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Clinical Trial Results:
A Randomized, Double-Blinded, Controlled with GARDASIL® (Human Papillomavirus Vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed)), Phase 3 Clinical Trial to Study the Immunogenicity and Tolerability of V503 (9-Valent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in 16- to 26-year-old men.

Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.

Summary
EudraCT number	2013-003399-10
Trial protocol	DE BE NL
Global end of trial date	22 Apr 2015

Results information
Results version number	v1(current)
This version publication date	23 Apr 2016
First version publication date	23 Apr 2016
Other versions

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

GDS07C

ISRCTN number

US NCT number

NCT02114385

WHO universal trial number (UTN)

Sponsor organisation name

Sanofi Pasteur MSD S.N.C.

Sponsor organisation address

162 avenue Jean Jaurès - CS 50712, Lyon Cedex 07, France, 69367

Public contact

Clinical Trials Disclosure, Sanofi Pasteur MSD S.N.C., ClinicalTrialsDisclosure@spmsd.com

Scientific contact

Clinical Trials Disclosure, Sanofi Pasteur MSD S.N.C., ClinicalTrialsDisclosure@spmsd.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

22 Apr 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

22 Apr 2015

Global end of trial reached?

Yes

Global end of trial date

22 Apr 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective is to demonstrate that administration of the 9-valent HPV L1 VLP (9vHPV) vaccine induces non-inferior Geometric Mean Titres (GMTs) for serum anti-HPV 6, 11, 16, and 18, compared to GARDASIL® (qHPV) in 16- to 26-year-old men.

Protection of trial subjects

Healthy men with known allergy to any vaccine component were excluded. Vaccines were administered by qualified study personnel. After each vaccination, subjects were kept under observation for at least 30 minutes to ensure their safety.

Background therapy

Evidence for comparator

# 9vHPV vaccine (= V503) is a prophylactic 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle (VLP) vaccine that is composed of VLPs of the 4 HPV types (Types 6, 11, 16, and 18) contained in qHPV vaccine (= GARDASIL®, a quadrivalent prophylactic HPV vaccine), plus the VLPs of 5 additional oncogenic HPV types (Types 31, 33, 45, 52, and 58). # qHPV vaccine has been approved by the European Medicines Agency (EMA) in September 2006 and is currently approved and marketed in over 100 countries. # This study was designed to provide a direct comparison of immunogenicity and tolerability of the 9vHPV vaccine versus qHPV vaccine in young men, 16 to 26 years of age.

Actual start date of recruitment

24 Mar 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 155

Country: Number of subjects enrolled

Belgium: 276

Country: Number of subjects enrolled

Germany: 69

Worldwide total number of subjects

500

EEA total number of subjects

500

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)

Adults (18-64 years)

425

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Study subjects were enrolled in 7 active centres in 3 European countries (Belgium, Germany, and The Netherlands) between 24 March 2014 and 17 September 2014.

Screening details

502 subjects were screened. 500 subjects were randomised. 490 subjects received all 3 doses of 9vHPV or qHPV vaccine. 489 subjects completed the study.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Blinded vaccines were presented in the same sealed outer packaging. The subjects, investigators (and his/her staff), laboratory staff, and the Sponsor remained blinded to subject vaccine allocation.

Are arms mutually exclusive

Yes

9vHPV vaccine

Arm description

# Subjects received 3 doses of 9vHPV vaccine* by intramuscular (IM) route: dose 1 at Visit 1 (V1, Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks). # Subjects were blood sampled (i) before vaccination (V1), and (ii) at V4, i.e., 3 to 7 weeks after V3 = Post-Dose 3. *9vHPV vaccine = V503 = 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle (VLP) vaccine (recombinant, absorbed)

Arm type

Experimental

Investigational medicinal product name

9-valent HPV VLP

Investigational medicinal product code

9vHPV

Other name

V503, GARDASIL®9

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL, IM route (deltoid muscle of the nondominant arm), 3 doses: dose 1 at V1 (Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks).

