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Clinical Trial Results:
A Phase 1/2 randomized, observer-blinded, multi-country study to evaluate safety and immunogenicity of investigational adjuvanted human papillomavirus vaccine in females (16 to 26 years of age)

Summary
EudraCT number	2022-000090-15
Trial protocol	DE LT FR BG EE CZ PL
Global end of trial date	23 Feb 2024

Results information
Results version number	v2(current)
This version publication date	12 Apr 2025
First version publication date	28 Dec 2024
Other versions	v1
Version creation reason

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

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Trial information

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Sponsor protocol code

213749

ISRCTN number

US NCT number

NCT05496231

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

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

Public contact

GSK Response Center, GlaxoSmithKline, 44 8664357343, GSKClinicalSupportHD@gsk.com

Scientific contact

GSK Response Center, GlaxoSmithKline, 44 8664357343, GSKClinicalSupportHD@gsk.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

09 Jul 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Feb 2024

Was the trial ended prematurely?

Main objective of the trial

• To evaluate the safety and reactogenicity of GlaxoSmithKline Biologicals SA (GSK)’s investigational adjuvanted human papillomavirus (HPV) vaccine formulations. • To evaluate the immune response to GSK’s investigational adjuvanted HPV vaccine formulations.

Protection of trial subjects

All participants were observed for 60 minutes after vaccine administration with appropriate medical treatment readily available. Vaccines were administered by qualified and trained personnel. Vaccines were administered only to eligible participants that had no contraindications to any components of the vaccines. Participants were followed-up for at least 28 days (for unsolicited AEs) and throughout the entire study period (for SAEs and pIMDs) after administration of each dose of the vaccine. Study safety monitoring was performed. Unblinding strategy in case of emergency safety situations was in place. Study stopping rules would have been applied in case of significant safety concerns.

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Aug 2022

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 8

Country: Number of subjects enrolled

Czechia: 74

Country: Number of subjects enrolled

Estonia: 364

Country: Number of subjects enrolled

France: 97

Country: Number of subjects enrolled

Germany: 32

Country: Number of subjects enrolled

Lithuania: 137

Country: Number of subjects enrolled

Poland: 169

Country: Number of subjects enrolled

United States: 199

Worldwide total number of subjects

1080

EEA total number of subjects

881

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)

1046

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was organized into 2 steps. Step 1 sentinel participants received the initial assigned dose prior to participants in Step 2 of the study, and sentinel participants had an additional blood sampling visit at Day 7 to assess for biochemical and hematological parameters.

Screening details

A total of 1080 participants were enrolled into the study, of which 1079 participants received at least 1 dose of vaccine and were included in the Exposed Set.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Blinding implementation details

The study was conducted in an observer-blind manner.

Are arms mutually exclusive

Yes

HPV9 High Group

Arm description

Participants received 3 doses of the high formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Arm type

Experimental

Investigational medicinal product name

HPV9-High formulation

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses of the high formulation of HPV9 investigational adjuvanted vaccine were administered intramuscularly at Day 1, Month 2 and Month 6.

HPV9 Med Group

Arm description

Participants received 3 doses of the medium formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Arm type

Experimental

Investigational medicinal product name

HPV9-Medium formulation

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses of the medium formulation of HPV9 investigational adjuvanted vaccine were administered intramuscularly at Day 1, Month 2 and Month 6.

HPV9 Low Group

Arm description

Participants received 3 doses of the low formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Arm type

Experimental

Investigational medicinal product name

HPV9-Low formulation

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses of the low formulation of HPV9 investigational adjuvanted vaccine were administered intramuscularly at Day 1, Month 2 and Month 6.

Gar9 Group

Arm description

Participants received 3 doses of the marketed Human Papilloma Virus (HPV) vaccine (Gardasil 9) at Day 1, Month 2, and Month 6.

Arm type

Active comparator

Investigational medicinal product name

Gardasil 9

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

3 doses of the marketed HPV vaccine (Gardasil 9) were administered intramuscularly at Day 1, Month 2 and Month 6.

