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Clinical Trial Results:
An Investigational Vaccine in Reducing the Incidence of Anogenital Warts in Young Men

Summary
EudraCT number	2004-002945-10
Trial protocol	FI SE DE ES Outside EU/EEA
Global end of trial date	03 Apr 2017

Results information
Results version number	v1(current)
This version publication date	08 Apr 2018
First version publication date	08 Apr 2018
Other versions

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

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Trial information

Sponsor protocol code

V501-020

ISRCTN number

-

US NCT number

NCT00090285

WHO universal trial number (UTN)

-

Sponsor organisation name

Merck Sharp & Dohme Corp.

Sponsor organisation address

2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033

Public contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

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

No

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

No

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

Yes

Analysis stage

Final

Date of interim/final analysis

03 Apr 2017

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

03 Apr 2017

Was the trial ended prematurely?

No

Main objective of the trial

This study was conducted to demonstrate that Gardasil™ (qHPV vaccine) 1) is well tolerated in young men, 2) reduces incidence of external genital lesions in young men, 3) reduces the incidence of anal intraepithelial neoplasia (AIN) or anal cancer in men having sex with men (MSM), and 4) reduces incidence of Human Papillomavirus (HPV) infection in young men. In the 7-month Base Study participants received randomly assigned qHPV vaccine or placebo at Day 1, Month 2, and Month 6. Base Study follow-up continued through Month 36. In Extension 1 (EXT1), participants who received placebo or an incomplete qHPV vaccine regimen in the Base Study were offered qHPV vaccine. Participants were followed in EXT1 for 7 months. In Extension 2 [LTFU (EXT2)], long-term effectiveness, immunogenicity, and safety of qHPV vaccine were followed up to 10 years following study enrollment. Participants who received ≥1 dose of qHPV vaccine in the Base Study or EXT1 were eligible to enroll in LTFU (EXT2).

Protection of trial subjects

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

03 Sep 2004

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 1048

Country: Number of subjects enrolled

Finland: 90

Country: Number of subjects enrolled

Netherlands: 41

Country: Number of subjects enrolled

Portugal: 90

Country: Number of subjects enrolled

Brazil: 402

Country: Number of subjects enrolled

Peru: 450

Country: Number of subjects enrolled

Mexico: 573

Country: Number of subjects enrolled

Canada: 47

Country: Number of subjects enrolled

Taiwan: 221

Country: Number of subjects enrolled

Costa Rica: 150

Country: Number of subjects enrolled

Norway: 100

Country: Number of subjects enrolled

Philippines: 51

Country: Number of subjects enrolled

South Africa: 538

Country: Number of subjects enrolled

Sweden: 53

Country: Number of subjects enrolled

Spain: 12

Country: Number of subjects enrolled

Australia: 89

Country: Number of subjects enrolled

Croatia: 11

Country: Number of subjects enrolled

Germany: 99

Worldwide total number of subjects

4065

EEA total number of subjects

496

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

187

Adults (18-64 years)

3878

From 65 to 84 years

0

85 years and over

0

Subject disposition

Recruitment details

A total of 4164 participants were screened and 4065 were randomized.

Screening details

Participants were healthy males between the ages of 16 years and 26 years + 364 days.

Period 1 title

Base Study Vaccination Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

qHPV Vaccine in Base Study

Arm description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6.

Arm type

Experimental

Investigational medicinal product name

qHPV vaccine, quadrivalent human papillomavirus vaccine

Investigational medicinal product code

Other name

(Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

Placebo in Base Study

Arm description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

Number of subjects in period 1	qHPV Vaccine in Base Study	Placebo in Base Study
Started	2032	2033
Vaccinated	2025	2030
Completed	1818	1814
Not completed	214	219
Protocol deviation	2	3
Randomized not treated	7	3
Moved	20	21
Adverse event	2	4
Participant incarcerated	2	2
Site terminated	1	-
HIV positive	1	1
Consent withdrawn by subject	64	69
Unspecified	2	2
Uncooperative	2	2
Lost to follow-up	111	112

Period 2 title

Base Study Follow-up Period

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

qHPV Vaccine in Base Study

Arm description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6. Follow-up for the Base Study encompassed Month 7 through Month 36. No vaccinations were administered during the follow-up.