qHPV vaccine

Arm description

# Subjects received 3 doses of qHPV vaccine* by intramuscular (IM) route: dose 1 at V1 (Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks). # Subjects were blood sampled (i) before vaccination (V1), and (ii) at V4, i.e., 3 to 7 weeks after V3 = Post-Dose 3. *qHPV vaccine = GARDASIL® = 4-valent HPV (Types 6, 11, 16 and 18) L1 virus-like particle (VLP) vaccine (recombinant, absorbed)

Arm type

Active comparator

Investigational medicinal product name

GARDASIL®

Investigational medicinal product code

qHPV

Other name

SILGARD®

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL, IM route (deltoid muscle of the nondominant arm), 3 doses: dose 1 at V1 (Day 1), dose 2 at V2 (2 months after Day 1, ±3 weeks), and dose 3 at V3 (6 months after Day 1, ±4 weeks).

Number of subjects in period 1	9vHPV vaccine	qHPV vaccine
Started	249	251
Completed	246	243
Not completed	3	8
Consent withdrawn by subject	3	2
Lost to follow-up	-	6

Baseline characteristics

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Reporting group title

9vHPV vaccine

Reporting group description

Reporting group title

qHPV vaccine

Reporting group description

Reporting group values	9vHPV vaccine	qHPV vaccine	Total
Number of subjects	249	251	500
Age categorical
Units: Subjects
16-17 years old	37	38	75
18-26 years old	212	213	425
Age continuous
Age at 1st dose
Units: years
arithmetic mean (standard deviation)	20.8 ( 2.7 )	21.3 ( 3 )	-
Gender categorical
Units: Subjects
Female	0	0	0
Male	249	251	500

End points

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Reporting group title

9vHPV vaccine

Reporting group description

Reporting group title

qHPV vaccine

Reporting group description

Primary: Non-inferiority of Geometric Mean Titres (GMTs) of anti-HPV types 6, 11, 16 and 18 antibodies (Abs) Post-Dose 3 (V4) of 9vHPV versus qHPV vaccine

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End point title

Non-inferiority of Geometric Mean Titres (GMTs) of anti-HPV types 6, 11, 16 and 18 antibodies (Abs) Post-Dose 3 (V4) of 9vHPV versus qHPV vaccine

End point description

Anti-HPV types 6, 11, 16 and 18 Ab titres were measured by competitive Luminex ImmunoAssay (cLIA) 3 to 7 weeks Post-Dose 3 of 9vHPV versus qHPV vaccine (V4). Ab titres are expressed in milli Merck units (mMU)/mL. Analysis was done on the HPV specific Per Protocol Sets (PPS), i.e., subjects who received all 3 vaccinations, and seronegative to the relevant HPV type at Day 1, excluding those with protocol deviation which could interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "9vHPV vaccine" and "qHPV vaccine", respectively.

End point type

Primary

End point timeframe

3 to 7 weeks Post-Dose 3 of 9vHPV versus qHPV vaccine.

End point values	9vHPV vaccine	qHPV vaccine
Number of subjects analysed	234	237
Units: mMU/mL
geometric mean (confidence interval 95%)
Anti-HPV 6 GMT (N=228, 226)	758.3 (665.9 to 863.4)	618.4 (554 to 690.3)
Anti-HPV 11 GMT (N=228, 226)	681.7 (608.9 to 763.4)	769.1 (683.5 to 865.3)
Anti-HPV 16 GMT (N=234, 237)	3924.1 (3513.8 to 4382.3)	3787.9 (3378.4 to 4247)
Anti-HPV 18 GMT (N=234, 236)	884.3 (766.4 to 1020.4)	790.9 (683 to 915.7)

Non-inferiority for HPV 6

Statistical analysis description

The estimate of the 9vHPV vaccine/qHPV vaccine GMT ratio for HPV 6 was calculated with its P-value and its 2-sided 95% confidence interval (CI) using an ANOVA model including group and age strata as independent variables. If the lower bound of the 95% CI was greater than 0.5 (i.e., the non-inferiority margin), it was concluded that 9vHPV GMT was non-inferior to qHPV GMT. Analysis was done on the HPV 6 specific PPS. N= 454 (9vHPV vaccine: 228, qHPV vaccine: 226).

