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Clinical Trial Results:
A Phase IIIb observer-blind, randomized, multicentre primary immunization study to evaluate the immunogenicity and safety of GSK Biologicals’ HPV-16/18 L1 VLP AS04 vaccine and Merck's Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine, when administered intramuscularly according to alternative 2-dose schedules in 9-14 year-old healthy females.

Summary
EudraCT number	2011-002035-26
Trial protocol	FR SE
Global end of trial date	27 Oct 2015

Results information
Results version number	v2
This version publication date	11 Nov 2016
First version publication date	21 Apr 2016
Other versions	v1 , v3
Version creation reason	New data added to full data set Data for M24 and M36 have been added.

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

115411

ISRCTN number

US NCT number

NCT01462357

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, 44 2089904466, GSKClinicalSupportHD@gsk.com

Scientific contact

Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, 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

Interim

Date of interim/final analysis

01 Apr 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Oct 2015

Global end of trial reached?

Yes

Global end of trial date

27 Oct 2015

Was the trial ended prematurely?

Main objective of the trial

To evaluate sequentially if the immunogenicity (as determined by enzyme-linked immunosorbent assay - ELISA) of GSK Biologicals’ HPV-16/18 L1 Virus-like-particle (VLP) AS04 vaccine administered according to a 2-dose schedule at 0, 6 months is non-inferior/superior to that of Merck's HPV-6/11/16/18 L1 VLP recombinant vaccine administered according to a 2-dose schedule at 0, 6 months in 9-14 year-old females, 1 month after the last dose (Month 7).

Protection of trial subjects

All subjects were supervised for 30 min after vaccination/product administration with appropriate medical treatment readily available. Vaccines/products 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/products. Subjects were followed-up for 30 days after the last vaccination/product administration.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Nov 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Sweden: 72

Country: Number of subjects enrolled

France: 231

Country: Number of subjects enrolled

Hong Kong: 534

Country: Number of subjects enrolled

Singapore: 242

Worldwide total number of subjects

1079

EEA total number of subjects

303

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)

539

Adolescents (12-17 years)

540

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

1079 subjects entered this study, of which 4 subjects signed an informed consent but did not receive a single dose of the vaccine and were hence not counted as starting the study.

Number of subjects started

1079

Number of subjects completed

1075

Reason: Number of subjects

No vaccine administered: 4

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Blinding implementation details

Data was collected in an observer-blind manner. By observer-blind, it is meant that during the course of the study, the vaccine recipient and those responsible for the evaluation of any study endpoint (e.g. immunogenicity, reactogenicity, and safety) were all unaware of which vaccine was administered. To do so, vaccine preparation and administration were be done by authorised medical personnel who did not participate in any of the study clinical evaluation assays.

Are arms mutually exclusive

Yes

Cervarix 2 dose Group

Arm description

Subjects who received 2 doses of Cervarix™ vaccine at Day 0 and Month 6 and 1 dose of placebo at Month 2. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.

Arm type

Experimental

Investigational medicinal product name

Cervarix™

Investigational medicinal product code

Other name

HPV 1

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 2 doses of Cervarix™ Day 0 and Month 6 and 1 dose of placebo at Month 2. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 1 dose of 0.5 mL supplied as a liquid in individual pre-filled syringes, administered intramuscularly in the deltoid muscle of the non-dominant arm at Month 2 to maintain blinding.

Gardasil 2 dose Group

Arm description

Subjects who received 2 doses of Gardasil® vaccine at Day 0 and Month 6 and 1 dose of placebo at Month 2. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.

Arm type

Experimental

Investigational medicinal product name

Gardasil®

Investigational medicinal product code

Other name

HPV 2

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 2 doses of Gardasil® vaccine at Day 0 and Month 6 and 1 dose of placebo at Month 2. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 1 dose of 0.5 mL supplied as a liquid in individual pre-filled syringes, administered intramuscularly in the deltoid muscle of the non-dominant arm at Month 2 to maintain blinding.

Gardasil 3 dose Group

Arm description

Subjects who received 3 doses of Gardasil® vaccine at Day 0 and at Months 2 and 6. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.

Arm type

Experimental

Investigational medicinal product name

Gardasil®

Investigational medicinal product code

Other name

HPV 2

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

Subjects received 3 doses of Gardasil® vaccine at Day 0, Month 2 and Month 6. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.

Number of subjects in period 1 ^[1]	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Started	359	358	358
Completed at Month 7	358	353	352
Completed at Month 12	356	348	350
Completed at Month 18	356	347	349
Completed at Month 24	355	344	349
Completed at Month 36	351	339	346
Completed	351	339	346
Not completed	8	19	12
Consent withdrawn by subject	3	11	3
Lost to follow-up (incomplete vaccination course)	-	-	2
Death	-	-	1
Lost to follow-up (complete vaccination course)	3	5	5
Migrated/moved from study area	2	3	1

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: 1079 subjects entered this study, of which 4 subjects signed an informed consent but did not receive a single dose of the vaccine and were hence not counted as starting the study.

Baseline characteristics

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Reporting group title

Cervarix 2 dose Group

Reporting group description

Reporting group title

Gardasil 2 dose Group

Reporting group description

Reporting group title

Gardasil 3 dose Group

Reporting group description

Subjects who received 3 doses of Gardasil® vaccine at Day 0 and at Months 2 and 6. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.

Reporting group values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group	Total
Number of subjects	359	358	358	1075
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age continuous
Units: years
arithmetic mean (standard deviation)	11.5 ± 1.64	11.5 ± 1.56	11.6 ± 1.64	-
Gender categorical
Units: Subjects
Female	359	358	358	1075
Male	0	0	0	0

End points

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Reporting group title

Cervarix 2 dose Group

Reporting group description

Reporting group title

Gardasil 2 dose Group

Reporting group description

Reporting group title

Gardasil 3 dose Group

Reporting group description

Subjects who received 3 doses of Gardasil® vaccine at Day 0 and at Months 2 and 6. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.

Primary: Number of seroconverted subjects for Anti-HPV-16/18, as assessed by the enzyme-immunosorbent assay (ELISA)

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End point title

Number of seroconverted subjects for Anti-HPV-16/18, as assessed by the enzyme-immunosorbent assay (ELISA)

End point description

Seroconversion was defined as the appearance of antibodies (i.e. anti-HPV-16 and anti-HPV-18 antibody titers respectively greater than or equal to 19 and 18 EL.U/mL) in the serum of subjects seronegative before vaccination in the primary study.

End point type

Primary

End point timeframe

One month after the last dose of study vaccine (Month 7)

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	337	334	334
Units: Subjects
Anti-HPV-16 (N=337,334,334)	337	334	334
Anti-HPV-18 (N=337,334,334)	337	334	334

Immune response to anti-HPV-16 in terms of SCR

Statistical analysis description

To evaluate sequentially if the immunogenicity (as determined by ELISA) of Cervarix™ vaccine administered according to a 2-dose schedule at 0, 6 months is non-inferior to that of Gardasil® vaccine administered according to a 2-dose schedule at 0, 6 months, in 9-14 year-old females, 1 month after the last dose (Month 7).

Comparison groups

Cervarix 2 dose Group v Gardasil 2 dose Group

Number of subjects included in analysis

671

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

Parameter type

Difference in SCR

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.16

upper limit

1.15

Notes
[1] - Non-inferiority with respect to seroconversion will be shown if, at Months 12, 18, 24 and 36, for both anti-HPV-16 and anti-HPV-18 antibodies, the upper limit of the 95% confidence interval (CI) for the difference (Gardasil 2 dose Group - Cervarix 2 dose Group ) is below 5%.

Immune response to anti-HPV-18 in terms of SCR

Statistical analysis description

To evaluate sequentially if the immunogenicity (as determined by ELISA) of Cervarix™ vaccine administered according to a 2-dose schedule at 0, 6 months is non-inferior to that of Gardasil® vaccine administered according to a 2- dose schedule at 0, 6 months, in 9-14 year-old females, 1 month after the last dose (Month 7).