Arm type

Experimental

Investigational medicinal product name

qHPV vaccine, quadrivalent human papillomavirus vaccine

Investigational medicinal product code

Other name

(Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

Placebo in Base Study

Arm description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6. Follow-up for the Base Study encompassed Month 7 through Month 36. No vaccinations were administered during the follow-up.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

Number of subjects in period 2	qHPV Vaccine in Base Study	Placebo in Base Study
Started	1818	1814
Completed	1487	1479
Not completed	335	342
Protocol deviation	1	-
Moved	41	36
Adverse event	3	10
Participant incarcerated	-	2
Consent withdrawn by subject	53	64
Unspecified	2	-
Uncooperative	3	4
Lost to follow-up	232	226
Joined	4	7
Did not complete qHPV regimen in Base Study	4	7

Period 3 title

Extension 1 (EXT1)

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

No

EXT1: Placebo in Base Study

Arm description

Participants in the placebo arm in the Base Study were offered 3 doses of open-label qHPV vaccine at EXT1 Day 1, Month 2, and Month 6. Participants were followed to EXT1 Month 7.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

Investigational medicinal product name

qHPV vaccine, quadrivalent human papillomavirus vaccine

Investigational medicinal product code

Other name

(Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in EXT1.

EXT1: Incomplete qHPV Regimen in Base Study

Arm description

Participants who received who received only 1 dose of qHPV vaccine in the Base Study were offered a complete 3-dose open-label qHPV vaccine regimen (administered at EXT1 Day 1, Month 2, and Month 6). Participants who received only 2 doses of qHPV vaccine in the Base Study were offered a single additional open-label dose of qHPV vaccine (administered at EXT1 Day 1). Participants were followed to EXT1 Month 7.

Arm type

Experimental

Investigational medicinal product name

qHPV vaccine, quadrivalent human papillomavirus vaccine

Investigational medicinal product code

Other name

(Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle, a full 3-dose regimen or 2 doses at Day 1, Month 2, and Month 6 in EXT1.

Investigational medicinal product name

qHPV vaccine, quadrivalent human papillomavirus vaccine

Investigational medicinal product code

Other name

(Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle, 1 or 2 doses in the Base Study.

Number of subjects in period 3	EXT1: Placebo in Base Study	EXT1: Incomplete qHPV Regimen in Base Study
Started	1098	16
Completed	1041	15
Not completed	57	1
Moved	3	-
Adverse event	2	-
Unspecified	4	-
Consent withdrawn by subject	13	1
Lost to follow-up	35	-

Period 4 title

Long-term Follow-up (EXT2)

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

No

LTFU (EXT2): Early Vaccination Group

Arm description

Participants received ≥1 dose of qHPV vaccine in Base Study and were followed up to a total of 10 years after their first dose of qHPV vaccine. No vaccinations were administered during LTFU (EXT2).

Arm type

Experimental

Investigational medicinal product name

qHPV vaccine, quadrivalent human papillomavirus vaccine

Investigational medicinal product code

Other name

(Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

LTFU (EXT2): Catch-up Vaccination Group

Arm description

Participants received placebo in Base Study and qHPV vaccine in EXT1 and were followed up to a total of 7 years after their first dose of qHPV vaccine. No vaccinations were administered during LTFU (EXT2).

Arm type

Experimental

Investigational medicinal product name

qHPV vaccine, quadrivalent human papillomavirus vaccine

Investigational medicinal product code

Other name

(Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle in EXT1.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

Number of subjects in period 4	LTFU (EXT2): Early Vaccination Group	LTFU (EXT2): Catch-up Vaccination Group
Started	936	867
Completed	709	664
Not completed	227	203
Physician decision	6	5
Adverse event	5	2
Consent withdrawn by subject	60	53
Lost to follow-up	156	143

Baseline characteristics

Reporting group title

qHPV Vaccine in Base Study

Reporting group description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6.

Reporting group title

Placebo in Base Study

Reporting group description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6.

Reporting group values	qHPV Vaccine in Base Study	Placebo in Base Study	Total
Number of subjects	2032	2033	4065
Age Categorical
Units: Subjects
Adolescents (12-17 years)	89	98	187
Adults (18-64 years)	1943	1935	3878
Age Continuous
Units: years
arithmetic mean (standard deviation)	20.6 ± 2.0	20.5 ± 2.0	-
Gender Categorical
Units: Subjects
Female	0	0	0
Male	2032	2033	4065
Race/Ethnicity
Units: Subjects
Asian	201	205	406
Black	405	400	805
Hispanic American	412	423	835
Native American	1	2	3
White	719	712	1431
Multi-racial	291	283	574
Indian (subcontinent)	1	8	9
Polynesian	2	0	2
Age
Units: Years
median (full range (min-max))	20 (16 to 26)	20 (15 to 27)	-

End points

Reporting group title

qHPV Vaccine in Base Study

Reporting group description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6.

Reporting group title

Placebo in Base Study

Reporting group description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6.

Reporting group title

qHPV Vaccine in Base Study

Reporting group description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6. Follow-up for the Base Study encompassed Month 7 through Month 36. No vaccinations were administered during the follow-up.

Reporting group title

Placebo in Base Study

Reporting group description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6. Follow-up for the Base Study encompassed Month 7 through Month 36. No vaccinations were administered during the follow-up.

Reporting group title

EXT1: Placebo in Base Study

Reporting group description

Participants in the placebo arm in the Base Study were offered 3 doses of open-label qHPV vaccine at EXT1 Day 1, Month 2, and Month 6. Participants were followed to EXT1 Month 7.