Comparison groups

9vHPV vaccine v qHPV vaccine

Number of subjects included in analysis

471

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

ANOVA

Parameter type

GMT ratio

Point estimate

1.23

Confidence interval

level

95%

sides

2-sided

lower limit

1.04

upper limit

1.45

Non-inferiority for HPV 11

Statistical analysis description

The estimate of the 9vHPV vaccine/qHPV vaccine GMT ratio for HPV 11 was calculated with its P-value and its 2-sided 95% confidence interval (CI) using an ANOVA model including group and age stratum as independent variables. If the lower bound of the 95% CI was greater than 0.5 (i.e., the non-inferiority margin), it was concluded that 9vHPV GMT was non-inferior to qHPV GMT. Analysis was done on the HPV 11 specific PPS. N= 454 (9vHPV vaccine: 228, qHPV vaccine: 226).

Comparison groups

9vHPV vaccine v qHPV vaccine

Number of subjects included in analysis

471

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

ANOVA

Parameter type

GMT ratio

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.04

Non-inferiority for HPV 16

Statistical analysis description

The estimate of the 9vHPV vaccine/qHPV vaccine GMT ratio for HPV 16 was calculated with its P-value and its 2-sided 95% confidence interval (CI) using an ANOVA model including group and age stratum as independent variables. If the lower bound of the 95% CI was greater than 0.5 (i.e., the non-inferiority margin), it was concluded that 9vHPV GMT was non-inferior to qHPV GMT. Analysis was done on the HPV 16 specific PPS. N= 471 (9vHPV vaccine: 234, qHPV vaccine: 237).

Comparison groups

9vHPV vaccine v qHPV vaccine

Number of subjects included in analysis

471

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

ANOVA

Parameter type

GMT ratio

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.21

Non-inferiority for HPV 18

Statistical analysis description

The estimate of the 9vHPV vaccine/qHPV vaccine GMT ratio for HPV 18 was calculated with its P-value and its 2-sided 95% confidence interval (CI) using an ANOVA model including group and age stratum as independent variables. If the lower bound of the 95% CI was greater than 0.5 (i.e., the non-inferiority margin), it was concluded that 9vHPV GMT was non-inferior to qHPV GMT. Analysis was done on the HPV 18 specific PPS. N= 470 (9vHPV vaccine: 234, qHPV vaccine: 236).

Comparison groups

9vHPV vaccine v qHPV vaccine

Number of subjects included in analysis

471

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

ANOVA

Parameter type

GMT ratio

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.37

Secondary: Seroconversion rates for anti-HPV types 6, 11, 16, and 18 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

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End point title

Seroconversion rates for anti-HPV types 6, 11, 16, and 18 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

End point description

The seroconversion rates to HPV types 6, 11, 16, and 18 defined as Ab titres ≥30 mMU/mL for anti-HPV 6, ≥16 mMU/mL for anti-HPV 11, ≥20 mMU/mL for anti-HPV 16, and ≥24 mMU/mL for anti-HPV 18 were determined 3 to 7 weeks Post-Dose 3 of 9vHPV or qHPV vaccine (V4). Ab titres were measured by cLIA. Analysis was done on the HPV specific Per Protocol Sets (PPS), i.e., subjects who received all 3 vaccinations, and seronegative to the relevant HPV type at Day 1, excluding those with protocol deviation which could interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "9vHPV vaccine" and "qHPV vaccine" groups, respectively.

End point type

Secondary

End point timeframe

3 to 7 weeks Post-Dose 3 of 9vHPV versus qHPV vaccine.

End point values	9vHPV vaccine	qHPV vaccine
Number of subjects analysed	234	237
Units: Percentage of subjects
number (confidence interval 95%)
Anti-HPV 6 ≥30 mMU/mL (N=228, 226)	98.2 (95.6 to 99.5)	98.7 (96.2 to 99.7)
Anti-HPV 11 ≥16 mMU/mL (N=228, 226)	100 (98.4 to 100)	100 (98.4 to 100)
Anti-HPV 16 ≥20 mMU/mL (N=234, 237)	100 (98.4 to 100)	100 (98.5 to 100)
Anti-HPV 18 ≥24 mMU/mL (N=234, 236)	99.6 (97.6 to 100)	99.6 (97.7 to 100)