Number of subjects in period 1 ^[1]	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Started	270	270	269	270
Completed	239	246	244	238
Not completed	31	24	25	32
Migrated/moved from the study area	3	5	3	3
Consent withdrawn by subject	5	5	4	11
Adverse event, non-fatal	1	1	-	4
Not specified	9	7	7	8
Lost to follow-up	13	6	11	6

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: A total of 1080 participants were enrolled into the study, of which 1079 participants received at least 1 dose of vaccine and were included in the Exposed Set.

Baseline characteristics

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Reporting group title

HPV9 High Group

Reporting group description

Participants received 3 doses of the high formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Reporting group title

HPV9 Med Group

Reporting group description

Participants received 3 doses of the medium formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Reporting group title

HPV9 Low Group

Reporting group description

Participants received 3 doses of the low formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Reporting group title

Gar9 Group

Reporting group description

Participants received 3 doses of the marketed Human Papilloma Virus (HPV) vaccine (Gardasil 9) at Day 1, Month 2, and Month 6.

Reporting group values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group	Total
Number of subjects	270	270	269	270	1079
Age categorical
Units: Participants
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age Continuous
Units: Years
arithmetic mean (standard deviation)	22.0 ( 2.32 )	21.9 ( 2.56 )	22.1 ( 2.45 )	22.2 ( 2.25 )	-
Sex: Female, Male
Units: Participants
Female	270	270	269	270	1079
Male	0	0	0	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	25	25	27	26	103
Not Hispanic or Latino	245	245	242	244	976
Unknown or Not Reported	0	0	0	0	0

End points

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Reporting group title

HPV9 High Group

Reporting group description

Participants received 3 doses of the high formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Reporting group title

HPV9 Med Group

Reporting group description

Participants received 3 doses of the medium formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Reporting group title

HPV9 Low Group

Reporting group description

Participants received 3 doses of the low formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Reporting group title

Gar9 Group

Reporting group description

Participants received 3 doses of the marketed Human Papilloma Virus (HPV) vaccine (Gardasil 9) at Day 1, Month 2, and Month 6.

Primary: Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 1

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End point title

Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 1 ^[1]

End point description

Assessed solicited administration site events included pain, redness and swelling at injection site. Grade 3 pain = significant pain at rest, which prevented normal everyday activities. Grade 3 redness/swelling = redness/swelling with a surface diameter greater than (>) 50 millimeters (mm). Analysis was performed on the Exposed Set, which included all participants who received a study vaccine, had the electronic diary (eDiary) for solicited events completed after the administration of vaccine Dose 1 and for whom data were available during the specified period.

End point type

Primary

End point timeframe

Within 7 days after vaccine Dose 1 (administered at Day 1)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	270	270	269	270
Units: Participants
Grade 3 Pain (N=270;270;269;270)	11	12	6	2
Grade 3 Redness (N=270;270;269;270)	2	4	2	0
Grade 3 Swelling (N=270;270;269;270)	5	3	2	0

No statistical analyses for this end point

Primary: Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 2

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End point title

Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 2 ^[2]

End point description

Assessed solicited administration site events included pain, redness and swelling at injection site. Grade 3 pain = significant pain at rest, which prevented normal everyday activities. Grade 3 redness/swelling = redness/swelling with a surface diameter >50 mm. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine, had the eDiary for solicited events completed after the administration of vaccine Dose 2 and for whom data were available during the specified period.

End point type

Primary

End point timeframe

Within 7 days after vaccine Dose 2 (administered at Month 2)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	257	261	258	260
Units: Participants
Grade 3 Pain (N=257;261;258;260)	13	6	11	1
Grade 3 Redness (N=257;261;258;260)	4	0	2	1
Grade 3 Swelling (N=257;261;258;260)	5	3	2	3

No statistical analyses for this end point

Primary: Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 3

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End point title

Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 3 ^[3]

End point description

Assessed solicited administration site events included pain, redness and swelling at injection site. Grade 3 pain = significant pain at rest, which prevented normal everyday activities. Grade 3 redness/swelling = redness/swelling with a surface diameter >50 mm. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine, had the eDiary for solicited events completed after the administration of vaccine Dose 3 and for whom data were available during the specified period.