Reporting group title

EXT1: Incomplete qHPV Regimen in Base Study

Reporting group description

Participants who received who received only 1 dose of qHPV vaccine in the Base Study were offered a complete 3-dose open-label qHPV vaccine regimen (administered at EXT1 Day 1, Month 2, and Month 6). Participants who received only 2 doses of qHPV vaccine in the Base Study were offered a single additional open-label dose of qHPV vaccine (administered at EXT1 Day 1). Participants were followed to EXT1 Month 7.

Reporting group title

LTFU (EXT2): Early Vaccination Group

Reporting group description

Participants received ≥1 dose of qHPV vaccine in Base Study and were followed up to a total of 10 years after their first dose of qHPV vaccine. No vaccinations were administered during LTFU (EXT2).

Reporting group title

LTFU (EXT2): Catch-up Vaccination Group

Reporting group description

Participants received placebo in Base Study and qHPV vaccine in EXT1 and were followed up to a total of 7 years after their first dose of qHPV vaccine. No vaccinations were administered during LTFU (EXT2).

Subject analysis set title

MSM qHPV Vaccine in Base Study

Subject analysis set type

Per protocol

Subject analysis set description

The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6. This per protocol population includes MSM participants who received ≥1 dose of qHPV in Base Study.

Primary: Base Study: Incidence of Human Papillomavirus (HPV) Type 6/11/16/18-related External Genital Warts, Penile/Perianal/Perineal Intraepithelial Neoplasia (PIN), Penile, Perianal or Perineal Cancer

End point title

Base Study: Incidence of Human Papillomavirus (HPV) Type 6/11/16/18-related External Genital Warts, Penile/Perianal/Perineal Intraepithelial Neoplasia (PIN), Penile, Perianal or Perineal Cancer

End point description

Participants with HPV 6/11/16/18-related external genital warts, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal or perineal cancer per 100 person-years of follow-up was assessed. Per-protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by Competitive Luminex Immunoassay, cLIA) at Day 1 and polymerase chain reaction (PCR) negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7.

End point type

Primary

End point timeframe

Base study: through Month 36

End point values	qHPV Vaccine in Base Study	Placebo in Base Study
Number of subjects analysed	1394	1404
Units: Incidence per 100 person-years
number (not applicable)	0.1	1.0

Percent Relative Risk Reduction

Comparison groups

Placebo in Base Study v qHPV Vaccine in Base Study

Number of subjects included in analysis

2798

Analysis specification

Pre-specified

Analysis type

other ^[1]

Method

Parameter type

Risk difference (RD)

Point estimate

90.6

Confidence interval

level

95%

sides

2-sided

lower limit

70.1

upper limit

98.2

Notes
[1] - Confidence Interval (CI) based on binomial tail probabilities and not from a dispersion parameter.

Primary: Base Study: Number of Participants with Severe Injection Site Adverse Experiences (AEs)

End point title

Base Study: Number of Participants with Severe Injection Site Adverse Experiences (AEs) ^[2]

End point description

An adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR'S product, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the SPONSOR'S product, is also an adverse experience. A severe AE is incapacitating with inability to work or do usual activities. The analysis population included all vaccinated participants excluding 6 participants who received non-compliant mixed regimens of qHPV vaccine and placebo.

End point type

Primary

End point timeframe

Base study: through Day 5 after any vaccination

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No between-group statistical analyses were planned or conducted for this endpoint.

End point values	qHPV Vaccine in Base Study	Placebo in Base Study
Number of subjects analysed	2020	2029
Units: Participants	25	20

No statistical analyses for this end point

Primary: Base Study: Number of Participants with Vaccine-Related Serious Adverse Events (SAEs)

End point title

Base Study: Number of Participants with Vaccine-Related Serious Adverse Events (SAEs) ^[3]

End point description

A serious adverse event is an AE that 1) results in death, 2) is life threatening, 3) results in persistent or significant disability or incapacity, 4) results in or prolongs an existing hospitalization, 5) is a congenital anomaly or birth defect, 6) is a cancer, 7) is an overdose, or 8) based on appropriate medical judgment may jeopardize the participant and may require medical or surgical intervention. A vaccine-related AE is one deemed to be possibly, probably or definitely related to study vaccine by the investigator. The analysis population included all vaccinated participants excluding 6 participants who received non-compliant mixed regimens of qHPV vaccine and placebo.

End point type

Primary

End point timeframe

Base study: through Month 36

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No between-group statistical analyses were planned or conducted for this endpoint.