No statistical analyses for this end point

Secondary: GMTs of anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

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End point title

GMTs of anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

End point description

Anti-HPV types 31, 33, 45, 52, and 58 Ab titres were measured by cLIA 3 to 7 weeks Post-Dose 3 of 9vHPV or qHPV vaccine (V4). Ab titres are expressed in mMU/mL. Analysis was done on the HPV specific Per Protocol Sets (PPS), i.e., subjects who received all 3 vaccinations, and seronegative to the relevant HPV type at Day 1, excluding those with protocol deviation which could interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "9vHPV vaccine" and "qHPV vaccine" groups, respectively.

End point type

Secondary

End point timeframe

3 to 7 weeks Post-Dose 3 of 9vHPV versus qHPV vaccine.

End point values	9vHPV vaccine	qHPV vaccine
Number of subjects analysed	236	237
Units: mMU/mL
geometric mean (confidence interval 95%)
Anti-HPV 31 GMT (N=234, 237)	794.4 (694.2 to 909.2)	14.8 (12.5 to 17.5)
Anti-HPV 33 GMT (N=236, 236)	460.5 (410.6 to 516.4)	3.4 (3.1 to 3.7)
Anti-HPV 45 GMT (N=232, 236)	262.9 (226.2 to 305.5)	2.5 (2.3 to 2.8)
Anti-HPV 52 GMT (N=235, 236)	430.7 (377.8 to 491)	1.9 (1.8 to 2.1)
Anti-HPV 58 GMT (N=232, 233)	691 (614.9 to 776.5)	5.7 (5 to 6.5)

No statistical analyses for this end point

Secondary: Seroconversion rates for anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

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End point title

Seroconversion rates for anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

End point description

The seroconversion rates to HPV types 31, 33, 45, 52, and 58 defined as Ab titres ≥10 mMU/mL for anti-HPV 31, and ≥8 mMU/mL for anti-HPV 33, anti-HPV 45, anti-HPV 52, and anti HPV 58 were determined 3 to 7 weeks Post-Dose 3 of 9vHPV or qHPV vaccine (V4). Ab titres were measured by cLIA. Analysis was done on the HPV specific Per Protocol Sets (PPS), i.e., subjects who received all 3 vaccinations, and seronegative to the relevant HPV type at Day 1, excluding those with protocol deviation which could interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "9vHPV vaccine" and "qHPV vaccine" groups, respectively.

End point type

Secondary

End point timeframe

3 to 7 weeks Post-Dose 3 of 9vHPV versus qHPV vaccine.

End point values	9vHPV vaccine	qHPV vaccine
Number of subjects analysed	236	237
Units: Percentage of subjects
number (confidence interval 95%)
Anti-HPV 31 ≥10 mMU/mL (N=234, 237)	100 (98.4 to 100)	61.6 (55.1 to 67.8)
Anti-HPV 33 ≥8 mMU/mL (N=236, 236)	100 (98.4 to 100)	16.9 (12.4 to 22.4)
Anti-HPV 45 ≥8 mMU/mL (N=232, 236)	100 (98.4 to 100)	9.3 (5.9 to 13.8)
Anti-HPV 52 ≥8 mMU/mL (N=235, 236)	100 (98.4 to 100)	2.5 (0.9 to 5.5)
Anti-HPV 58 ≥8 mMU/mL (N=232, 233)	100 (98.4 to 100)	36.1 (29.9 to 42.6)

No statistical analyses for this end point

Secondary: Global summary of safety from D1 to D15 after any vaccination (3 doses of 9vHPV or qHPV)

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End point title

Global summary of safety from D1 to D15 after any vaccination (3 doses of 9vHPV or qHPV)

End point description

Adverse events (AEs) were recorded as follows. 1/ From D1 to D5 after each vaccination: # oral temperature ≥37.8°C, # solicited (erythema, pain, and swelling at injection-site) and # other injection-site adverse reactions (ISRs). 2/ From D1 to D15 after each vaccination: systemic AEs. AEs at injection sites were always considered as related to vaccine (ISRs). The investigator had to assess whether systemic AEs were vaccine-related systemic AEs or not. The percentage of subjects presenting at least once the considered events after any vaccination is reported hereafter. Analyses following any doses were based on the vaccines corresponding to the highest number of doses received by the subject. Analysis was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of the study vaccines and who had safety follow-up data.