End point type

Primary

End point timeframe

Within 7 days after vaccine Dose 3 (administered at Month 6)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	244	247	244	236
Units: Participants
Grade 3 Pain (N=244;247;244;236)	9	3	6	1
Grade 3 Redness (N=244;247;244;236)	0	2	1	1
Grade 3 Swelling (N=244;247;244;236)	0	4	1	2

No statistical analyses for this end point

Primary: Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 1

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End point title

Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 1 ^[4]

End point description

Assessed solicited systemic events included fever, headache, myalgia, arthralgia and fatigue. Grade 3 fever = body temperature >39.0 degrees Celsius (°C) or 102.2 Fahrenheit (°F). The preferred location for measuring temperature was the axilla. Grade 3 headache, myalgia, arthralgia and fatigue = symptoms that prevented normal, every day activities. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine, had the eDiary for solicited events completed after the administration of vaccine Dose 1 and for whom data were available during the specified period.

End point type

Primary

End point timeframe

Within 7 days after vaccine Dose 1 (administered at Day 1)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	270	270	269	270
Units: Participants
Grade 3 Fever (N=270;270;269;270)	1	0	0	0
Grade 3 Headache (N=270;270;269;270)	11	3	6	3
Grade 3 Myalgia (N=270;270;269;270)	5	2	2	1
Grade 3 Arthralgia (N=270;270;269;270)	1	1	1	0
Grade 3 Fatigue (N=270;270;269;270)	12	9	7	5

No statistical analyses for this end point

Primary: Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 2

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End point title

Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 2 ^[5]

End point description

Assessed solicited systemic events included fever, headache, myalgia, arthralgia and fatigue. Grade 3 fever = body temperature >39.0°C or 102.2°F. The preferred location for measuring temperature was the axilla. Grade 3 headache, myalgia, arthralgia and fatigue = symptoms that prevented normal, every day activity. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine, had the eDiary for solicited events completed after the administration of vaccine Dose 2 and for whom data were available during the specified period.

End point type

Primary

End point timeframe

Within 7 days after vaccine Dose 2 (administered at Month 2)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	257	261	258	260
Units: Participants
Grade 3 Fever (N=257;261;258;260)	0	1	0	1
Grade 3 Headache (N=257;261;258;260)	7	7	8	5
Grade 3 Myalgia (N=257;261;258;260)	4	0	3	2
Grade 3 Arthralgia (N=257;261;258;260)	0	2	1	1
Grade 3 Fatigue (N=257;261;258;260)	12	11	12	11

No statistical analyses for this end point

Primary: Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 3

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End point title

Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 3 ^[6]

End point description

Assessed solicited systemic events included fever, headache, myalgia, arthralgia and fatigue. Grade 3 fever = body temperature >39.0°C or 102.2°F. The preferred location for measuring temperature was the axilla. Grade 3 headache, myalgia, arthralgia and fatigue = symptoms that prevented normal, every day activity. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine, had the eDiary for solicited events completed after the administration of vaccine Dose 3 and for whom data were available during the specified period.

End point type

Primary

End point timeframe

Within 7 days after vaccine Dose 3 (administered at Month 6)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	244	247	244	236
Units: Participants
Grade 3 Fever (N=244;247;244;236)	0	1	0	0
Grade 3 Headache (N=244;247;244;236)	10	4	9	7
Grade 3 Myalgia (N=244;247;244;236)	3	3	2	2
Grade 3 Arthralgia (N=244;247;244;236)	2	1	0	0
Grade 3 Fatigue (N=244;247;244;236)	15	8	11	6

No statistical analyses for this end point

Primary: Number of participants reporting Grade 3 unsolicited adverse events (AEs) after vaccine Dose 1

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End point title

Number of participants reporting Grade 3 unsolicited adverse events (AEs) after vaccine Dose 1 ^[7]

End point description

An unsolicited AE is defined as an AE that was not included in the list of solicited events using an eDiary and that was spontaneously communicated by a participant/participant's parent(s)/legally acceptable representative(s) [LAR(s)] who has signed the informed consent. Also, any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited AE. Grade 3 unsolicited AEs = an AE which prevented normal, everyday activities. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine and for whom data were available for the specified period after the administration of vaccine Dose 1.