End point values	qHPV Vaccine in Base Study	Placebo in Base Study
Number of subjects analysed	2020	2029
Units: Participants	0	0

No statistical analyses for this end point

Primary: Overall Study: Incidence of HPV Type 6/11-related Genital Warts

End point title

Overall Study: Incidence of HPV Type 6/11-related Genital Warts ^[4] ^[5]

End point description

Incidence of HPV Type 6/11-related genital warts is expressed as events per 10,000 person-years of follow-up. Per protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with the evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7. This endpoint applied only to participants in the Base Study qHPV vaccine group.

End point type

Primary

End point timeframe

Up to 10 years after the first dose of qHPV vaccine

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No between-group statistical analyses were planned or conducted for this endpoint.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint applied only to participants in the Base Study qHPV vaccine group.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	1243
Units: Incidence per 10,000 person-years
number (confidence interval 95%)	4.3 (0.9 to 12.5)

No statistical analyses for this end point

Primary: Overall Study: Incidence of HPV Type 6/11/16/18-related External Genital Warts, PIN, Penile, Perianal or Perineal Cancer

End point title

Overall Study: Incidence of HPV Type 6/11/16/18-related External Genital Warts, PIN, Penile, Perianal or Perineal Cancer ^[6] ^[7]

End point description

Incidence of HPV Type 6/11/16/18-related external genital warts, PIN, penile, perianal or perineal cancer is expressed as events per 10,000 person-years of follow-up. Per protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with the evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7. This endpoint applied only to participants in the Base Study qHPV vaccine group.

End point type

Primary

End point timeframe

Up to 10 years after the first dose of qHPV vaccine

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No between-group statistical analyses were planned or conducted for this endpoint.
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint applied only to participants in the Base Study qHPV vaccine group.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	1395
Units: Incidence per 10,000 person-years
number (confidence interval 95%)	3.8 (0.8 to 11.1)

No statistical analyses for this end point

Primary: Overall Study: Incidence of HPV Type 6/11/16/18-related Anal Intraepithelial Neoplasia (AIN) and Anal Cancer

End point title

Overall Study: Incidence of HPV Type 6/11/16/18-related Anal Intraepithelial Neoplasia (AIN) and Anal Cancer ^[8]

End point description

Incidence of HPV Type 6/11/16/18-related AIN and anal cancer is expressed as events per 10,000 person-years of follow-up. Per protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with the evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7. This endpoint applied only to MSM participants in the Base Study qHPV vaccine group.

End point type

Primary

End point timeframe

Up to 10 years after the first dose of qHPV vaccine

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: This endpoint applied only to MSM participants in the Base Study qHPV vaccine group.

End point values	MSM qHPV Vaccine in Base Study
Number of subjects analysed	194
Units: Incidence per 10,000 person-years
number (confidence interval 95%)	69.3 (25.4 to 150.8)

No statistical analyses for this end point

Primary: LTFU (EXT2): Number of Participants with Vaccine-Related SAEs

End point title

LTFU (EXT2): Number of Participants with Vaccine-Related SAEs ^[9]

End point description

An SAE is an AE that 1) results in death, 2) is life threatening, 3) results in persistent or significant disability or incapacity, 4) results in or prolongs an existing hospitalization, 5) is a congenital anomaly or birth defect, 6) is a cancer, 7) is an overdose, or 8) based on appropriate medical judgment may jeopardize the participant and may require medical or surgical intervention. A vaccine-related AE is one deemed to be possibly, probably or definitely related to study vaccine by the investigator. The population analyzed was all randomized participants receiving at least 1 dose of qHPV vaccine in the Base Study or EXT1 and enrolled in LTFU (EXT2).

End point type

Primary

End point timeframe

qHPV Vaccine in Base Study: up to 12 years after last dose of qHPV vaccine; Placebo in Base Study: up to 7 years after last dose of qHPV vaccine

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The population analyzed included only participants who enrolled in LTFU (EXT2).

End point values	qHPV Vaccine in Base Study	Placebo in Base Study
Number of subjects analysed	936	867
Units: Participants	0	0

No statistical analyses for this end point

Primary: LTFU (EXT2): Number of Participants who Died

End point title

LTFU (EXT2): Number of Participants who Died ^[10]

End point description

The number of participants who died was assessed. The population analyzed was all randomized participants receiving at least 1 dose of qHPV vaccine in the Base Study or EXT1 and enrolled in LTFU (EXT2).

End point type

Primary

End point timeframe

qHPV Vaccine in Base Study: up to 12 years after last dose of qHPV vaccine; Placebo in Base Study: up to 7 years after last dose of qHPV vaccine

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The population analyzed included only participants who enrolled in LTFU (EXT2).

End point values	qHPV Vaccine in Base Study	Placebo in Base Study
Number of subjects analysed	936	867
Units: Participants	5	2

No statistical analyses for this end point

Secondary: Base Study: Incidence of HPV Type 6/11/16/18-related Persistent Infection

End point title

Base Study: Incidence of HPV Type 6/11/16/18-related Persistent Infection

End point description

Participants with HPV Type 6/11/16/18-related persistent infection per 100 person-years of follow-up was assessed. Per-protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7.

