363.5)
anti-HPV-16 ≥ 19 EL.U/mL, females (18.5Y) (N=688)	2609.6 (2444.4 to 2785.9)
anti-HPV-18 ≥ 7 EL.U/mL, males (Day 0) (N=535)	3.8 (3.7 to 4.0)
anti-HPV-18 ≥ 7 EL.U/mL, males (Month 7) (N=535)	8583.9 (7974.7 to 9239.5)
anti-HPV-18 ≥ 18 EL.U/mL, males (18.5Y) (N=217)	837.7 (727.3 to 964.9)
anti-HPV-18 ≥ 7 EL.U/mL, females (Day 0) (N=1160)	3.9 (3.8 to 4.0)
anti-HPV-18 ≥ 7 EL.U/mL,females (Month 7) (N=1160)	8227.3 (7847.7 to 8625.4)
anti-HPV-18 ≥ 18 EL.U/mL, females (18.5Y) (N=686)	890.0 (826.2 to 958.7)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited AEs:within 7 days post-vaccination. Unsolicited AEs:within 30 days post-vaccination. SAEs: during the entire study (from Day 0 up to Visit 5 [at 18.5 years of age] or up to the day before 19 years of age for subjects who did not attend Visit 5).

Adverse event reporting additional description

AEs were collected in the TVC-Diary Card subset. The Total Number of Participants Affected in Other AEs Table is populated with the highest value within the Other AEs table since consolidated analysis was not technically possible for solicited/unsolicited AEs. Moreover, the N of affected subjects is equal to N of events for the Other AEs section.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Engerix-B Pooled Group

Reporting group description

Male and female subjects vaccinated with Engerix-B vaccine. The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Reporting group title

Cervarix Pooled Group

Reporting group description

Male and female subjects vaccinated with Cervarix vaccine. The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule.