Comparison groups

Cervarix 2 dose Group v Gardasil 2 dose Group

Number of subjects included in analysis

671

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

Parameter type

Difference in SCR

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.15

upper limit

1.14

Notes
[2] - Non-inferiority with respect to seroconversion will be shown if, at Months 12, 18, 24 and 36, for both anti-HPV-16 and anti-HPV-18 antibodies, the upper limit of the 95% confidence interval (CI) for the difference (Gardasil 2 dose Group - Cervarix 2 dose Group ) is below 5%.

Primary: Anti-HPV-16/18 antibody concentrations assessed by ELISA

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End point title

Anti-HPV-16/18 antibody concentrations assessed by ELISA

End point description

Anti-HPV 16/18 antibody concentrations were presented as geometric mean concentrations (GMC) and expressed in ELISA units per milliliter (EL.U/mL) based on ELISA.

End point type

Primary

End point timeframe

One month after the last dose of study vaccine (Month 7)

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	337	334	334
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-HPV-16 (N=337,334,334)	8311.4 (7745.8 to 8918.3)	5061 (4604.1 to 5563.3)	4864 (4481.9 to 5278.7)
Anti-HPV-18 (N=337,334,334)	5249.7 (4835.4 to 5699.5)	1213 (1098.7 to 1339.1)	1654.5 (1485.8 to 1842.4)

Immune response to anti-HPV-16 in terms of GMT

Statistical analysis description

Comparison groups

Cervarix 2 dose Group v Gardasil 2 dose Group

Number of subjects included in analysis

671

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

0.69

Notes
[3] - Non-inferiority with respect to GMT will be shown if, at Months 12, 18, 24 and 36, for both anti- HPV-16 and anti-HPV-18 antibodies, the upper limit of the 95% confidence interval (CI) for the GMT ratio (Gardasil 2 dose Group/Cervarix 2 dose Group) is below 2.

Immune response to anti-HPV-18 in terms of GMT

Statistical analysis description

To evaluate sequentially if the immunogenicity (as determined by ELISA) of Cervarix™ vaccine administered according to a 2-dose schedule at 0, 6 months is non-inferior to that of Gardasil® vaccine administered according to a 2- dose schedule at 0, 6 months, in 9-14 year-old females, 1 month after the last dose (Month 7).

Comparison groups

Cervarix 2 dose Group v Gardasil 2 dose Group

Number of subjects included in analysis

671

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

0.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

0.26

Notes
[4] - Non-inferiority with respect to GMT will be shown if, at Months 12, 18, 24 and 36, for both anti- HPV-16 and anti-HPV-18 antibodies, the upper limit of the 95% confidence interval (CI) for the GMT ratio (Gardasil 2 dose Group/Cervarix 2 dose Group) is below 2.

Anti-HPV-18 immune response

Statistical analysis description

To evaluate sequentially if the immunogenicity (as determined by ELISA) of Cervarix™ vaccine administered according to a 2-dose schedule at 0, 6 months is superior to that of Gardasil® vaccine administered according to a 2-dose schedule at 0, 6 months, in 9-14 year-old females, 1 month after the last dose (Month 7).

Comparison groups

Cervarix 2 dose Group v Gardasil 2 dose Group

Number of subjects included in analysis

671

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

4.52

Confidence interval

level

95%

sides

2-sided

lower limit

3.97

upper limit

5.13

Notes
[5] - Superiority will be shown if the lower limit of the 95% confidence interval (CI) for the ratio of geometric mean titers (GMTs) (Cervarix 2 dose Group divided by Gardasil 2 dose Group) is above 1 for anti-HPV-18 antibodies with the associated p-value.

Anti-HPV-16 immune response

Statistical analysis description

Comparison groups

Cervarix 2 dose Group v Gardasil 2 dose Group

Number of subjects included in analysis

671

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

1.69

Confidence interval

level

95%

sides

2-sided

lower limit

1.49

upper limit

1.91

Notes
[6] - Superiority will be shown if the lower limit of the 95% confidence interval (CI) for the ratio of geometric mean titers (GMTs) (Cervarix 2 dose Group divided by Gardasil 2 dose Group) is above 1 for anti-HPV-16 antibodies with the associated p-value.

Primary: Anti-HPV-16/18 seroconversion rates assessed by ELISA

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End point title

Anti-HPV-16/18 seroconversion rates assessed by ELISA ^[7]

End point description

Seroconversion was defined as the appearance of antibodies [i.e. anti-HPV-16 and anti-HPV-18 antibody titers greater than or equal to 3.1 and 3.2 international units per milliliter (IU/mL), respectively], in the serum of subjects who were seronegative before vaccination in the primary study. The assay cut-offs used for analyses at Month 36 were modified to 3.1 and 3.2 IU/mL, after applying the conversion factor from EL.U/mL to IU/mL.

End point type

Primary

End point timeframe

At Month 36

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.

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	324	313	321
Units: Subjects
Anti-HPV-16, Month 36 (N=324,313,321)	324	310	320
Anti-HPV-18, Month 36 (N=324,313,321)	324	270	298

No statistical analyses for this end point

Primary: Anti-HPV-16/18 antibody concentrations assessed by ELISA

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End point title

Anti-HPV-16/18 antibody concentrations assessed by ELISA ^[8]

End point description

Anti-HPV 16/18 antibody concentrations were presented as geometric mean titers (GMT) and expressed in IU/mL. Assay cut-offs used for analyses at Month 36 were modified to 3.1 and 3.2 IU/mL respectively, after applying the conversion factor from EL.U/mL to IU/mL.

End point type

Primary

End point timeframe

At Month 36

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.

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	324	313	321
Units: IU/mL
geometric mean (confidence interval 95%)
Anti-HPV-16, Month 36 (N=324,313,321)	175.2 (160.6 to 191.2)	61.6 (54.1 to 70.1)	77.8 (70.2 to 86.3)
Anti-HPV-18, Month 36 (N=324,313,321)	85.5 (77 to 95)	12.5 (11 to 14.3)	21.1 (18.3 to 24.3)

No statistical analyses for this end point

Secondary: Anti-HPV-16/18 seroconversion rates assessed by ELISA

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End point title

Anti-HPV-16/18 seroconversion rates assessed by ELISA

End point description

Seroconversion was defined as the appearance of antibodies (i.e. anti-HPV-16 and anti-HPV-18 antibody titers greater than or equal to 19 and 18 EL.U/mL, respectively) in the serum of subjects seronegative before vaccination in the primary study.

End point type

Secondary

End point timeframe

At Day 0 and Months 12, 18 and 24

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	337	334	334
Units: Subjects
Anti-HPV-16, Day 0 (N=337,334,334)	7	7	12
Anti-HPV-18, Day 0 (N=337,334,334)	3	3	1
Anti-HPV-16, Month 12 (N=331,325,327)	330	325	327
Anti-HPV-18, Month 12 (N=331,325,327)	330	324	327
Anti-HPV-16, Month 18 (N=329,327,330)	329	326	330
Anti-HPV-18, Month 18 (N=329,327,330)	329	310	322
Anti-HPV-16, Month 24 (N=324,320,324)	324	319	324
Anti-HPV-18, Month 24 (N=324,320,324)	324	298	313

No statistical analyses for this end point

Secondary: Anti-HPV-16/18 antibody concentrations assessed by ELISA

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End point title

Anti-HPV-16/18 antibody concentrations assessed by ELISA

End point description

Anti-HPV 16/18 antibody concentrations were presented as geometric mean concentrations (GMC) and expressed in ELISA units per milliliter (EL.U/mL) based on ELISA.