End point type

Secondary

End point timeframe

Base study: through Month 36

End point values	qHPV Vaccine in Base Study	Placebo in Base Study
Number of subjects analysed	1390	1402
Units: Infection per 100 person-years
number (not applicable)	0.7	4.8

Percent Relative Risk Reduction

Comparison groups

qHPV Vaccine in Base Study v Placebo in Base Study

Number of subjects included in analysis

2792

Analysis specification

Pre-specified

Analysis type

other ^[11]

Method

Parameter type

Risk difference (RD)

Point estimate

85.5

Confidence interval

level

95%

sides

2-sided

lower limit

77

upper limit

91.3

Notes
[11] - Confidence interval based on binomial tail probabilities and not from a dispersion parameter. Hochberg multiplicity adjustment applied to the CI.

Secondary: Base Study: Incidence of HPV 6/11/16/18-related Deoxyribonucleic Acid (DNA) Detection

End point title

Base Study: Incidence of HPV 6/11/16/18-related Deoxyribonucleic Acid (DNA) Detection

End point description

Participants with HPV 6/11/16/18-related DNA detection per 100 person-years of follow-up was assessed. Per protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with the evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7.

End point type

Secondary

End point timeframe

Base study: through Month 36

End point values	qHPV Vaccine in Base Study	Placebo in Base Study
Number of subjects analysed	1390	1402
Units: Detection per 100 person-years
number (not applicable)	5.3	10.7

Percent Relative Risk Reduction

Comparison groups

qHPV Vaccine in Base Study v Placebo in Base Study

Number of subjects included in analysis

2792

Analysis specification

Pre-specified

Analysis type

other ^[12]

Method

Parameter type

Risk difference (RD)

Point estimate

51

Confidence interval

level

95%

sides

2-sided

lower limit

40.3

upper limit

59.9

Notes
[12] - Confidence interval based on binomial tail probabilities and not from a dispersion parameter. Hochberg multiplicity adjustment applied to the CI.

Secondary: Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 7 Assessed by cLIA

End point title

Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 7 Assessed by cLIA ^[13]

End point description

Antibodies to HPV types were measured using cLIA. Antibody titers were expressed as cLIA milli Merck units/mL (cLIA mMU/mL). The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point type

Secondary

End point timeframe

Month 7

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	2025
Units: cLIA mMU/mL
number (confidence interval 95%)
HPV Type 6 (n=1090)	447.7 (415.9 to 481.9)
HPV Type 11 (n=1090)	624.4 (588.4 to 662.6)
HPV Type 16 (n=1133)	2406.1 (2245.0 to 2578.8)
HPV Type 18 (n=1173)	402.8 (373.9 to 433.9)

No statistical analyses for this end point

Secondary: Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 36 Assessed by cLIA

End point title

Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 36 Assessed by cLIA ^[14]

End point description

Antibodies to HPV types were measured using cLIA. Antibody titers were expressed as cLIA milli Merck units/mL (cLIA mMU/mL). The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point type

Secondary

End point timeframe

Month 36

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	2025
Units: cLIA mMU/mL
number (confidence interval 95%)
HPV Type 6 (n=845)	71.5 (66.7 to 76.7)
HPV Type 11 (n=845)	82.5 (77.0 to 88.5)
HPV Type 16 (n=875)	293.6 (271.6 to 317.4)
HPV Type 18 (n=904)	33.2 (30.2 to 36.4)

No statistical analyses for this end point

Secondary: Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 72 Assessed by cLIA

End point title

Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 72 Assessed by cLIA ^[15]

End point description

Antibodies to HPV types were measured using cLIA. Antibody titers were expressed as cLIA milli Merck units/mL (cLIA mMU/mL). The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point type

Secondary

End point timeframe

Month 72 [first sample in LTFU (EXT2) ranged from Month 48 to 84 with a median of Month 72]

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	2025
Units: cLIA mMU/mL
number (confidence interval 95%)
HPV Type 6 (n=575)	57.2 (52.3 to 62.5)
HPV Type 11 (n=575)	62.1 (56.7 to 68.1)
HPV Type 16 (n=609)	249.4 (225.6 to 275.8)
HPV Type 18 (n=633)	25.9 (23.2 to 28.9)

No statistical analyses for this end point

Secondary: Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 120 Assessed by cLIA

End point title

Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 120 Assessed by cLIA ^[16]

End point description

Antibodies to HPV types were measured using cLIA. Antibody titers were expressed as cLIA milli Merck units/mL (cLIA mMU/mL). The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point type

Secondary

End point timeframe

Month 120

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	2025
Units: cLIA mMU/mL
geometric mean (confidence interval 95%)
HPV Type 6 (n=374)	49.4 (44.1 to 55.4)
HPV Type 11 (n=374)	38.7 (34.5 to 43.5)
HPV Type 16 (n=393)	182.9 (161.4 to 207.3)
HPV Type 18 (n=408)	17.6 (15.5 to 19.9)