Serious adverse events	Engerix-B Pooled Group	Cervarix Pooled Group
Total subjects affected by serious adverse events
subjects affected / exposed	152 / 17338 (0.88%)	188 / 14837 (1.27%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Astrocytoma, low grade
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenoma benign
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Benign hydatidiform mole
subjects affected / exposed	1 / 17338 (0.01%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Behcet's syndrome
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion missed
subjects affected / exposed	15 / 17338 (0.09%)	10 / 14837 (0.07%)
occurrences causally related to treatment / all	0 / 15	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion spontaneous
subjects affected / exposed	18 / 17338 (0.10%)	32 / 14837 (0.22%)
occurrences causally related to treatment / all	0 / 20	0 / 32
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion spontaneous complete
subjects affected / exposed	2 / 17338 (0.01%)	4 / 14837 (0.03%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion spontaneous incomplete
subjects affected / exposed	3 / 17338 (0.02%)	10 / 14837 (0.07%)
occurrences causally related to treatment / all	0 / 3	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Ectopic pregnancy
subjects affected / exposed	5 / 17338 (0.03%)	5 / 14837 (0.03%)
occurrences causally related to treatment / all	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Peripartum haemorrhage
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pre-eclampsia
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Premature baby
subjects affected / exposed	6 / 17338 (0.03%)	11 / 14837 (0.07%)
occurrences causally related to treatment / all	0 / 6	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Small for dates baby
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stillbirth
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 17338 (0.00%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 17338 (0.00%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Testicular torsion
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperventilation
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neonatal asphyxia
subjects affected / exposed	0 / 17338 (0.00%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumomediastinum
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disturbance in social behaviour
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Emotional disorder of childhood
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Panic disorder
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hallucination
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypnagogic hallucination
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sleep attacks
subjects affected / exposed	1 / 17338 (0.01%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Alcohol poisoning
subjects affected / exposed	1 / 17338 (0.01%)	3 / 14837 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 17338 (0.00%)	4 / 14837 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 17338 (0.00%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 17338 (0.00%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 17338 (0.00%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neck injury
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle rupture
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic rupture
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic renal injury
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	2 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Forearm fracture
subjects affected / exposed	1 / 17338 (0.01%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	1 / 17338 (0.01%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Vitello-intestinal duct remnant
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 17338 (0.01%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cataplexy
subjects affected / exposed	1 / 17338 (0.01%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	2 / 17338 (0.01%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Guillain-barre syndrome
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple sclerosis
subjects affected / exposed	1 / 17338 (0.01%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Narcolepsy
subjects affected / exposed	1 / 17338 (0.01%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Optic neuritis
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Splenomegaly
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	2 / 17338 (0.01%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Colitis ulcerative
subjects affected / exposed	14 / 17338 (0.08%)	12 / 14837 (0.08%)
occurrences causally related to treatment / all	3 / 14	5 / 12
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 17338 (0.00%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	15 / 17338 (0.09%)	7 / 14837 (0.05%)
occurrences causally related to treatment / all	5 / 15	2 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Proctitis ulcerative
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dermatitis
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Henoch-schonlein purpura
subjects affected / exposed	1 / 17338 (0.01%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stevens-johnson syndrome
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Tubulointerstitial nephritis and uveitis syndrome
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Thyroiditis
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basedow's disease
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Exostosis
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis reactive
subjects affected / exposed	2 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Juvenile idiopathic arthritis
subjects affected / exposed	4 / 17338 (0.02%)	3 / 14837 (0.02%)
occurrences causally related to treatment / all	0 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sacroiliitis
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sjogren's syndrome
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	3 / 17338 (0.02%)	5 / 14837 (0.03%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Infectious mononucleosis
subjects affected / exposed	1 / 17338 (0.01%)	4 / 14837 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	1 / 17338 (0.01%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	1 / 17338 (0.01%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 17338 (0.00%)	2 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis bacterial
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis bacterial
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	2 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Genital infection
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle abscess
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic infection
subjects affected / exposed	1 / 17338 (0.01%)	0 / 14837 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 17338 (0.00%)	1 / 14837 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 17338 (0.00%)	4 / 14837 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Type 1 diabetes mellitus
subjects affected / exposed	25 / 17338 (0.14%)	13 / 14837 (0.09%)
occurrences causally related to treatment / all	9 / 25	3 / 13
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Engerix-B Pooled Group	Cervarix Pooled Group
Total subjects affected by non serious adverse events
subjects affected / exposed	411 / 17338 (2.37%)	506 / 14837 (3.41%)
General disorders and administration site conditions
Arthralgia
Additional description: Solicited symptom during the 7-day post-vaccination period (across doses).
subjects affected / exposed ^[1]	97 / 1028 (9.44%)	107 / 604 (17.72%)
occurrences all number	97	107
Fatigue
Additional description: Solicited symptom during the 7-day post-vaccination period (across doses).
subjects affected / exposed ^[2]	411 / 1028 (39.98%)	291 / 604 (48.18%)
occurrences all number	411	291
Headache
Additional description: Solicited symptom during the 7-day post-vaccination period (across doses).
subjects affected / exposed ^[3]	371 / 1028 (36.09%)	261 / 604 (43.21%)
occurrences all number	371	261
Pain
Additional description: Solicited symptom during the 7-day post-vaccination period (across doses).
subjects affected / exposed ^[4]	251 / 1028 (24.42%)	506 / 603 (83.91%)
occurrences all number	251	506
Redness
Additional description: Solicited symptom during the 7-day post-vaccination period (across doses).
subjects affected / exposed ^[5]	131 / 1028 (12.74%)	169 / 603 (28.03%)
occurrences all number	131	169
Fever (Axillary)
Additional description: Solicited symptom during the 7-day post-vaccination period (across doses).
subjects affected / exposed ^[6]	85 / 1028 (8.27%)	48 / 604 (7.95%)
occurrences all number	85	48
Gastrointestinal
Additional description: Solicited symptom during the 7-day post-vaccination period (across doses).
subjects affected / exposed ^[7]	163 / 1028 (15.86%)	106 / 604 (17.55%)
occurrences all number	163	106
Swelling
Additional description: Solicited symptom during the 7-day post-vaccination period (across doses).
subjects affected / exposed ^[8]	46 / 1028 (4.47%)	131 / 603 (21.72%)
occurrences all number	46	131
Myalgia
Additional description: Solicited symptom during the 7-day post-vaccination period (across doses).
subjects affected / exposed ^[9]	250 / 1028 (24.32%)	321 / 604 (53.15%)
occurrences all number	250	321
Infections and infestations
Nasopharyngitis
Additional description: Unsolicited symptom during the 30-day post-vaccination period (across doses).
subjects affected / exposed ^[10]	17 / 1047 (1.62%)	33 / 643 (5.13%)
occurrences all number	17	33