End point type

Secondary

End point timeframe

At Day 0 and Months 12, 18 and 24

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	337	334	334
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-HPV-16, Day 0 (N=337,334,334)	9.8 (9.5 to 10.2)	9.8 (9.5 to 10.1)	10 (9.7 to 10.3)
Anti-HPV-18, Day 0 (N=337,334,334)	9.1 (9 to 9.2)	9.1 (9 to 9.2)	9 (9 to 9.1)
Anti-HPV-16, Month 12 (N=331,325,327)	2247.9 (2052.2 to 2462.2)	1283.9 (1152.1 to 1430.8)	1610.5 (1468.9 to 1765.8)
Anti-HPV-18, Month 12 (N=331,325,327)	1311.4 (1187.3 to 1448.4)	266 (236.2 to 299.4)	477.8 (422.7 to 540.1)
Anti-HPV-16, Month 18 (N=329,327,330)	1516.2 (1393.4 to 1649.8)	675.8 (600 to 761.1)	828 (749.8 to 914.4)
Anti-HPV-18, Month 18 (N=329,327,330)	763.1 (691.3 to 842.5)	133.8 (117.6 to 152.1)	230.8 (202.1 to 263.6)
Anti-HPV-16, Month 24 (N=324,320,324)	1317.5 (1213.9 to 1430)	514.4 (456.9 to 579.2)	639.9 (579.6 to 706.6)
Anti-HPV-18, Month 24 (N=324,317,324)	628.6 (569.4 to 694)	107.8 (94.8 to 122.6)	182.2 (159.6 to 208)

No statistical analyses for this end point

Secondary: Anti-HPV-16/18 seroconversion rates assessed by pseudovirion-based neutralization assay (PBNA) in a subset of subjects

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End point title

Anti-HPV-16/18 seroconversion rates assessed by pseudovirion-based neutralization assay (PBNA) in a subset of subjects

End point description

Seroconversion was defined as the appearance of antibodies (i.e. anti-HPV-16 and anti-HPV-18 antibody titers greater than or equal to ≥ 40 ED50) in the serum of subjects seronegative before vaccination in the primary study. The analysis was based on the According-to-Protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available at the time of the analysis.

End point type

Secondary

End point timeframe

At Day 0 and Months 7, 12 and 18

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	92	95	93
Units: Subjects
Anti-HPV-16, Day 0 (N=92,95,93)	0	1	0
Anti-HPV-18, Day 0 (N=92,95,93)	0	0	0
Anti-HPV-16, Month 7 (N=92,95,93)	92	95	93
Anti-HPV-18, Month 7 (N=92,95,93)	92	95	93
Anti-HPV-16, Month 12 (N=90,93,91)	90	93	91
Anti-HPV-18, Month 12 (N=90,93,91)	90	91	91
Anti-HPV-16, Month 18 (N=90,92,91)	90	89	90
Anti-HPV-18, Month 18 (N=89,92,92)	89	81	90

No statistical analyses for this end point

Secondary: Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

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End point title

Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

End point description

Anti-HPV 16/18 antibody titers were presented as geometric mean titers (GMTs) and expressed in titers using the PBNA. The analysis was based on the ATP cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available at the time of the analysis.

End point type

Secondary

End point timeframe

At Day 0 and Months 7, 12 and 18

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	92	95	93
Units: Titer
geometric mean (confidence interval 95%)
Anti-HPV-16, Day 0 (N=92,95,93	20 (20 to 20)	20.2 (19.8 to 20.5)	20 (20 to 20)
Anti-HPV-18, Day 0 (N=92,95,93)	20 (20 to 20)	20 (20 to 20)	20 (20 to 20)
Anti-HPV-16, Month 7 (N=92,95,93)	51043.8 (42657.9 to 61078.3)	19119.4 (15249 to 23972.1)	21377.9 (16900.1 to 27042.2)
Anti-HPV-18, Month 7 (N=92,95,93)	23228 (18677 to 28887.8)	4709.9 (3604.2 to 6154.9)	8009.4 (6111.1 to 10497.4)
Anti-HPV-16, Month 12 (N=90,93,91)	10635.3 (8555.9 to 13220)	3959.4 (3039.1 to 5158.4)	5858.1 (4610.9 to 7442.8)
Anti-HPV-18, Month 12 (N=90,93,91)	3651.5 (2903.6 to 4592.1)	656.3 (493.6 to 872.6)	1734.2 (1268.4 to 2371)
Anti-HPV-16, Month 18 (N=90,92,91)	8388.4 (6647.7 to 10584.9)	1953.5 (1386.6 to 2752.3)	2988.9 (2227.2 to 4011.2)
Anti-HPV-18, Month 18 (N=89,92,92)	2381.1 (1858.7 to 3050.2)	283.1 (209.4 to 382.7)	805.7 (574.4 to 1130.2)

No statistical analyses for this end point

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

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End point title

T-cell-mediated immune responses in the sub-cohort for CMI

End point description

Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumour necrosis factor-alpha (TNF-α) and CD40-ligand (CD40-L).

End point type

Secondary

End point timeframe

At Day 0 and Months 7, 12

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	71	68	70
Units: T-cells/million cells
median (inter-quartile range (Q1-Q3))
CD4+ All doubles, Anti-HPV-16, Day 0 (N=57,47,55)	14 (1 to 97)	22 (1 to 73)	33 (1 to 80)
CD4+ All doubles, Anti-HPV-18, Day 0 (N=57,46,56)	20 (1 to 83)	19 (1 to 101)	24 (1 to 91.5)
CD4+ All doubles, Anti-HPV-16, Month 7(N=68,63,65)	1604.5 (634.5 to 3253.5)	853 (429 to 1324)	1131 (694 to 1969)
CD4+ All doubles, Anti-HPV-18, Month 7(N=67,63,66)	897 (522 to 2497)	459 (240 to 761)	654.5 (384 to 1284)
CD4+ All doubles, Anti-HPV-16, Month12(N=71,66,70)	1121 (659 to 2340)	622.5 (316 to 1261)	844.5 (546 to 1652)
CD4+ All doubles, Anti-HPV-18, Month12(N=71,68,70)	789 (400 to 1492)	355 (209 to 673.5)	465.5 (205 to 901)
CD4-d-CD40L, Anti-HPV-16,Day 0 (N=57,47,55)	10 (1 to 78)	14 (1 to 73)	30 (1 to 80)
CD4-d-CD40L, Anti-HPV-18,Day 0 (N=57,46,56)	14 (1 to 83)	27 (1 to 101)	25.5 (1 to 68.5)
CD4-d-CD40L, Anti-HPV-16,Month 7(N=68,63.65)	1507.5 (631.5 to 3043)	779 (426 to 1219)	1054 (670 to 1938)
CD4-d-CD40L, Anti-HPV-18,Month7 (N=67,63,66)	866 (509 to 2379)	418 (227 to 775)	616.5 (344 to 1193)
CD4-d-CD40L, Anti-HPV-16,Month 12(N=71,66,70)	990 (594 to 2236)	592.5 (280 to 1135)	805 (469 to 1545)
CD4-d-CD40L, Anti-HPV-18,Month 12(N=71,68,70)	688 (346 to 1435)	340.5 (168 to 604.5)	404 (219 to 737)

No statistical analyses for this end point

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

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End point title

T-cell-mediated immune responses in the sub-cohort for CMI

End point description

Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumour necrosis factor-alpha (TNF-α) and CD40-ligand (CD40-L).