No statistical analyses for this end point

Secondary: Percentage of Participants Seropositive for HPV Type 6, 11, 16, and 18 at Month 7 Assessed by cLIA

End point title

Percentage of Participants Seropositive for HPV Type 6, 11, 16, and 18 at Month 7 Assessed by cLIA ^[17]

End point description

Antibodies to HPV types were measured using cLIA. Thresholds for seropositive were ≥20, 16, 20, and 24 cLIA mMU/mL for HPV Types 6, 11, 16, and 18, respectively. The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point type

Secondary

End point timeframe

Month 7

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	2025
Units: Percentage of participants
number (confidence interval 95%)
HPV Type 6 (n=1090)	98.9 (98.1 to 99.4)
HPV Type 11 (n=1090)	99.2 (98.4 to 99.6)
HPV Type 16 (n=1133)	98.8 (97.9 to 99.3)
HPV Type 18 (n=1173)	97.4 (96.3 to 98.2)

No statistical analyses for this end point

Secondary: Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 36 Assessed by cLIA

End point title

Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 36 Assessed by cLIA ^[18]

End point description

Antibodies to HPV types were measured using cLIA. Thresholds for seropositive were ≥20, 16, 20, and 24 cLIA mMU/mL for HPV Types 6, 11, 16, and 18, respectively. The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point type

Secondary

End point timeframe

Month 36

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	2025
Units: Percentage of participants
number (confidence interval 95%)
HPV Type 6 (n=845)	88.9 (86.6 to 90.9)
HPV Type 11 (n=845)	94.0 (92.1 to 95.5)
HPV Type 16 (n=875)	97.9 (96.8 to 98.8)
HPV Type 18 (n=904)	57.1 (53.8 to 60.3)

No statistical analyses for this end point

Secondary: Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 72 Assessed by cLIA

End point title

Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 72 Assessed by cLIA ^[19]

End point description

Antibodies to HPV types were measured using cLIA. Thresholds for seropositive were ≥20, 16, 20, and 24 cLIA mMU/mL for HPV Types 6, 11, 16, and 18, respectively. The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point type

Secondary

End point timeframe

Month 72 [first sample in LTFU (EXT2) ranged from Month 48 to 84 with a median of Month 72]

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	2025
Units: Percentage of participants
number (confidence interval 95%)
HPV Type 6 (n=575)	84.3 (81.1 to 87.2)
HPV Type 11 (n=575)	88.0 (85.1 to 90.5)
HPV Type 16 (n=609)	97.0 (95.4 to 98.2)
HPV Type 18 (n=633)	49.6 (45.6 to 53.6)

No statistical analyses for this end point

Secondary: Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 120 Assessed by cLIA

End point title

Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 120 Assessed by cLIA ^[20]

End point description

Antibodies to HPV types were measured using cLIA. Thresholds for seropositive were ≥20, 16, 20, and 24 cLIA mMU/mL for HPV Types 6, 11, 16, and 18, respectively. The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point type

Secondary

End point timeframe

Month 120

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	2025
Units: Percentage of participants
number (confidence interval 95%)
HPV Type 6 (n=374)	79.1 (74.7 to 83.2)
HPV Type 11 (n=374)	79.9 (75.5 to 83.9)
HPV Type 16 (n=393)	94.9 (92.2 to 96.9)
HPV Type 18 (n=408)	40.2 (35.4 to 45.1)

No statistical analyses for this end point

Secondary: Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 120 Assessed by Immunoglobulin G Luminex Immunoassay (IgG LIA)

End point title

Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 120 Assessed by Immunoglobulin G Luminex Immunoassay (IgG LIA) ^[21]

End point description

Antibodies to HPV types were measured using Luminex immunoassay (IgG-LIA). The unit of measure for this assay is IgG LIA mMU/mL; this unit cannot be directly compared with the cLIA mMU/mL unit reported for the cLIA results. The per-protocol population included all participants who 1) were seronegative at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point type

Secondary

End point timeframe

Month 120

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	2025
Units: IgG LIA mMU/mL
geometric mean (confidence interval 95%)
HPV Type 6 (n=278)	38.8 (34.0 to 44.2)
HPV Type 11 (n=274)	31.0 (27.2 to 35.3)
HPV Type 16 (n=291)	162.0 (141.2 to 185.7)
HPV Type 18 (n=305)	19.7 (17.0 to 22.9)

No statistical analyses for this end point

Secondary: Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 120 Assessed by IgG LIA

End point title

Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 120 Assessed by IgG LIA ^[22]

End point description

Antibodies to HPV types were measured using IgG LIA. Thresholds for seropositive were ≥9, 6, 5, and 5 IgG LIA mMU/mL for HPV Types 6, 11, 16,and 18, respectively. The per-protocol population included all participants who 1) were seronegative at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point type

Secondary

End point timeframe

Month 120

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.