End point type

Primary

End point timeframe

Within 28 days after vaccine Dose 1 (administered at Day 1)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	270	270	269	270
Units: Participants	0	1	0	1

No statistical analyses for this end point

Primary: Number of participants reporting Grade 3 unsolicited AEs after vaccine Dose 2

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End point title

Number of participants reporting Grade 3 unsolicited AEs after vaccine Dose 2 ^[8]

End point description

An unsolicited AE is defined as an AE that was not included in the list of solicited events using an eDiary and that was spontaneously communicated by a participant/participant's parent(s)/LAR(s) who has signed the informed consent. Also, any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited AE. Grade 3 unsolicited AEs = an AE which prevented normal, everyday activities. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine and for whom data were available for the specified period after the administration of vaccine Dose 2.

End point type

Primary

End point timeframe

Within 28 days after vaccine Dose 2 (administered at Month 2)

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	257	261	258	260
Units: Participants	4	1	3	3

No statistical analyses for this end point

Primary: Number of participants reporting Grade 3 unsolicited AEs after vaccine Dose 3

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End point title

Number of participants reporting Grade 3 unsolicited AEs after vaccine Dose 3 ^[9]

End point description

An unsolicited AE is defined as an AE that was not included in the list of solicited events using an eDiary and that was spontaneously communicated by a participant/ participant's parent(s)/LAR(s) who has signed the informed consent. Also, any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited AE. Grade 3 unsolicited AEs = an AE which prevented normal, everyday activities. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine and for whom data were available for the specified period after the administration of vaccine Dose 3.

End point type

Primary

End point timeframe

Within 28 days after vaccine Dose 3 (administered at Month 6)

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 analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	244	247	244	236
Units: Participants	0	0	1	2

No statistical analyses for this end point

Primary: Number of participants reporting serious adverse events (SAEs)

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End point title

Number of participants reporting serious adverse events (SAEs) ^[10]

End point description

An SAE is defined as any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect in the offspring of a study participant, or resulted in abnormal pregnancy outcomes, or in other situations that were considered serious per medical or scientific judgment. Analysis was performed on the Exposed Set, which included participants who received a study vaccine and for whom data were available for the specified period.

End point type

Primary

End point timeframe

From first vaccination (Day 1) to study end (Month 12)

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 analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	270	270	269	270
Units: Participants	1	4	2	7

No statistical analyses for this end point

Primary: Number of participants in Step 1 subset with clinically relevant biochemical abnormalities

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End point title

Number of participants in Step 1 subset with clinically relevant biochemical abnormalities ^[11]

End point description

As pre-specified in the protocol, the assessed biochemical parameters were blood urea nitrogen (BUN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Assessment of intensity: Grading of the biochemical parameters was based on the institutional normal reference ranges and derived from the standard Food and Drug Administration (FDA) Toxicity Grading Scale. Changes compared to normal reference ranges were graded as follows: Grade 0 = a non-missing parameter value for which grade could not be derived according to the grading scale and does not belong to Grade 1-4; Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life-Threatening. Unknown = parameter value missing for the specified parameter. Analysis was performed on the Step 1 subset from the Exposed Set, which included sentinel adult participants for whom blood samples were collected for the specified biochemical analyses at Day 7.

End point type

Primary

End point timeframe

At Day 7

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	12	12	12	12
Units: Participants
BUN, Grade 0 (N=12;12;12;12)	11	12	11	11
BUN, Grade 1 (N=12;12;12;12)	0	0	0	0
BUN, Grade 2 (N=12;12;12;12)	0	0	0	0
BUN, Grade 3 (N=12;12;12;12)	0	0	0	0
BUN, Grade 4 (N=12;12;12;12)	0	0	0	0
BUN, Unknown (N=12;12;12;12)	1	0	1	1
AST, Grade 0 (N=12;12;12;12)	11	12	11	12
AST, Grade 1 (N=12;12;12;12)	0	0	0	0
AST, Grade 2 (N=12;12;12;12)	0	0	0	0
AST, Grade 3 (N=12;12;12;12)	0	0	0	0
AST, Grade 4 (N=12;12;12;12)	0	0	0	0
AST, Unknown (N=12;12;12;12)	1	0	1	0
ALT, Grade 0 (N=12;12;12;12)	11	12	11	12
ALT, Grade 1 (N=12;12;12;12)	0	0	0	0
ALT, Grade 2 (N=12;12;12;12)	0	0	0	0
ALT, Grade 3 (N=12;12;12;12)	0	0	0	0
ALT, Grade 4 (N=12;12;12;12)	0	0	0	0
ALT, Unknown (N=12;12;12;12)	1	0	1	0