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total vaccinated cohort, only on subjects with their symptom sheets completed.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total vaccinated cohort, only on subjects with their symptom sheets completed.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total vaccinated cohort, only on subjects with their symptom sheets completed.
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total vaccinated cohort, only on subjects with their symptom sheets completed.
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total vaccinated cohort, only on subjects with their symptom sheets completed.
[6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total vaccinated cohort, only on subjects with their symptom sheets completed.
[7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total vaccinated cohort, only on subjects with their symptom sheets completed.
[8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total vaccinated cohort, only on subjects with their symptom sheets completed.
[9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total vaccinated cohort, only on subjects with their symptom sheets completed.
[10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: The analysis was performed on the Total vaccinated cohort, only on subjects with their symptom sheets completed.

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Were there any global substantial amendments to the protocol? Yes

24 Oct 2007

•As the HPV-16/18 L1 VLP AS04 vaccine has been licensed in Europe in September 2007, the introduction was updated accordingly. In addition, reference to recently published efficacy results from the phase III study HPV-008 and to the current Investigator Brochure was made. •The indication of the HPV-16/18 L1 VLP AS04 vaccine has been updated in accordance with the current Summary of Product Characteristics. •The list of common diseases that are not to be recorded as medically significant conditions has been updated to include injury. •Instructions for the reporting of NOADs retrieved from the Hospital Discharge Registry, pregnancies retrieved from the Medical Birth Registry, and new neoplastic diseases (CIN3 and ICC) retrieved from the Finnish Cancer Registry have been clarified throughout the protocol. •The length of study visit intervals has been changed to allow for maximum attendance of study participants at the study visits. •The study procedures for study participants who become pregnant during the effectiveness evaluation phase have been clarified to allow for continuation of blood sampling (if applicable) and completion of the behavioural questionnaire. •Section 7.5 was updated to clarify that AEs not previously documented in the study need to be recorded in the Adverse Event section in the study participant’s eCRF only for subjects included in the Diary Card subset. In addition, subheadings were added in this section to further clarify the reporting of AEs and SAEs. •The enrolment period has been extended to facilitate recruitment of the prespecified number of subjects.

04 Mar 2008

•A note has been added regarding the timing of the baseline behavioural questionnaire at Visit 3. This was completed at Visit 3 for study participants aged 15 years. The other study participants received it by mail after they have reached their 15th birthday. •A note to the Visit 1 (vaccination visit) has been added to mention that randomization may be done before the Visit 1 date, provided that written informed consent/assent has been obtained. •The recruitment period has been extended until May 2008 for subjects born in 1992, until December 2008 for subjects born in 1993 and until December 2009 for subjects born in 1994 and 1995. Taking this change into account, the recruitment period lasted approximately 2 years starting from the time the first birth cohort started to be enrolled. •The list of autoimmune diseases (checked during the passive safety surveillance) has been updated.

10 Feb 2009

The HPV-040 protocol was amended for the following reasons: •Update of the introduction in order to include the results of the first immunogenicity and safety study of GSK Biologicals’ HPV vaccine in males 10-18 years of age and update of the introduction and rationale in order to reflect changes in the marketing and licensure status of the vaccine. •Amendment of Arm A and Arm C males in the Diary Card subset descriptions with regards to subject vaccination status. •The enrolment of female subjects in the immunological subset (IS) was stopped according to the recommendation of the Steering Committee. The number of female subjects in the immunological subset has been changed from approximately 3000 subjects to 1500 subjects. •Replacement of the term “medical examination” by the term “clinical examination” in the context of Study Visit 1. •The history directed clinical examination at Study Visit 1 was not mandatory, but performed only if needed. The protocol has been updated accordingly. •The Hospital Discharge Registry which allows retrieval of NOADs was updated once a year, not four times a year. The protocol has been updated accordingly. •Update of the instructions for vaccine storage. •Instructions for pregnancy and SAE reporting have been amended to clarify that any pregnancy outcome meets the criteria of serious adverse events, it should be reported as an SAE irrespective of its relationship to vaccination. •The National Public Health Institute (KTL) and the Research and Development Centre for Social Welfare and Health (STAKES) merged in 2009. The new acronym is THL and the official name in English is National Institute for Health and Welfare. The protocol has been updated accordingly. •Change of the title “List of autoimmune diseases” to “List of immune-mediated diseases” (with no change in content).