End point values	qHPV Vaccine in Base Study
Number of subjects analysed	2025
Units: Percentage of participants
number (confidence interval 95%)
HPV Type 6 (n=278)	91.7 (87.8 to 94.7)
HPV Type 11 (n=274)	92.0 (88.1 to 94.9)
HPV Type 16 (n=291)	99.7 (98.1 to 100)
HPV Type 18 (n=305)	92.1 (88.5 to 94.9)

No statistical analyses for this end point

Other pre-specified: Base Study: Sub-study to Evaluate the Incidence of HPV Type 6/11/16/18-related Anal Intraepithelial Neoplasia (AIN) and Anal Cancer in Men Having Sex with Men (MSM)

End point title

Base Study: Sub-study to Evaluate the Incidence of HPV Type 6/11/16/18-related Anal Intraepithelial Neoplasia (AIN) and Anal Cancer in Men Having Sex with Men (MSM)

End point description

Participants with HPV 6/11/16/18-related AIN or anal cancer per 100 person-years of follow-up was assessed. Only a subset of the enrolled population was used for the analysis of this sub-study. Per protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7.

End point type

Other pre-specified

End point timeframe

Base study: through Month 36

End point values	qHPV Vaccine in Base Study	Placebo in Base Study
Number of subjects analysed	194	208
Units: Incidence per 100 person-years
number (not applicable)	1.3	5.8

Percent Relative Risk Reduction

Comparison groups

qHPV Vaccine in Base Study v Placebo in Base Study

Number of subjects included in analysis

402

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Risk difference (RD)

Point estimate

77.5

Confidence interval

level

95%

sides

2-sided

lower limit

39.6

upper limit

93.3

Adverse events

Timeframe for reporting adverse events

Base study: all AEs through Month 36 of Base Study. EXT1: SAEs through Month 7 of EXT1. LTFU (EXT2): SAEs and deaths through 7 years of LTFU (EXT2). Non-serious AEs were not solicited during EXT1 or LTFU (EXT2).

Adverse event reporting additional description

Analysis population: Base Study: all participants vaccinated in Base Study excluding 6 participants who received non-compliant mixed regimens of qHPV vaccine and placebo; EXT1: all participants who received qHPV vaccine in EXT1 and had follow-up data; LTFU (EXT2): all participants enrolled in LTFU (EXT2).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

qHPV Vaccine in Base Study

Reporting group description

The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6.

Reporting group title

Placebo in Base Study

Reporting group description

The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6.

Reporting group title

qHPV Vaccine in EXT1

Reporting group description

Participants who received placebo and participants who received only 1 dose of qHPV vaccine in the Base Study were offered a complete 3-dose qHPV vaccine regimen (administered at EXT1 Day 1, Month 2 and Month 6). Participants who received only 2 doses of qHPV vaccine in the base Study were offered a single additional dose of qHPV vaccine (administered at EXT1 Day 1).

Reporting group title

LTFU (EXT2)

Reporting group description

Participants received ≥1 dose of qHPV vaccine in Base Study, or received placebo in Base Study and qHPV vaccine in EXT1.

Serious adverse events	qHPV Vaccine in Base Study	Placebo in Base Study	qHPV Vaccine in EXT1	LTFU (EXT2)
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 2020 (0.40%)	11 / 2029 (0.54%)	3 / 1084 (0.28%)	7 / 1803 (0.39%)
number of deaths (all causes)	3	10	2	7
number of deaths resulting from adverse events	0	0	0	0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 2020 (0.00%)	1 / 2029 (0.05%)	1 / 1084 (0.09%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	1 / 2020 (0.05%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Chemical poisoning
subjects affected / exposed	0 / 2020 (0.00%)	1 / 2029 (0.05%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 2020 (0.00%)	1 / 2029 (0.05%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gun shot wound
subjects affected / exposed	1 / 2020 (0.05%)	3 / 2029 (0.15%)	1 / 1084 (0.09%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 3	0 / 1	0 / 1
Head injury
subjects affected / exposed	0 / 2020 (0.00%)	1 / 2029 (0.05%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Multiple drug overdose
subjects affected / exposed	0 / 2020 (0.00%)	1 / 2029 (0.05%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	1 / 2020 (0.05%)	1 / 2029 (0.05%)	0 / 1084 (0.00%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
Traumatic brain injury
subjects affected / exposed	1 / 2020 (0.05%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	1 / 2020 (0.05%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Blast injury
subjects affected / exposed	0 / 2020 (0.00%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Burns second degree
subjects affected / exposed	0 / 2020 (0.00%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Craniocerebral injury
subjects affected / exposed	0 / 2020 (0.00%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Subarachnoid haemorrhage
subjects affected / exposed	0 / 2020 (0.00%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroma
subjects affected / exposed	0 / 2020 (0.00%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cardiac disorders
Cardiac arrest
subjects affected / exposed	1 / 2020 (0.05%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 2020 (0.00%)	1 / 2029 (0.05%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pericardial haemorrhage
subjects affected / exposed	0 / 2020 (0.00%)	1 / 2029 (0.05%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 2020 (0.00%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 2020 (0.05%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Convulsion
subjects affected / exposed	1 / 2020 (0.05%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 2020 (0.00%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	1 / 2020 (0.05%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Completed suicide
subjects affected / exposed	0 / 2020 (0.00%)	2 / 2029 (0.10%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
Metabolism and nutrition disorders
Metabolic acidosis
subjects affected / exposed	0 / 2020 (0.00%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 2020 (0.05%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 2020 (0.05%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
subjects affected / exposed	1 / 2020 (0.05%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 2020 (0.00%)	0 / 2029 (0.00%)	1 / 1084 (0.09%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
HIV infection
subjects affected / exposed	0 / 2020 (0.00%)	0 / 2029 (0.00%)	0 / 1084 (0.00%)	1 / 1803 (0.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1