No statistical analyses for this end point

Primary: Number of participants in Step 1 subset with clinically relevant hematological abnormalities

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End point title

Number of participants in Step 1 subset with clinically relevant hematological abnormalities ^[12]

End point description

As pre-specified in the protocol, the assessed hematological parameters were hemoglobin, white blood cells (WBC) increase, WBC decrease, lymphocyte decrease, neutrophils decrease, eosinophils, and platelets decrease. Assessment of intensity: Grading of the biochemical parameters was based on the institutional normal reference ranges and derived from the standard FDA Toxicity Grading Scale. Changes compared to normal reference ranges were graded as follows: Grade 0 = a non-missing parameter value for which grade could not be derived according to the grading scale and does not belong to Grade 1-4; Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life-Threatening; Unknown = parameter value missing for the specified parameter. Analysis was performed on the Step 1 subset from the Exposed Set, which included sentinel adult participants for whom blood samples were collected for the specified hematological analyses at Day 7.

End point type

Primary

End point timeframe

At Day 7

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	12	12	12	12
Units: Participants
Hemoglobin, Grade 0 (N=12;12;12;12)	8	10	9	8
Hemoglobin, Grade 1 (N=12;12;12;12)	3	1	2	4
Hemoglobin, Grade 2 (N=12;12;12;12)	0	0	0	0
Hemoglobin, Grade 3 (N=12;12;12;12)	0	1	0	0
Hemoglobin, Grade 4 (N=12;12;12;12)	0	0	0	0
Hemoglobin, Unknown (N=12;12;12;12)	1	0	1	0
WBC Increase, Grade 0 (N=12;12;12;12)	11	12	11	11
WBC Increase, Grade 1 (N=12;12;12;12)	0	0	0	1
WBC Increase, Grade 2 (N=12;12;12;12)	0	0	0	0
WBC Increase, Grade 3 (N=12;12;12;12)	0	0	0	0
WBC Increase, Grade 4 (N=12;12;12;12)	0	0	0	0
WBC Increase, Unknown (N=12;12;12;12)	1	0	1	0
WBC Decrease, Grade 0 (N=12;12;12;12)	11	11	10	11
WBC Decrease, Grade 1 (N=12;12;12;12)	0	1	1	1
WBC Decrease, Grade 2 (N=12;12;12;12)	0	0	0	0
WBC Decrease, Grade 3 (N=12;12;12;12)	0	0	0	0
WBC Decrease, Grade 4 (N=12;12;12;12)	0	0	0	0
WBC Decrease, Unknown (N=12;12;12;12)	1	0	1	0
Lymphocyte Decrease, Grade 0 (N=12;12;12;12)	11	12	11	12
Lymphocyte Decrease, Grade 1 (N=12;12;12;12)	0	0	0	0
Lymphocyte Decrease, Grade 2 (N=12;12;12;12)	0	0	0	0
Lymphocyte Decrease, Grade 3 (N=12;12;12;12)	0	0	0	0
Lymphocyte Decrease, Grade 4 (N=12;12;12;12)	0	0	0	0
Lymphocyte Decrease, Unknown (N=12;12;12;12)	1	0	1	0
Neutrophils Decrease, Grade 0 (N=12;12;12;12)	10	11	10	11
Neutrophils Decrease, Grade 1 (N=12;12;12;12)	1	0	1	1
Neutrophils Decrease, Grade 2 (N=12;12;12;12)	0	1	0	0
Neutrophils Decrease, Grade 3 (N=12;12;12;12)	0	0	0	0
Neutrophils Decrease, Grade 4 (N=12;12;12;12)	0	0	0	0
Neutrophils Decrease, Unknown (N=12;12;12;12)	1	0	1	0
Eosinophils, Grade 0 (N=12;12;12;12)	11	12	11	11
Eosinophils, Grade 1 (N=12;12;12;12)	0	0	0	1
Eosinophils, Grade 2 (N=12;12;12;12)	0	0	0	0
Eosinophils, Grade 3 (N=12;12;12;12)	0	0	0	0
Eosinophils, Grade 4 (N=12;12;12;12)	0	0	0	0
Eosinophils, Unknown (N=12;12;12;12)	1	0	1	0
Platelet Decrease, Grade 0 (N=12;12;12;12)	11	12	11	12
Platelet Decrease, Grade 1 (N=12;12;12;12)	0	0	0	0
Platelet Decrease, Grade 2 (N=12;12;12;12)	0	0	0	0
Platelet Decrease, Grade 3 (N=12;12;12;12)	0	0	0	0
Platelet Decrease, Grade 4 (N=12;12;12;12)	0	0	0	0
Platelet Decrease, Unknown (N=12;12;12;12)	1	0	1	0