End point type

Secondary

End point timeframe

From Day 1 (D1) to D15 after any vaccination (3 doses of 9vHPV or qHPV).

End point values	9vHPV vaccine	qHPV vaccine
Number of subjects analysed	248	248
Units: Percentage of subjects
number (confidence interval 95%)
At least 1 AE (D1-D15)	82.3 (76.9 to 86.8)	81.9 (76.5 to 86.4)
At least 1 vaccine-related AE (D1-D15)	81.5 (76 to 86.1)	79 (73.4 to 83.9)
At least 1 ISR (D1-D5)	79 (73.4 to 83.9)	72.2 (66.2 to 77.7)
At least 1 solicited ISR (D1-D5)	78.6 (73 to 83.6)	71.4 (65.3 to 76.9)
At least 1 other ISR (D1-D5)	9.7 (6.3 to 14.1)	9.3 (6 to 13.6)
At least 1 severe ISR (D1-D5)	1.2 (0.3 to 3.5)	1.6 (0.4 to 4.1)
At least 1 systemic AE (D1-D15)	40.7 (34.6 to 47.1)	40.3 (34.2 to 46.7)
At least 1 vaccine-related systemic AE (D1-D15)	23 (17.9 to 28.7)	21.8 (16.8 to 27.4)

No statistical analyses for this end point

Secondary: Percentage of subjects reporting ISRs from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)

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End point title

Percentage of subjects reporting ISRs from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)

End point description

The percentage of subjects presenting at least once solicited (erythema, pain, and swelling) or other ISRs from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV) is reported hereafter. AEs at injection-site were always considered as related to vaccine (ISRs). Analyses following any doses were based on the vaccines corresponding to the highest number of doses received by the subject. Analysis was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of the study vaccines and who had safety follow-up data.

End point type

Secondary

End point timeframe

From Day 1 (D1) to D5 after any vaccination (3 doses of 9vHPV or qHPV).

End point values	9vHPV vaccine	qHPV vaccine
Number of subjects analysed	248	248
Units: Percentage of subjects
number (not applicable)
Solicited injection-site erythema	15.3	17.3
Solicited injection-site swelling	14.5	9.3
Solicited injection-site pain	77.8	70.2
Unsolicited injection-site movement impairment	2	3.6
Unsolicited injection-site induration	1.6	2.4
Unsolicited injection-site pruritus	1.6	2
Unsolicited injection-site haematoma	1.6	0.8
Unsolicited injection-site haemorrhage	0.8	0.4
Unsolicited injection-site bruising	0.4	0.4
Unsolicited injection-site joint pain	0.4	0.4
Unsolicited injection-site reaction	0	0.8
Unsolicited injection-site lymphadenopathy	0.4	0
Unsolicited injection-site paraesthesia	0.4	0
Unsolicited injection-site urticaria	0.4	0
Unsolicited injection-site warmth	0.4	0

No statistical analyses for this end point

Secondary: Percentage of subjects reporting oral temperature [37.8°C-38.9°C[ or [38.9°C-39.9°C[ from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)

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End point title

Percentage of subjects reporting oral temperature [37.8°C-38.9°C[ or [38.9°C-39.9°C[ from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)

End point description

Maximum oral temperatures recorded daily were reported from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV). The percentage of subjects presenting at least once temperature [37.8°C-38.9°C[ and [38.9°C-39.9°C[ is presented hereafter. Analyses following any doses were based on the vaccines corresponding to the highest number of doses received by the subject. Analysis was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of the study vaccines and who had safety follow-up data.

End point type

Secondary

End point timeframe

From Day 1 (D1) to D5 after any vaccination (3 doses of 9vHPV or qHPV).