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

Non-serious adverse events	qHPV Vaccine in Base Study	Placebo in Base Study	qHPV Vaccine in EXT1	LTFU (EXT2)
Total subjects affected by non serious adverse events
subjects affected / exposed	1277 / 2020 (63.22%)	1183 / 2029 (58.30%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	38 / 2020 (1.88%)	37 / 2029 (1.82%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	38	37	0	0
Nervous system disorders
Headache
subjects affected / exposed	179 / 2020 (8.86%)	207 / 2029 (10.20%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	222	275	0	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	118 / 2020 (5.84%)	125 / 2029 (6.16%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	131	149	0	0
Injection-site erythema
subjects affected / exposed	304 / 2020 (15.05%)	275 / 2029 (13.55%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	446	384	0	0
Injection-site pain
subjects affected / exposed	1116 / 2020 (55.25%)	992 / 2029 (48.89%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	2087	1767	0	0
Injection-site pruritus
subjects affected / exposed	23 / 2020 (1.14%)	24 / 2029 (1.18%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	27	29	0	0
Injection-site swelling
subjects affected / exposed	219 / 2020 (10.84%)	187 / 2029 (9.22%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	318	270	0	0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	19 / 2020 (0.94%)	23 / 2029 (1.13%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	21	23	0	0
Diarrhoea
subjects affected / exposed	40 / 2020 (1.98%)	36 / 2029 (1.77%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	44	38	0	0
Nausea
subjects affected / exposed	27 / 2020 (1.34%)	16 / 2029 (0.79%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	30	16	0	0
Infections and infestations
Influenza
subjects affected / exposed	42 / 2020 (2.08%)	44 / 2029 (2.17%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	43	47	0	0
Nasopharyngitis
subjects affected / exposed	44 / 2020 (2.18%)	50 / 2029 (2.46%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	46	59	0	0
Pharyngitis
subjects affected / exposed	22 / 2020 (1.09%)	20 / 2029 (0.99%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	23	21	0	0
Upper respiratory tract infection
subjects affected / exposed	27 / 2020 (1.34%)	20 / 2029 (0.99%)	0 / 1084 (0.00%)	0 / 1803 (0.00%)
occurrences all number	28	22	0	0

More information

Were there any global substantial amendments to the protocol? Yes

14 Jun 2005

Amendment 2: clarified terms for external genital endpoints, changed enrollment to 3700, added wording that participants who do not complete the 3-dose series will be allowed to continue in the study, clarified timing of retention contact visits, revised criteria for the clinical impression of external genital lesions, revised procedures for high-resolution anoscopy

13 Mar 2006

Amendment 3: changed enrollment to 3870, clarified that participants who test positive for HIV will not be discontinued, clarified wording as to management of lesions observed on Day 1 as to etiology, assumed vaccine efficacy for MSM endpoint changed to 85%.

21 May 2007

Amendment 4: adopted registered trademark name, GARDASIL™, updated planned enrollment numbers, clarified sexual history information, updated competitive Luminex immunoassay information, clarified or corrected details for sample handling, notifications, and other technical matters.

21 May 2009

Amendment 10: provided for the vaccination of placebo recipients, clarified the MSM sub-study endpoint, described the Type 1 Error adjustment for testing the MSM sub-study hypothesis, clarified the visit schedule to finalize efficacy phase, added and clarified criteria to unblind participants, added information on eligibility of participants to receive the vaccination series in the Study Vaccination Extension.

29 Mar 2010

Amendment 20: provided for long term evaluation of vaccine effectiveness in males, through active follow-up of study participants for up to 10 years from the day of enrollment into the Base Study.

01 Dec 2010

Amendment 21: clarified definitions of AE relationship to study vaccine, added or clarified details for sample collection and study visits.

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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