End point type

Secondary

End point timeframe

At Day 0 and Months 7, 12

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	71	68	70
Units: T cells/million cells
median (inter-quartile range (Q1-Q3))
CD4-d- IFNγ, Anti-HPV-16,Day 0 (N=57,47,55)	1 (1 to 30)	14 (1 to 42)	1 (1 to 28)
CD4-d- IFNγ, Anti-HPV-18,Day 0(N=57,46,56)	14 (1 to 32)	7 (1 to 35)	1.5 (1 to 31.5)
CD4-d- IFNγ, Anti-HPV-16,Month 7(N=68,63,65)	351 (164.5 to 829)	314 (141 to 602)	398 (193 to 708)
CD4-d- IFNγ, Anti-HPV-18,Month 7(N=67,63,66)	218 (108 to 631)	127 (70 to 247)	181.5 (70 to 371)
CD4-d- IFNγ, Anti-HPV-16,Month 12(N=71,66,70)	326 (110 to 688)	241.5 (86 to 606)	337 (135 to 734)
CD4-d- IFNγ, Anti-HPV-18,Month 12(N=71,68,70)	174 (87 to 444)	114 (56.5 to 259.5)	155.5 (56 to 315)
CD4-d-IL-2, Anti-HPV-16,Day 0 (N=57,47,55)	16 (1 to 71)	24 (1 to 68)	33 (1 to 58)
CD4-d-IL-2, Anti-HPV-18, Day 0 (N=57,46,56)	1 (1 to 42)	30 (1 to 66)	20 (1 to 58)
CD4-d-IL-2, Anti-HPV-16,Month 7(N=68,63,65)	1323 (537 to 2702.5)	710 (368 to 1058)	875 (580 to 1431)
CD4-d-IL-2, Anti-HPV-18,Month 7(N=67,63,66)	737 (420 to 2185)	321 (206 to 573)	503 (295 to 869)
CD4-d-IL-2, Anti-HPV-16,Month 12(N=71,66,70)	922 (528 to 2050)	487.5 (285 to 991)	702.5 (450 to 1379)
CD4-d-IL-2, Anti-HPV-18,Month 12(N=71,68,70)	620 (311 to 1157)	274 (164.5 to 550.5)	380 (160 to 705)

No statistical analyses for this end point

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

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End point title

T-cell-mediated immune responses in the sub-cohort for CMI

End point description

Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumour necrosis factor-alpha (TNF-α) and CD40-ligand (CD40-L).

End point type

Secondary

End point timeframe

At Day 0 and Months 7, 12

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	71	68	70
Units: T cells/million cells
median (inter-quartile range (Q1-Q3))
CD4-d-TNFα, Anti-HPV-16,Day 0 (N=57,47,55)	6 (1 to 52)	32 (1 to 73)	16 (1 to 71)
CD4-d-TNFα, Anti-HPV-18,Day 0 (N=57,46,56)	24 (1 to 73)	19 (1 to 82)	21 (1 to 57)
CD4-d-TNFα, Anti-HPV-16,Month 7(N=68,63,65)	1103 (432 to 2399)	605 (276 to 919)	804 (458 to 1512)
CD4-d-TNFα, Anti-HPV-18,Month 7(N=67,63,66)	647 (371 to 1765)	319 (153 to 594)	517 (272 to 978)
CD4-d-TNFα, Anti-HPV-16,Month 12(N=71,66,70)	884 (488 to 1924)	527 (210 to 1033)	725 (383 to 1445)
CD4-d-TNFα, Anti-HPV-18,Month 12(N=71,68,70)	674 (290 to 1272)	299 (144.5 to 600)	403 (175 to 771)

No statistical analyses for this end point

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

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End point title

T-cell-mediated immune responses in the sub-cohort for CMI

End point description

Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumour necrosis factor-alpha (TNF-α) and CD40-ligand (CD40-L).

End point type

Secondary

End point timeframe

At Day 0 and Months 7, 12

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	71	68	70
Units: T cells/million cells
median (inter-quartile range (Q1-Q3))
CD8-ALL DOUBLES, Anti-HPV-16, Day 0 (N=57,47,55)	1 (1 to 14)	2 (1 to 43)	1 (1 to 32)
CD8-ALL DOUBLES, Anti-HPV-18, Day 0 (N=57,46,56)	1 (1 to 10)	1 (1 to 29)	1 (1 to 23.5)
CD8-ALL DOUBLES, Anti-HPV-16,Month 7(N=68,63,65)	1 (1 to 33)	1 (1 to 40)	1 (1 to 33)
CD8-ALL DOUBLES, Anti-HPV-18,Month 7(N=67,63,66)	1 (1 to 19)	1 (1 to 37)	1 (1 to 40)
CD8-ALL DOUBLES, Anti-HPV-16,Month 12(N=71,66,70)	1 (1 to 31)	1 (1 to 44)	1 (1 to 32)
CD8-ALL DOUBLES, Anti-HPV-18,Month 12(N=71,68,70)	1 (1 to 27)	1 (1 to 32.5)	1 (1 to 20)
CD8-d-CD40L, Anti-HPV-16, Day 0 (N=57,47,55)	1 (1 to 1)	1 (1 to 3)	1 (1 to 1)
CD8-d-CD40L, Anti-HPV-18, Day 0 (N=57,46,56)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
CD8-d-CD40L, Anti-HPV-16,Month 7(N=68,63,65)	1 (1 to 1)	1 (1 to 28)	1 (1 to 24)
CD8-d-CD40L, Anti-HPV-18,Month 7(N=67,63,66)	1 (1 to 1)	1 (1 to 24)	1 (1 to 20)
CD8-d-CD40L, Anti-HPV-16,Month 12(N=71,66,70)	1 (1 to 1)	1 (1 to 1)	1 (1 to 3)
CD8-d-CD40L, Anti-HPV-18,Month 12(N=71,68,70)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)

No statistical analyses for this end point

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

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End point title

T-cell-mediated immune responses in the sub-cohort for CMI

End point description

Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumour necrosis factor-alpha (TNF-α) and CD40-ligand (CD40-L).

End point type

Secondary

End point timeframe

At Day 0 and Months 7, 12

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	71	68	70
Units: T cells/ million cells
median (inter-quartile range (Q1-Q3))
CD8-d-IFNγ, Anti-HPV-16, Day 0 (N=57,47,55)	1 (1 to 1)	1 (1 to 36)	1 (1 to 30)
CD8-d-IFNγ, Anti-HPV-18, Day 0 (N=57,46,56)	1 (1 to 2)	1 (1 to 24)	1 (1 to 14)
CD8-d-IFNγ, Anti-HPV-16,Month 7(N=68,63,65)	1 (1 to 31)	1 (1 to 36)	1 (1 to 30)
CD8-d-IFNγ, Anti-HPV-18,Month 7(N=67,63,66)	1 (1 to 1)	1 (1 to 27)	1 (1 to 28)
CD8-d-IFNγ, Anti-HPV-16,Month 12(N=71,66,70)	1 (1 to 28)	1 (1 to 29)	1 (1 to 28)
CD8-d-IFNγ, Anti-HPV-18, Month 12 (N=71,68,70)	1 (1 to 26)	1 (1 to 32.5)	1 (1 to 10)
CD8-d-IL-2, Anti-HPV-16, Day 0 (N=57,47,55)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
CD8-d-IL-2, Anti-HPV-18,Day 0 (N=57,46,56)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
CD8-d-IL-2, Anti-HPV-16,Month 7(N=68,63,65)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
CD8-d-IL-2, Anti-HPV-18,Month 7(N=67,63,66)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
CD8-d-IL-2, Anti-HPV-16,Month 12(N=71,66,70)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
CD8-d-IL-2, Anti-HPV-18,Month 12(N=71,68,70)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)

No statistical analyses for this end point

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

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End point title

T-cell-mediated immune responses in the sub-cohort for CMI

End point description

Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumour necrosis factor-alpha (TNF-α) and CD40-ligand (CD40-L).

End point type

Secondary

End point timeframe

At Day 0 and Months 7, 12

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	71	68	70
Units: T cells/million cells
median (inter-quartile range (Q1-Q3))
CD8-d-TNFα, Anti-HPV-16, Day 0 (N=57,47,55)	1 (1 to 1)	1 (1 to 36)	1 (1 to 22)
CD8-d-TNFα, Anti-HPV-18, Day 0 (N=57,46,56)	1 (1 to 25)	1 (1 to 30)	1 (1 to 13.5)
CD8-d-TNFα, Anti-HPV-16,Month 7(N=68,63,65)	1 (1 to 26)	1 (1 to 25)	1 (1 to 22)
CD8-d-TNFα, Anti-HPV-18,Month 7(N67,63,66)	1 (1 to 1)	1 (1 to 1)	1 (1 to 23)
CD8-d-TNFα, Anti-HPV-16,Month 12(N=71,66,70)	1 (1 to 1)	1 (1 to 25)	1 (1 to 29)
CD8-d-TNFα, Anti-HPV-18,Month 12(N=71,68,70)	1 (1 to 8)	1 (1 to 21.5)	1 (1 to 24)

No statistical analyses for this end point

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

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End point title

T-cell-mediated immune responses in the sub-cohort for CMI

End point description

Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumour necrosis factor-alpha (TNF-α) and CD40-ligand (CD40-L).