No statistical analyses for this end point

Primary: Number of participants in Step 1 subset with clinically relevant abnormalities in hemoglobin change from baseline levels

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End point title

Number of participants in Step 1 subset with clinically relevant abnormalities in hemoglobin change from baseline levels ^[13]

End point description

The number of participants with clinically relevant abnormalities in hemoglobin change from baseline levels is reported. Assessment of intensity:Grading of the biochemical parameters was based on the institutional normal reference ranges and derived from the standard FDA Toxicity Grading Scale. Changes compared to normal reference ranges were graded as follows: Grade 0=a non-missing parameter value for which grade could not be derived according to the grading scale and does not belong to Grade 1-4; Grade 1=Mild; Grade 2=Moderate; Grade 3=Severe; Grade 4=Potentially Life-Threatening; Unknown=parameter value missing for the specified parameter. Change from baseline=the difference between a participant's baseline (pre-intervention) parameter values and their follow-up (post-intervention) parameter values. Analysis was performed on the Step 1 subset from the Exposed Set.

End point type

Primary

End point timeframe

At Day 7 compared to baseline (Day 1)

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	12	12	12	12
Units: Participants
Hemoglobin change, Grade 0 (N=12;12;12;12)	5	1	1	5
Hemoglobin change, Grade 1 (N=12;12;12;12)	5	11	8	6
Hemoglobin change, Grade 2 (N=12;12;12;12)	0	0	1	0
Hemoglobin change, Grade 3 (N=12;12;12;12)	0	0	0	0
Hemoglobin change, Grade 4 (N=12;12;12;12)	0	0	0	0
Hemoglobin change, Unknown (N=12;12;12;12)	2	0	2	1

No statistical analyses for this end point

Primary: Anti-HPV immunoglobulin G (IgG) antibody concentrations

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End point title

Anti-HPV immunoglobulin G (IgG) antibody concentrations ^[14]

End point description

Anti-HPV IgG antibody concentrations were determined by electrochemiluminescence (ECL) assay and expressed as geometric mean concentrations (GMCs) in arbitrary units per milliliter (AU/mL). The assessed antigens were: HPV 6, HPV 11, HPV 16, HPV 18, HPV 31, HPV 33, HPV 45, HPV 52 and HPV 58 type antigens. Analysis was performed on Per Protocol Set (PPS) for immunogenicity, which included all participants from Exposed Set who met all eligibility criteria, followed the protocol for vaccine administration, adhered to vaccination schedule and blood sampling timings, and had post-vaccination immunogenicity results available for the specified analysis at the specified time point. The PPS excluded those participants with protocol deviations, interfering medications, or intercurrent medical conditions.

End point type

Primary

End point timeframe

At Month 7 (one month after vaccine Dose 3 administration)