End point values	9vHPV vaccine	qHPV vaccine
Number of subjects analysed	248	248
Units: Percentage of subjects
number (not applicable)
Oral temperature [37.8°C-38.9°C[	2.8	2
Oral temperature [38.9°C-39.9°C[	0	0.4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Systemic adverse events (AEs) were collected from D1 to D15 after each dose of 9vHPV or qHPV vaccine. Serious AEs and deaths were collected throughout the study.

Adverse event reporting additional description

Analysis of AEs was done on the Safety Analysis Set, i.e., all subjects who received at least 1 dose of the study vaccines and who had safety follow-up data. Unsolicited non-serious systemic AEs (vaccine-related or not) with incidence ≥1% are presented hereafter. None of the serious AEs were vaccine-related.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

9vHPV vaccine

Reporting group description

# Subjects received 3 doses of 9vHPV vaccine (V503) by IM route: dose 1 at Visit 1 (Day 1), dose 2 at Visit 2 (2 months after Day 1, ±3 weeks), and dose 3 at Visit 3 (6 months after Day 1, ±4 weeks). # Respectively, 101 (40.7%) subjects reported at least 1 unsolicited systemic AE, and 57 (23%) subjects reported at least 1 vaccine-related unsolicited systemic AE within 15 days after any vaccination (3 doses of 9vHPV vaccine).

Reporting group title

qHPV vaccine

Reporting group description

# Subjects received 3 doses of qHPV vaccine (GARDASIL®) by IM route: dose 1 at Visit 1 (Day 1), dose 2 at Visit 2 (2 months after Day 1, ±3 weeks), and dose 3 at Visit 3 (6 months after Day 1, ±4 weeks). # Respectively, 100 (40.3%) subjects reported at least 1 unsolicited systemic AE, and 54 (21.8%) subjects reported at least 1 vaccine-related unsolicited systemic AE within 15 days after any vaccination (3 doses of qHPV vaccine).

Serious adverse events	9vHPV vaccine	qHPV vaccine
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 248 (0.00%)	6 / 248 (2.42%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Injury, poisoning and procedural complications
Foot fracture
subjects affected / exposed	0 / 248 (0.00%)	1 / 248 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 248 (0.00%)	1 / 248 (0.40%)
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	0 / 248 (0.00%)	1 / 248 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	0 / 248 (0.00%)	1 / 248 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament injury
subjects affected / exposed	0 / 248 (0.00%)	1 / 248 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Cytomegalovirus infection
subjects affected / exposed	0 / 248 (0.00%)	1 / 248 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	9vHPV vaccine	qHPV vaccine
Total subjects affected by non serious adverse events
subjects affected / exposed	101 / 248 (40.73%)	100 / 248 (40.32%)
Nervous system disorders
Headache
subjects affected / exposed	29 / 248 (11.69%)	37 / 248 (14.92%)
occurrences all number	43	51
Dizziness
subjects affected / exposed	5 / 248 (2.02%)	1 / 248 (0.40%)
occurrences all number	5	1
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	6 / 248 (2.42%)	0 / 248 (0.00%)
occurrences all number	6	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	9 / 248 (3.63%)	8 / 248 (3.23%)
occurrences all number	12	11
Fatigue
subjects affected / exposed	8 / 248 (3.23%)	9 / 248 (3.63%)
occurrences all number	8	9
Hangover
subjects affected / exposed	1 / 248 (0.40%)	5 / 248 (2.02%)
occurrences all number	1	8
Influenza like illness
subjects affected / exposed	3 / 248 (1.21%)	2 / 248 (0.81%)
occurrences all number	4	2
Immune system disorders
Seasonal allergy
subjects affected / exposed	3 / 248 (1.21%)	1 / 248 (0.40%)
occurrences all number	3	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	7 / 248 (2.82%)	12 / 248 (4.84%)
occurrences all number	8	12
Nausea
subjects affected / exposed	6 / 248 (2.42%)	5 / 248 (2.02%)
occurrences all number	7	7
Abdominal pain upper
subjects affected / exposed	3 / 248 (1.21%)	2 / 248 (0.81%)
occurrences all number	3	3
Abdominal pain
subjects affected / exposed	3 / 248 (1.21%)	1 / 248 (0.40%)
occurrences all number	3	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	8 / 248 (3.23%)	9 / 248 (3.63%)
occurrences all number	8	10
Psychiatric disorders
Sleep disorder
subjects affected / exposed	3 / 248 (1.21%)	0 / 248 (0.00%)
occurrences all number	3	0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	5 / 248 (2.02%)	2 / 248 (0.81%)
occurrences all number	5	2
Musculoskeletal stiffness
subjects affected / exposed	3 / 248 (1.21%)	2 / 248 (0.81%)
occurrences all number	4	2
Pain in extremity
subjects affected / exposed	3 / 248 (1.21%)	1 / 248 (0.40%)
occurrences all number	4	1
Back pain
subjects affected / exposed	3 / 248 (1.21%)	0 / 248 (0.00%)
occurrences all number	3	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	11 / 248 (4.44%)	14 / 248 (5.65%)
occurrences all number	13	16
Upper respiratory tract infection
subjects affected / exposed	3 / 248 (1.21%)	7 / 248 (2.82%)
occurrences all number	4	7
Rhinitis
subjects affected / exposed	5 / 248 (2.02%)	4 / 248 (1.61%)
occurrences all number	5	5
Gastroenteritis
subjects affected / exposed	4 / 248 (1.61%)	4 / 248 (1.61%)
occurrences all number	4	4
Influenza
subjects affected / exposed	2 / 248 (0.81%)	3 / 248 (1.21%)
occurrences all number	2	3
Oral herpes
subjects affected / exposed	3 / 248 (1.21%)	1 / 248 (0.40%)
occurrences all number	3	1