End point type

Secondary

End point timeframe

At Month 24

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	71	68	70
Units: T cells/million cells
median (inter-quartile range (Q1-Q3))
CD4+ All doubles, Anti-HPV-16,Month 24(N=66,65,71)	1097 (489 to 2410)	738 (360 to 1109)	974 (573 to 1838)
CD4+ All doubles, Anti-HPV-18,Month 24(N=65,65,70)	630 (301 to 1383)	348 (202 to 549)	561.5 (258 to 972)
CD4-d-CD40L, Anti-HPV-16,Month 24(N=66,65,71)	1083 (510 to 2269)	734 (346 to 1084)	964 (582 to 1802)
CD4-d-CD40L, Anti-HPV-18,Month 24(N=65,65,70)	587 (282 to 1344)	333 (206 to 534)	563.5 (289 to 940)
CD4-d- IFNγ, Anti-HPV-16,Month 24(N=66,65,71)	276 (111 to 781)	315 (128 to 519)	431 (157 to 777)
CD4-d- IFNγ, Anti-HPV-18,Month 24(N=65,65,70)	169 (59 to 440)	106 (51 to 227)	218 (63 to 362)
CD4-d-IL-2, Anti-HPV-16,Month 24(N=66,65,71)	879.5 (429 to 1711)	574 (280 to 898)	687 (479 to 1480)
CD4-d-IL-2, Anti-HPV-18,Month 24(N=65,65,70)	494 (238 to 926)	248 (138 to 415)	400.5 (206 to 713)
CD4-d-TNFα, Anti-HPV-16,Month 24(N=66,65,71)	755 (375 to 1668)	524 (235 to 876)	791 (416 to 1516)
CD4-d-TNFα, Anti-HPV-18,Month 24(N=65,65,70)	479 (183 to 1036)	238 (130 to 478)	519 (228 to 793)

No statistical analyses for this end point

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

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End point title

T-cell-mediated immune responses in the sub-cohort for CMI

End point description

Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumour necrosis factor-alpha (TNF-α) and CD40-ligand (CD40-L).

End point type

Secondary

End point timeframe

At Month 24

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	71	68	70
Units: T cells/million cells
median (inter-quartile range (Q1-Q3))
CD8-ALL DOUBLES, Anti-HPV-16,Month 24(N=66,65,71)	1 (1 to 29)	1 (1 to 1)	1 (1 to 2)
CD8-ALL DOUBLES, Anti-HPV-18,Month 24(N=65,65,70)	1 (1 to 30)	1 (1 to 30)	1 (1 to 31)
CD8-d-CD40L, Anti-HPV-16,Month 24(N=66,65,71)	1 (1 to 23)	1 (1 to 1)	1 (1 to 1)
CD8-d-CD40L, Anti-HPV-18,Month 24(N=65,65,70)	1 (1 to 1)	1 (1 to 1)	1 (1 to 23)
CD8-d-IFNγ, Anti-HPV-16,Month 24(N=66,65,71)	1 (1 to 19)	1 (1 to 1)	1 (1 to 3)
CD8-d-IFNγ, Anti-HPV-18,Month 24(N=65,65,70)	1 (1 to 1)	1 (1 to 23)	1 (1 to 23)
CD8-d-IL-2, Anti-HPV-16,Month 24(N=66,65,71)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
CD8-d-IL-2, Anti-HPV-18,Month 24(N=65,65,70)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
CD8-d-TNFα, Anti-HPV-16,Month 24(N=66,65,71)	1 (1 to 27)	1 (1 to 1)	1 (1 to 1)
CD8-d-TNFα, Anti-HPV-18,Month 24(N=65,65,70)	1 (1 to 18)	1 (1 to 23)	1 (1 to 21)

No statistical analyses for this end point

Secondary: B-cell-mediated immune responses in the sub-cohort for CMI

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End point title

B-cell-mediated immune responses in the sub-cohort for CMI

End point description

The frequency of B-cell Elispot response to HPV-16/18 by overall status was presented.

End point type

Secondary

End point timeframe

At Day 0 and Months 7, 12 and 24

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	76	72	80
Units: B cells/million cells
median (inter-quartile range (Q1-Q3))
HPV-16, PRE (N=74,59,73)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)
HPV-18, PRE (N=74,59,73)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)
HPV-16, M7 (N=76,72,80)	1605.5 (593.5 to 3483.5)	1097.5 (449 to 2068)	687 (115.5 to 1966.5)
HPV-18, M7 (N=76,72,80)	593.5 (103.5 to 1771)	80 (0 to 376)	111 (0 to 391)
HPV-16, M12 (N=56,56,57)	396.5 (89 to 1044)	248 (61.5 to 756)	281 (47 to 974)
HPV-18, M12 (N=56,56,57)	252 (77 to 635)	67 (0 to 182.5)	65 (0 to 220)
HPV-16, M24 (N=52,50,61)	254.5 (13 to 706)	204 (16 to 578)	256 (68 to 600)
HPV-18, M24 (N=52,50,61)	125.5 (31 to 370.5)	45 (0 to 143)	110 (0 to 287)

No statistical analyses for this end point

Secondary: Number of subjects with any, grade 3 and related solicited local symptoms

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End point title

Number of subjects with any, grade 3 and related solicited local symptoms

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 millimetres (mm) of injection site. Relationship analysis was not performed.

End point type

Secondary

End point timeframe

During the 7-day period (Days 0-6) following vaccination (across doses)

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	357	356
Units: Subjects
Any Pain	329	276	295
Grade 3 Pain	42	17	18
Any Redness	191	134	157
Grade 3 Redness	0	0	2
Any Swelling	163	98	118
Grade 3 Swelling	5	0	2

No statistical analyses for this end point

Secondary: Number of subjects with any, grade 3 and related solicited general symptoms

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End point title

Number of subjects with any, grade 3 and related solicited general symptoms

End point description

Assessed solicited general symptoms were arthralgia, fatigue, gastrointestinal symptoms, headache, myalgia, rash, temperature [defined as oral temperature equal to or above 37.5 degrees Celsius (°C)] 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.

End point type

Secondary

End point timeframe

During the 7-day period (Days 0-6) following vaccination (across doses)

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	357	356
Units: Subjects
Any Arthralgia	68	81	67
Grade 3 Arthralgia	6	4	1
Related Arthralgia	51	55	51
Any Fatigue	192	199	193
Grade 3 Fatigue	18	15	7
Related Fatigue	151	151	143
Any Gastrointestinal	55	74	69
Grade 3 Gastrointestinal	5	6	3
Related Gastrointestinal	31	49	40
Any Headache	147	133	151
Grade 3 Headache	17	7	4
Related Headache	106	88	100
Any Myalgia	166	143	136
Grade 3 Mylagia	8	8	6
Related Myalgia	128	111	100
Any Rash	26	16	18
Grade 3 Rash	0	0	0
Related Rash	16	10	12
Any Temperature	53	59	47
Grade 3 Temperature	7	2	4
Related Temperature	35	31	30
Any Urticaria	27	13	25
Grade 3 Urticaria	4	1	0
Related Urticaria	15	11	9

No statistical analyses for this end point

Secondary: Number of subjects with any, grade 3 and related unsolicited adverse events (AEs)

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End point title

Number of subjects with any, grade 3 and related unsolicited adverse events (AEs)

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.

End point type

Secondary

End point timeframe

During the 30-day period (Days 0-29) post-vaccination

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	358	358
Units: Subjects
Subjects with any AE(s)	91	96	101
Subjects with any Grade 3 AE(s)	18	8	20
Subjects with any Related AE(s)	8	14	15

No statistical analyses for this end point

Secondary: Number of subjects with potentially immune mediated diseases (pIMDs)

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End point title

Number of subjects with potentially immune mediated diseases (pIMDs)

End point description

Note: Results beyond Month 24 will be updated when validated results become available.