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	211	201	206	203
Units: AU/mL
geometric mean (confidence interval 95%)
HPV 6 type antigen, (N=210;201;206;203)	124141.35 (110854.94 to 139020.20)	117881.81 (103701.90 to 134000.65)	119724.25 (105236.23 to 136206.84)	54710.66 (47259.35 to 63336.80)
HPV 11 type antigen, (N=211;201;205;203)	276225.68 (243524.62 to 313317.91)	250405.46 (217218.09 to 288663.30)	260309.15 (223319.56 to 303425.52)	187507.09 (162968.13 to 215740.99)
HPV 16 type antigen, (N=202;191;202;197)	297480.37 (254936.96 to 347123.34)	272728.60 (231905.67 to 320737.69)	294326.70 (252346.28 to 343290.99)	154844.90 (131166.44 to 182797.86)
HPV 18 type antigen, (N=211;200;205;203)	181939.71 (157766.95 to 209816.17)	172862.73 (148117.04 to 201742.65)	183180.47 (156207.11 to 214811.50)	86756.51 (73744.88 to 102063.92)
HPV 31 type antigen, (N=211;200;206;203)	241644.97 (215104.30 to 271460.37)	221590.60 (192869.71 to 254588.41)	230875.63 (202104.78 to 263742.19)	104667.37 (90853.53 to 120581.53)
HPV 33 type antigen, (N=208;200;198;198)	154537.14 (133354.03 to 179085.17)	146931.12 (125717.81 to 171723.90)	150919.88 (128301.37 to 177525.85)	96875.65 (84426.91 to 111159.96)
HPV 45 type antigen, (N=211;201;206;203)	170959.55 (149389.05 to 195644.64)	174740.31 (151200.15 to 201945.41)	174014.45 (150322.39 to 201440.58)	71768.92 (61224.65 to 84129.14)
HPV 52 type antigen, (N=211;200;206;201)	203994.24 (180491.88 to 230556.91)	196454.98 (172561.35 to 223657.02)	204005.75 (178367.04 to 233329.81)	103497.80 (90571.68 to 118268.69)
HPV 58 type antigen, (N=210;199;205;202)	193735.34 (167223.71 to 224450.13)	186513.90 (161169.95 to 215843.18)	190767.16 (162753.08 to 223603.20)	93456.26 (80147.35 to 108975.18)

No statistical analyses for this end point

Secondary: Number of participants reporting any solicited administration site events

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End point title

Number of participants reporting any solicited administration site events

End point description

Assessed solicited administration site events included pain, redness and swelling at injection site. Any = occurrence of the symptom regardless of intensity grade. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine, had the eDiary for solicited events completed after the administration of each vaccine dose and for whom data were available during the specified period.

End point type

Secondary

End point timeframe

Within 7 days after each vaccine dose (administered at Day 1, Month 2, and Month 6)

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	270	270	269	270
Units: Participants
Any pain, post-dose 1, (N=270;270;269;270)	240	244	245	188
Any redness, post-dose 1, (N=270;270;269;270)	71	70	91	47
Any swelling, post-dose 1, (N=270;270;269;270)	61	54	66	21
Any pain, post-dose 2, (N=257;261;258;260)	208	221	218	185
Any redness, post-dose 2, (N=257;261;258;260)	79	83	69	46
Any swelling, post-dose 2, (N=257;261;258;260)	68	55	59	35
Any pain, post-dose 3, (N=244;247;244;236)	188	191	191	155
Any redness, post-dose 3, (N=244;247;244;236)	61	64	64	37
Any swelling, post-dose 3, (N=244;247;244;236)	59	52	58	24

No statistical analyses for this end point

Secondary: Number of participants reporting any solicited systemic events

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End point title

Number of participants reporting any solicited systemic events

End point description

Assessed solicited systemic events included fever (defined as body temperature >=37.5°C/99.5°F), headache, myalgia, arthralgia and fatigue. The preferred location for measuring temperature was the axilla. Any = occurrence of the symptom regardless of intensity grade or relation to study vaccination. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine, had the eDiary for solicited events completed after the administration of each vaccine dose and for whom data were available during the specified period.