02 Apr 2010

The HPV-040 protocol was amended for the following reasons: •Only subjects born between 1992-1995, approximately 18.5 years of age at Visit 5, were eligible for the effectiveness evaluation phase of the study. •The primary endpoint of HPV-16/-18 DNA positivity (by PCR) in all 18-19-year old female study participants has been replaced by two co-primary endpoints. •Tertiary objectives and endpoints have been added. •The list of communities has been amended for a discrepancy in the number of females and males. •The enrolment description has been updated to reflect that the enrolment period was extended from 2 years to 2.5 years. •Male and female vaccinated subjects, enrolled in the immunization phase who did not return at Visit 5, were unblinded once they reached 19 years of age. •Amendment of the description of the passive safety follow-up. •Qualitative monitoring of the occurrence of NOADs and cervical neoplastic diseases (CIN3+). •Calculation of the standardized incidence ratios of CIN3+. •Update of the study contact information and the contact information for the back-up study contact for reporting SAEs. •Addition of information on emergency unblinding/code breaking study contact. •Information regarding the Effectiveness evaluation phase (e.g., invitation to the effectiveness evaluation phase, clinical management algorithm) was subjected to changes. •Modification of the instructions for vaccine immunogenicity and immunological read-outs. •Urine and/or a self-obtained cervical sample were not provided as part of the study, but as part of the Finnish National Chlamydia Screening Programme. •The gene expression profile of HPV viruses was not evaluated. •All laboratory assays were performed by GSK Biologicals/a validated laboratory designated by GSK Biologicals. • Only one safety/immunogenicity interim analysis was performed. •Amendment of the description of the interim analysis for effectiveness. •Other miscellaneous updates.

16 Feb 2012

The HPV-040 protocol was amended for the following reasons: •The interim analysis for effectiveness was not performed in order to reserve maximal study power for end of study analyses. •Oropharyngeal samples for HPV DNA testing were collected at Visit 5 from female subjects born in 1993, 1994 and 1995, who joined the effectiveness evaluation phase of the study. •Tertiary objectives and endpoints have been added. •HPV infection has been specified as "genital" or "oropharyngeal" for all objectives/endpoints. •The Multiplex Type-specific (MPTS) PCR assay HPV PCR Luminex was performed in parallel with the SPF-10 PCR-DEIA/LiPA assay already described in the protocol, in order to align laboratory data from the HPV-040 PRI study with other studies in the project. •Any pIMDs reported to the investigator were reported to GSK Biologicals using SAE screens and were not time-expedited. •Standardized incidence rate ratios of CIN3+ and of NOADs in the cohort (RVI) of HPV vaccinated study participants versus the 1992-1995 born HPV unvaccinated population in the cohort (RVI) in the study communities were calculated at the final analysis. •A registry of vaccinated individuals (RVI) containing personal identifiers has been established at the National Institute for Health and Welfare (THL) at study enrolment. •The number of study participants has been updated with the number of study participants enrolled in immunization phase. •Study procedures at Visit 5 have been clarified. •Clarifications regarding the Engerix formulation. •Update of the introduction. Addition of recent references to literature. •Update of the sponsor information, the list of contributing authors, the list of abbreviations and the list of references.

22 Jun 2012

As the investigators had immediate and direct access to the individual treatment codes via the SBIR system, Section 7.13 “Emergency unblinding” was not applicable and was removed from the protocol.

09 May 2013

The HPV-040 protocol was amended to: •Further substantiate the rationale behind including long-term follow-up for pregnancy and pregnancy outcomes via Finnish health registries in this study. •Allow usage of the Care Register for Social Welfare and Health Care for passive surveillance of pregnancy and pregnancy outcomes in this study.

28 Nov 2013

The HPV-040 protocol was amended for the following reason: The assay used to measure anti-HPV-16/-18 antibody concentrations at the designated laboratory was improved to increase the assay precision by changing the assay cut-off value from 8 EL.U/mL to 19 EL.U/mL for HPV-16 and from 7 EL.U/mL to 18 EL.U/mL for HPV-18. This change in the assay was implemented for the testing of samples from Visit 5 onwards.