End point type

Secondary

End point timeframe

From Day 0 to Month 36 (throughout the study period)

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	358	358
Units: Subjects
Subjects with any pIMD(s), Month 7	2	1	0
Subjects with any pIMD(s), Month 12	3	3	0
Subjects with any pIMD(s), Month 18	3	3	0
Subjects with any pIMD(s), Month 24	3	3	0

No statistical analyses for this end point

Secondary: Number of subjects with medically significant conditions (MSCs)

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End point title

Number of subjects with medically significant conditions (MSCs)

End point description

MSCs were defined as AEs prompting emergency room (ER) or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs not related to common diseases. Common diseases include: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities and injury.

End point type

Secondary

End point timeframe

From Day 0 to Month 36 (throughout the study period)

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	358	358
Units: Subjects
Subjects with any MSC(s), Month 7	43	49	39
Subjects with any MSC(s), Month 12	52	57	47
Subjects with any MSC(s), Month 18	65	64	54
Subjects with any MSC(s), Month 24	71	75	56

No statistical analyses for this end point

Secondary: Number of subjects with Serious Adverse Events (SAEs)

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End point title

Number of subjects with Serious Adverse Events (SAEs)

End point description

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 to Month 36 (throughout the study period)

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	358	358
Units: Subjects
Any SAE(s)	21	11	14

No statistical analyses for this end point

Secondary: Number of subjects starting a concomitant medication

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End point title

Number of subjects starting a concomitant medication

End point description

The outcome presents the number of subjects starting any concomitant medication, as well as any antipyretic, any prophylactic antipyretic and any antibiotic.

End point type

Secondary

End point timeframe

During the 30-day (Days 0-29) post-vaccination period

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	358	358
Units: Subjects
Any concomitant medication	127	126	129
Any antipyretic	76	86	81
Any antibiotic	23	27	33
Prophylactic antipyretic	5	2	2
Prophylactic antibiotic	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects starting a concomitant medication

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End point title

Number of subjects starting a concomitant medication

End point description

The outcome presents the number of subjects starting any concomitant medication, as well as any antipyretic, any prophylactic antipyretic and any antibiotic.

End point type

Secondary

End point timeframe

From Day 0 to Month 36 (throughout the study period)

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	358	354
Units: Subjects
Any antipyretic, M7 [N=359,358,354]	68	74	71
Any concomitant medication, M7 [N=359,358,354]	127	127	129
Any antibiotic, M7 [N=359,358,354]	23	27	32
Any concomitant medication, M12 [N=356,348,350]	158	138	153
Any antipyretic, M12 [N=356,348,350]	90	80	81
Any antibiotic, M12 [N=356,348,350]	37	33	43
Any concomitant medication, M18 [N=356,347,349]	158	138	153
Any antipyretic, M18 [N=356,347,349]	90	80	81
Any antibiotic, M18 [N=356,347,349]	37	33	43
Prophylactic antipyretic, M12 [N=356,348,350]	5	2	2
Prophylactic antipyretic, M18 [N=356,347,349]	5	2	2
Any concomitant medication, M24 [N=355,344,349]	163	146	157
Any antipyretic, M24 [N=355,344,349]	94	82	80
Prophylactic antipyretic, M24 [N=356,347,349]	5	2	2
Any antibiotic, M24 [N=355,344,349]	43	38	158
Any concomitant medication, M36 [N=351,339,346]	166	147	94
Any antipyretic, M36 [N=351,339,346]	105	97	94
Prophylactic antipyretic, M36 [N=351,339,346]	5	2	2
Any antibiotic, M36 [N=351,339,346]	48	40	49
Prophylactic antibiotic, M36 [N=351,339,346]	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects completing the vaccination schedule

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End point title

Number of subjects completing the vaccination schedule

End point description

The number of subjects who have completed the three-dose vaccination schedule in all groups.

End point type

Secondary

End point timeframe

Throughout the study period (From Day 0 up to Month 36)

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	358	358
Units: Subjects
Subjects receiving all 3 vaccine doses	357	352	354

No statistical analyses for this end point

Secondary: Number of subjects with pregnancies

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End point title

Number of subjects with pregnancies

End point description

Note: No pregnancies were reported up to the Month 36 time point.

End point type

Secondary

End point timeframe

Throughout the study period (From Day 0 up to Month 36)

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	358	358
Units: Subjects
Subjects with any pregnancy, M12	0	0	0
Subjects with any pregnancy, M18	0	0	0
Subjects with any pregnancy, M24	0	0	0
Subjects with any pregnancy, M36	0	0	0

No statistical analyses for this end point

Secondary: Anti-HPV-16/18 seroconversion rates assessed by ELISA

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End point title

Anti-HPV-16/18 seroconversion rates assessed by ELISA

End point description

End point type

Secondary

End point timeframe

At Month 36

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	324	313	321
Units: Subjects
Anti-HPV-16, Month 36 (N=324,313,321)	324	310	320
Anti-HPV-18, Month 36 (N=324,313,321)	324	270	298

No statistical analyses for this end point

Secondary: Anti-HPV-16/18 seroconversion rates assessed by PBNA in a subset of subjects

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End point title

Anti-HPV-16/18 seroconversion rates assessed by PBNA in a subset of subjects

End point description

Seroconversion was defined as the appearance of antibodies (i.e. anti-HPV-16 and anti-HPV-18 antibody titers greater than or equal to ≥ 40 ED50) in the serum of subjects seronegative before vaccination in the primary study. The analysis was based on the ATP cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available at the time of the analysis.

End point type

Secondary

End point timeframe

At Months 24 and 36

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	89	88	92
Units: Subjects
Anti-HPV-16, Month 24 (N=88,88,92)	88	88	91
Anti-HPV-18, Month 24 (N=88,86,92)	88	77	89
Anti-HPV-16, Month 36 (N=89,87,91)	89	87	91
Anti-HPV-18, Month 36 (N=89,87,91)	89	75	86

No statistical analyses for this end point

Secondary: Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

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End point title

Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

End point description

End point type

Secondary

End point timeframe

At Months 24 and 36

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	89	88	92
Units: Titer
geometric mean (confidence interval 95%)
Anti-HPV-16, Month 24 (N=88,88,92)	5059.5 (4112.2 to 6225.1)	1138.1 (845.5 to 1531.9)	1965.5 (1510.6 to 2557.3)
Anti-HPV-18, Month 24 (N=88,86,92)	1725.1 (1359.3 to 2189.4)	234.6 (175.8 to 313.2)	568 (419 to 770.1)
Anti-HPV-16, Month 36 (N=89,87,91)	4357.8 (3577.8 to 5307.9)	1071.7 (811.2 to 1415.7)	1577 (1210.4 to 2054.5)
Anti-HPV-18, Month 36 (N=89,87,91)	1613.9 (1267.6 to 2054.7)	185.8 (140.4 to 245.8)	472.8 (345.8 to 646.4)

No statistical analyses for this end point

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

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End point title

T-cell-mediated immune responses in the sub-cohort for CMI

End point description

Immune markers expressed were among Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumour necrosis factor-alpha (TNF-α) and CD40-ligand (CD40-L).