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Were there any global substantial amendments to the protocol? Yes

05 Feb 2014

Country-specific protocol amendment for the Netherlands: - at the EC’s request, the withdrawal criteria were clarified to specify that subjects could be withdrawn for any event likely to affect the safety of the subject, or any serious GCP issue (previously “administrative reasons”), - the phone number for immediate reporting of adverse events was corrected, - the instructions to Investigators for immediate reporting of adverse events were clarified, - reporting of medical errors to the Sponsor was added.

04 Mar 2014

Country-specific protocol amendment for Germany: - the address for the Sponsor Sanofi Pasteur MSD was updated, as their offices had moved, - the Coordinating Investigator and instructions for immediate reporting of adverse events for France were removed, as the clinical trial application was withdrawn in France, - a justification of the choice of non-inferiority margin was added to the statistical methods and the sample size and power calculations section.

31 Mar 2014

Protocol amendment applicable to all countries: Same as Protocol Amendment 2 (issued on 4 March 2014) which was only applicable to Germany.

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: Non-inferiority of Geometric Mean Titres (GMTs) of anti-HPV types 6, 11, 16 and 18 antibodies (Abs) Post-Dose 3 (V4) of 9vHPV versus qHPV vaccine

Primary: Non-inferiority of Geometric Mean Titres (GMTs) of anti-HPV types 6, 11, 16 and 18 antibodies (Abs) Post-Dose 3 (V4) of 9vHPV versus qHPV vaccine

Secondary: Seroconversion rates for anti-HPV types 6, 11, 16, and 18 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

Secondary: Seroconversion rates for anti-HPV types 6, 11, 16, and 18 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

Secondary: GMTs of anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

Secondary: GMTs of anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

Secondary: Seroconversion rates for anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

Secondary: Seroconversion rates for anti-HPV types 31, 33, 45, 52, and 58 Abs Post-Dose 3 (V4) of 9vHPV or qHPV vaccine

Secondary: Global summary of safety from D1 to D15 after any vaccination (3 doses of 9vHPV or qHPV)

Secondary: Global summary of safety from D1 to D15 after any vaccination (3 doses of 9vHPV or qHPV)

Secondary: Percentage of subjects reporting ISRs from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)

Secondary: Percentage of subjects reporting ISRs from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)

Secondary: Percentage of subjects reporting oral temperature [37.8°C-38.9°C[ or [38.9°C-39.9°C[ from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)

Secondary: Percentage of subjects reporting oral temperature [37.8°C-38.9°C[ or [38.9°C-39.9°C[ from D1 to D5 after any vaccination (3 doses of 9vHPV or qHPV)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Latvia
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