24 Mar 2014

The HPV-040 protocol was amended for the following reasons: •Oropharyngeal samples were being collected from female subjects born in 1992 to maximize the chance of detecting vaccine effect against oropharyngeal infection. •Additional study objectives and endpoints to evaluate vaccine effectiveness against oropharyngeal infection were added. •The end-of-study analysis plan was clarified.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of female subjects with overall vaccine effectiveness against genital infection with Human Papilloma Virus (HPV)-16/18 types in Cervarix/Engerix-B B Group versus Engerix-B Group and in Cervarix/Engerix-B A Group versus Engerix-B Group

Primary: Number of female subjects with overall vaccine effectiveness against genital infection with Human Papilloma Virus (HPV)-16/18 types in Cervarix/Engerix-B B Group versus Engerix-B Group and in Cervarix/Engerix-B A Group versus Engerix-B Group

Secondary: Number of female subjects with overall vaccine effectiveness against genital infection with HPV-16/18 types in Cervarix/Engerix-B A Group versus Cervarix/Engerix-B B Group

Secondary: Number of female subjects with overall vaccine effectiveness against genital infection with HPV-16/18 types in Cervarix/Engerix-B A Group versus Cervarix/Engerix-B B Group

Secondary: Number of female subjects with overall vaccine effectiveness against genital oncogenic infection with specific HPV types

Secondary: Number of female subjects with overall vaccine effectiveness against genital oncogenic infection with specific HPV types

Secondary: Number of female subjects with total vaccine effectiveness against oropharyngeal infection with HPV-16/18 types

Secondary: Number of female subjects with total vaccine effectiveness against oropharyngeal infection with HPV-16/18 types

Secondary: Number of female subjects with total vaccine effectiveness against oropharyngeal oncogenic infection with specific HPV types

Secondary: Number of female subjects with total vaccine effectiveness against oropharyngeal oncogenic infection with specific HPV types

Secondary: Number of male subjects reporting any and Grade 3 solicited local symptoms, in a subset of subjects

Secondary: Number of male subjects reporting any and Grade 3 solicited local symptoms, in a subset of subjects

Secondary: Number of male subjects reporting any, Grade 3 and related to vaccination solicited general symptoms, in a subset of subjects

Secondary: Number of male subjects reporting any, Grade 3 and related to vaccination solicited general symptoms, in a subset of subjects

Secondary: Number of male subjects reporting any, Grade 3 and related to vaccination unsolicited adverse events (AEs), in a subset of subjects

Secondary: Number of male subjects reporting any, Grade 3 and related to vaccination unsolicited adverse events (AEs), in a subset of subjects

Secondary: Number of male subjects with urticaria/rash within 30 minutes after each vaccination dose, in a subset of subjects

Secondary: Number of male subjects with urticaria/rash within 30 minutes after each vaccination dose, in a subset of subjects

Secondary: Number of male subjects reporting medically significant conditions (MSCs), in a subset of subjects

Secondary: Number of male subjects reporting medically significant conditions (MSCs), in a subset of subjects

Secondary: Number of male subjects reporting any serious adverse events (SAEs) and SAEs causally related to vaccination, in a subset of subjects

Secondary: Number of male subjects reporting any serious adverse events (SAEs) and SAEs causally related to vaccination, in a subset of subjects

Secondary: Number of subjects reporting SAEs assessed by the investigator as possibly related to vaccination

Secondary: Number of subjects reporting SAEs assessed by the investigator as possibly related to vaccination

Secondary: Number of subjects with new onset of autoimmune diseases (NOADs), retrieved from Care Register for Social Welfare and Health Care (HILMO)

Secondary: Number of subjects with new onset of autoimmune diseases (NOADs), retrieved from Care Register for Social Welfare and Health Care (HILMO)

Secondary: Number of subjects reporting pregnancies and outcomes of reported pregnancies with onset during the study period, retrieved from Medical Birth Registry and HILMO

Secondary: Number of subjects reporting pregnancies and outcomes of reported pregnancies with onset during the study period, retrieved from Medical Birth Registry and HILMO

Secondary: Number of subjects with HPV-16 and HPV-18 antibody concentrations equal to or above the cut-off values, by gender, in a subset of subjects

Secondary: Number of subjects with HPV-16 and HPV-18 antibody concentrations equal to or above the cut-off values, by gender, in a subset of subjects

Secondary: Anti-HPV-16 and anti-HPV-18 antibody concentrations, by gender, in a subset of subjects

Secondary: Anti-HPV-16 and anti-HPV-18 antibody concentrations, by gender, in a subset of subjects

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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