End point type

Secondary

End point timeframe

At Month 36

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	58	55	64
Units: T-cells/million cells
median (inter-quartile range (Q1-Q3))
CD4+ All doubles, Anti-HPV-16,Month 36(N=58,55,64)	1012 (427 to 2373)	685 (385 to 1321)	842.5 (437.5 to 1624)
CD4+ All doubles, Anti-HPV-18,Month 36(N=57,55,63)	682 (313 to 1425)	350 (196 to 665)	516 (270 to 1029)
CD4-d-CD40L, Anti-HPV-16, Month 36 (N=58,55,64)	957 (465 to 2303)	685 (349 to 1321)	778.5 (416.5 to 1560.5)
CD4-d-CD40L, Anti-HPV-18, Month 36 (N=57,55,63)	671 (290 to 1435)	337 (204 to 648)	499 (264 to 1020)
CD4-d-IFNγ, Anti-HPV-16, Month 36 (N=58,55,64)	253.5 (81 to 667)	301 (134 to 571)	270.5 (129 to 666.5)
CD4-d-IFNγ, Anti-HPV-18, Month 36 (N=57,55,63)	193 (51 to 376)	109 (27 to 230)	155 (45 to 314)
CD4-d-IL-2, Anti-HPV-16, Month 36 (N=58,55,64)	784 (331 to 1673)	517 (295 to 1014)	680 (308 to 1245.5)
CD4-d-IL-2, Anti-HPV-18, Month 36 (N=57,55,63)	507 (213 to 1069)	274 (137 to 467)	341 (168 to 798)
CD4-d-TNFα, Anti-HPV-16, Month 36 (N=58,55,64)	786.5 (343 to 1930)	547 (282 to 1005)	724.5 (368 to 1338)
CD4-d-TNFα, Anti-HPV-18, Month 36 (N=57,55,63)	588 (250 to 1138)	301 (120 to 453)	479 (200 to 808)
CD8- All doubles, Anti-HPV-16,Month 36(N=58,55,64)	1 (1 to 48)	1 (1 to 28)	1 (1 to 38.5)
CD8- All doubles, Anti-HPV-18,Month 36(N=57,55,63)	4 (1 to 40)	2 (1 to 41)	1 (1 to 28)
CD8-d-CD40L, Anti-HPV-16, Month 36 (N=58,55,64)	1 (1 to 31)	1 (1 to 24)	1 (1 to 29)
CD8-d-CD40L, Anti-HPV-18, Month 36 (N=57,55,63)	1 (1 to 6)	1 (1 to 27)	1 (1 to 28)
CD8-d-IFNγ, Anti-HPV-16, Month 36 (N=58,55,64)	1 (1 to 47)	1 (1 to 25)	1 (1 to 33)
CD8-d-IFNγ, Anti-HPV-18, Month 36 (N=57,55,63)	1 (1 to 31)	2 (1 to 40)	1 (1 to 25)
CD8-d-IL-2, Anti-HPV-16, Month 36 (N=58,55,64)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
CD8-d-IL-2, Anti-HPV-18, Month 36 (N=57,55,63)	1 (1 to 1)	1 (1 to 1)	1 (1 to 1)
CD8-d-TNFα, Anti-HPV-16, Month 36 (N=58,55,64)	1 (1 to 24)	1 (1 to 1)	1 (1 to 26)
CD8-d-TNFα, Anti-HPV-18, Month 36 (N=57,55,63)	1 (1 to 31)	1 (1 to 21)	1 (1 to 12)

No statistical analyses for this end point

Secondary: B-cell-mediated immune responses in the sub-cohort for CMI

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End point title

B-cell-mediated immune responses in the sub-cohort for CMI

End point description

The frequency of B-cell Elispot response to HPV-16/18 by overall status was presented.

End point type

Secondary

End point timeframe

At Month 36

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	59	54	53
Units: B cells/million cells
median (inter-quartile range (Q1-Q3))
HPV-16, M36 (N=59,54,53)	353 (91 to 927)	382.5 (166 to 614)	246 (21 to 565)
HPV-18, M36 (N=59,54,53)	116 (1 to 329)	25 (1 to 228)	63 (1 to 150)

No statistical analyses for this end point

Secondary: Number of subjects with medically significant conditions (MSCs)

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End point title

Number of subjects with medically significant conditions (MSCs)

End point description

End point type

Secondary

End point timeframe

At Month 36

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	359	358	358
Units: Subjects
Subjects with Any MSC(S), Month 36	77	79	63

No statistical analyses for this end point

Secondary: Anti-HPV-16/18 seroconversion rates assessed by PBNA in a subset of subjects

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End point title

Anti-HPV-16/18 seroconversion rates assessed by PBNA in a subset of subjects

End point description

Seroconversion was defined as the appearance of antibodies (i.e. anti-HPV-16 and anti-HPV-18 antibody titers greater than or equal to ≥ 40 ED50) in the serum of subjects seronegative before vaccination in the primary study. The analysis was based on the Total Vaccinated cohort, which included all subjects with at least one study vaccine administered, on subjects with symptom sheets completed.

End point type

Secondary

End point timeframe

At Months 24 and 36

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	98	92	99
Units: Subjects
Anti-HPV-16, Month 24 (N=96,91,99)	95	91	98
Anti-HPV-18, Month 24 (N=96,89,99)	96	80	95
Anti-HPV-16, Month 36 (N=98,92,98)	97	92	98
Anti-HPV-18, Month 36 (N=97,92,98)	97	80	92

No statistical analyses for this end point

Secondary: Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

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End point title

Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

End point description

Anti-HPV 16/18 antibody titers were presented as geometric mean titers (GMT) and expressed in titers using the PBNA. The analysis was based on the Total Vaccinated cohort, which included all subjects with at least one study vaccine administered, on subjects with symptom sheets completed.

End point type

Secondary

End point timeframe

At Months 24 and 36

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	98	92	99
Units: Titers
geometric mean (confidence interval 95%)
Anti-HPV-16, Month 24 (N=96,91,99)	4609.1 (3673.5 to 5782.9)	1133.9 (848.1 to 1516)	1948.1 (1515 to 2505)
Anti-HPV-18, Month 24 (N=96,89,99)	1638.6 (1297.9 to 2068.8)	237.2 (179.1 to 314.3)	573 (425 to 772.5)
Anti-HPV-16, Month 36 (N=98,92,98)	4011.7 (3229.7 to 4983)	1058.4 (806.3 to 1389.2)	1517.2 (1174.7 to 1959.4)
Anti-HPV-18, Month 36 (N=97,92,98)	1513.7 (1197.5 to 1913.2)	185.8 (142.2 to 242.7)	468.6 (346.3 to 634)

No statistical analyses for this end point

Secondary: Anti-HPV-16/18 antibody concentrations assessed by ELISA

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End point title

Anti-HPV-16/18 antibody concentrations assessed by ELISA

End point description

Anti-HPV 16/18 antibody concentrations were presented as geometric mean concentrations (GMC) and expressed in ELISA units per milliliter (EL.U/mL) based on ELISA.

End point type

Secondary

End point timeframe

At Month 36

End point values	Cervarix 2 dose Group	Gardasil 2 dose Group	Gardasil 3 dose Group
Number of subjects analysed	324	313	321
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-HPV-16, Month 36 (N=324,313,321)	1068.9 (979.6 to 1166.5)	375.4 (329.6 to 427.5)	475.3 (428.7 to 527)
Anti-HPV-18, Month 36 (N=324,313,321)	487.8 (439.3 to 541.8)	71.3 (62.3 to 81.5)	120.2 (104.3 to 138.5)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited symptoms: up to Day 7 post vaccination. AEs: up to Day 30 post vaccination. SAEs throughout the study period (up to Month 36).

Adverse event reporting additional description

For the systematically assessed other (non-serious) adverse events, the number of participants at risk included those from Total Vaccinated cohort who had the symptom sheet completed.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Cervarix 2 dose Group

Reporting group description

Reporting group title

Gardasil 3 dose Group

Reporting group description

Subjects who received 3 doses of Gardasil® vaccine at Day 0 and at Months 2 and 6. The vaccines were administered intramuscularly, in the deltoid muscle of the non-dominant upper arm.

Reporting group title

Gardasil 2 dose Group

Reporting group description

Serious adverse events	Cervarix 2 dose Group	Gardasil 3 dose Group	Gardasil 2 dose Group
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 359 (5.85%)	14 / 358 (3.91%)	11 / 358 (3.07%)
number of deaths (all causes)	0	1	0
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Teratoma
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Orthostatic hypotension
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous incomplete
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anaphylactic shock
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Menorrhagia
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vulval ulceration
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	2 / 359 (0.56%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Completed suicide
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Depression
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	2 / 359 (0.56%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Forearm fracture
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foreign body
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon injury
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Epilepsy
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tension headache
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphadenitis
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mouth cyst
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erythema nodosum
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Juvenile idiopathic arthritis
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epstein-barr virus infection
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	3 / 359 (0.84%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 359 (0.00%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 359 (0.28%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	1 / 359 (0.28%)	0 / 358 (0.00%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 359 (0.56%)	1 / 358 (0.28%)	0 / 358 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 359 (0.00%)	0 / 358 (0.00%)	1 / 358 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cervarix 2 dose Group	Gardasil 3 dose Group	Gardasil 2 dose Group
Total subjects affected by non serious adverse events
subjects affected / exposed	329 / 359 (91.64%)	295 / 358 (82.40%)	276 / 358 (77.09%)
General disorders and administration site conditions
Pain
subjects affected / exposed	329 / 359 (91.64%)	295 / 358 (82.40%)	276 / 358 (77.09%)
occurrences all number	329	295	276
Redness
subjects affected / exposed	191 / 359 (53.20%)	157 / 358 (43.85%)	134 / 358 (37.43%)
occurrences all number	191	157	134
Swelling
subjects affected / exposed	163 / 359 (45.40%)	118 / 358 (32.96%)	98 / 358 (27.37%)
occurrences all number	163	118	98
Arthralgia
subjects affected / exposed	68 / 359 (18.94%)	67 / 358 (18.72%)	81 / 358 (22.63%)
occurrences all number	68	67	81
Fatigue
subjects affected / exposed	192 / 359 (53.48%)	193 / 358 (53.91%)	199 / 358 (55.59%)
occurrences all number	192	193	199
Gastrointestinal
subjects affected / exposed	55 / 359 (15.32%)	69 / 358 (19.27%)	74 / 358 (20.67%)
occurrences all number	55	69	74
Headache
subjects affected / exposed	147 / 359 (40.95%)	151 / 358 (42.18%)	133 / 358 (37.15%)
occurrences all number	147	151	133
Myalgia
subjects affected / exposed	166 / 359 (46.24%)	136 / 358 (37.99%)	143 / 358 (39.94%)
occurrences all number	166	136	143
Rash
subjects affected / exposed	26 / 359 (7.24%)	18 / 358 (5.03%)	16 / 358 (4.47%)
occurrences all number	26	18	16
Temperature
subjects affected / exposed	53 / 359 (14.76%)	47 / 358 (13.13%)	59 / 358 (16.48%)
occurrences all number	53	47	59
Urticaria
subjects affected / exposed	27 / 359 (7.52%)	25 / 358 (6.98%)	13 / 358 (3.63%)
occurrences all number	27	25	13
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	27 / 359 (7.52%)	31 / 358 (8.66%)	29 / 358 (8.10%)
occurrences all number	27	31	29
Nasopharyngitis
subjects affected / exposed	8 / 359 (2.23%)	20 / 358 (5.59%)	11 / 358 (3.07%)
occurrences all number	8	20	11

More information

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Were there any global substantial amendments to the protocol? Yes

02 Jul 2012

Amendment 1 At the European Medicines Agency’s (EMA) request, GSK Biologicals has updated its procedure for emergency unblinding during the conduct of a clinical study. According to the revised procedure, the responsibility and the decision to break the treatment code in emergency situations resides solely with the investigator and consequently, the investigator will have full authority to break the treatment code

24 Jun 2014

Amendment 3 At the time of study initiation, Cervarix was approved to be administered according to a 3-dose vaccination schedule. Subjects belonging to the study groups HPV_2D and Gard_2D received two doses of either Cervarix or Gardasil during the primary study epoch. These subjects were to be offered a third dose of the vaccine that they received, at the end of the study, at Month 36. Recently, the 2-dose schedule of Cervarix and Gardasil has been approved in some countries, and hence the protocol is being amended to reflect that a third dose of the vaccine that they received will be offered to the subjects in the two 2-dose groups (HPV_2D and Gard_2D) only if required based on local prescribing recommendations. In addition, the indication for Cervarix and the list of contributing authors have been updated. The number of countries in which Cervarix and Gardasil are licensed has been updated. Minor changes have been made in a few sections to correct typographical errors.

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 seroconverted subjects for Anti-HPV-16/18, as assessed by the enzyme-immunosorbent assay (ELISA)

Primary: Number of seroconverted subjects for Anti-HPV-16/18, as assessed by the enzyme-immunosorbent assay (ELISA)

Primary: Anti-HPV-16/18 antibody concentrations assessed by ELISA

Primary: Anti-HPV-16/18 antibody concentrations assessed by ELISA

Primary: Anti-HPV-16/18 seroconversion rates assessed by ELISA

Primary: Anti-HPV-16/18 seroconversion rates assessed by ELISA

Primary: Anti-HPV-16/18 antibody concentrations assessed by ELISA

Primary: Anti-HPV-16/18 antibody concentrations assessed by ELISA

Secondary: Anti-HPV-16/18 seroconversion rates assessed by ELISA

Secondary: Anti-HPV-16/18 seroconversion rates assessed by ELISA

Secondary: Anti-HPV-16/18 antibody concentrations assessed by ELISA

Secondary: Anti-HPV-16/18 antibody concentrations assessed by ELISA

Secondary: Anti-HPV-16/18 seroconversion rates assessed by pseudovirion-based neutralization assay (PBNA) in a subset of subjects

Secondary: Anti-HPV-16/18 seroconversion rates assessed by pseudovirion-based neutralization assay (PBNA) in a subset of subjects

Secondary: Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

Secondary: Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: B-cell-mediated immune responses in the sub-cohort for CMI

Secondary: B-cell-mediated immune responses in the sub-cohort for CMI

Secondary: Number of subjects with any, grade 3 and related solicited local symptoms

Secondary: Number of subjects with any, grade 3 and related solicited local symptoms

Secondary: Number of subjects with any, grade 3 and related solicited general symptoms

Secondary: Number of subjects with any, grade 3 and related solicited general symptoms

Secondary: Number of subjects with any, grade 3 and related unsolicited adverse events (AEs)

Secondary: Number of subjects with any, grade 3 and related unsolicited adverse events (AEs)

Secondary: Number of subjects with potentially immune mediated diseases (pIMDs)

Secondary: Number of subjects with potentially immune mediated diseases (pIMDs)

Secondary: Number of subjects with medically significant conditions (MSCs)

Secondary: Number of subjects with medically significant conditions (MSCs)

Secondary: Number of subjects with Serious Adverse Events (SAEs)

Secondary: Number of subjects with Serious Adverse Events (SAEs)

Secondary: Number of subjects starting a concomitant medication

Secondary: Number of subjects starting a concomitant medication

Secondary: Number of subjects starting a concomitant medication

Secondary: Number of subjects starting a concomitant medication

Secondary: Number of subjects completing the vaccination schedule

Secondary: Number of subjects completing the vaccination schedule

Secondary: Number of subjects with pregnancies

Secondary: Number of subjects with pregnancies

Secondary: Anti-HPV-16/18 seroconversion rates assessed by ELISA

Secondary: Anti-HPV-16/18 seroconversion rates assessed by ELISA

Secondary: Anti-HPV-16/18 seroconversion rates assessed by PBNA in a subset of subjects

Secondary: Anti-HPV-16/18 seroconversion rates assessed by PBNA in a subset of subjects

Secondary: Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

Secondary: Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: T-cell-mediated immune responses in the sub-cohort for CMI

Secondary: B-cell-mediated immune responses in the sub-cohort for CMI

Secondary: B-cell-mediated immune responses in the sub-cohort for CMI

Secondary: Number of subjects with medically significant conditions (MSCs)

Secondary: Number of subjects with medically significant conditions (MSCs)

Secondary: Anti-HPV-16/18 seroconversion rates assessed by PBNA in a subset of subjects

Secondary: Anti-HPV-16/18 seroconversion rates assessed by PBNA in a subset of subjects

Secondary: Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

Secondary: Anti-HPV-16/18 antibody titers assessed by PBNA in a subset of subjects

Secondary: Anti-HPV-16/18 antibody concentrations assessed by ELISA