End point type

Secondary

End point timeframe

Within 7 days after each vaccine dose (administered at Day 1, Month 2, and Month 6)

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	270	270	269	270
Units: Participants
Any fever, post-dose 1, (N=270;270;269;270)	15	12	10	13
Any headache, post-dose 1, (N=270;270;269;270)	137	113	131	127
Any myalgia, post-dose 1, (N=270;270;269;270)	87	105	92	75
Any arthralgia, post-dose 1, (N=270;270;269;270)	27	25	22	23
Any fatigue, post-dose 1, (N=270;270;269;270)	180	166	146	149
Any fever, post-dose 2, (N=257;261;258;260)	8	13	9	16
Any headache, post-dose 2, (N=257;261;258;260)	113	106	118	101
Any myalgia, post-dose 2, (N=257;261;258;260)	80	67	66	56
Any arthralgia, post-dose 2, (N=257;261;258;260)	25	19	21	20
Any fatigue, post-dose 2, (N=257;261;258;260)	152	132	124	127
Any fever, post-dose 3, (N=244;247;244;236)	13	11	11	8
Any headache, post-dose 3, (N=244;247;244;236)	106	81	84	85
Any myalgia, post-dose 3, (N=244;247;244;236)	61	59	54	45
Any arthralgia, post-dose 3, (N=244;247;244;236)	21	15	19	10
Any fatigue, post-dose 3, (N=244;247;244;236)	122	103	103	102

No statistical analyses for this end point

Secondary: Number of participants reporting any unsolicited AEs

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End point title

Number of participants reporting any unsolicited AEs

End point description

An unsolicited AE is defined as an AE that was not included in the list of solicited events using an eDiary and that was spontaneously communicated by a participant/participant's parent(s)/LAR(s) who has signed the informed consent. Also, any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited AE. Any = occurrence of the symptom regardless of intensity grade or relation to study vaccination. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine and for whom data were available for the specified period after the administration of each vaccine dose.

End point type

Secondary

End point timeframe

Within 28 days after each vaccine dose (administered at Day 1, Month 2, and Month 6)

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	270	270	269	270
Units: Participants
Any unsolicited AEs,post-dose1,(N=270;270;269;270)	70	72	70	70
Any unsolicited AEs,post-dose2,(N=257;261;258;260)	51	38	58	55
Any unsolicited AEs,post-dose3,(N=244;247;244;236)	37	41	45	31

No statistical analyses for this end point

Secondary: Number of participants reporting potential immune-mediated diseases (pIMDs)

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End point title

Number of participants reporting potential immune-mediated diseases (pIMDs)

End point description

pIMDs are defined as a subset of AEs of special interest (AESIs) that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology. Analysis was performed on the Exposed set, which included all participants who received a study vaccine and for whom data were available for the specified period.

End point type

Secondary

End point timeframe

From first vaccination (Day 1) to study end (Month 12)

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	270	270	269	270
Units: Participants	0	0	2	2

No statistical analyses for this end point

Secondary: Number of participants reporting pregnancies

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End point title

Number of participants reporting pregnancies

End point description

The number of participants who experienced pregnancy while participating in this study is reported. Analysis was performed on the Exposed Set, which included all participants who received a study vaccine and for whom data were available for the specified period.

End point type

Secondary

End point timeframe

From Day 1 of pregnancy to study end (Month 12)

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	270	270	269	270
Units: Participants	1	3	0	5

No statistical analyses for this end point

Secondary: Number of participants with outcomes of reported pregnancies

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End point title

Number of participants with outcomes of reported pregnancies

End point description

The participants with confirmed pregnancies were followed up to determine the outcomes of the reported pregnancies. Pregnancy outcomes were live infant, no apparent congenital anomaly (CA); elective termination, no apparent congenital anomaly (CA), and ectopic pregnancy. Analysis was performed on the Exposed set, which included all participants who received a study vaccine, who reported any pregnancy and for whom data were available for the specified period.

End point type

Secondary

End point timeframe

From Day 1 of pregnancy up to study end (Month 12)

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	1	3	0 ^[15]	5
Units: Participants
Live infant, no apparent CA (N=1;3;0;5)	1	2		2
Elective termination, no apparent CA (N=1;3;0;5)	0	1		2
Ectopic pregnancy (N=1;3;0;5)	0	0		1

Notes
[15] - There were no participants with confirmed pregnancies in this group.

No statistical analyses for this end point

Secondary: Anti-HPV IgG antibody concentrations

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End point title

Anti-HPV IgG antibody concentrations

End point description

Anti-HPV IgG antibody concentrations were determined by ECL assay and expressed as GMCs in AU/mL. The assessed antigens were: HPV 6, HPV 11, HPV 16, HPV 18, HPV 31, HPV 33, HPV 45, HPV 52 and HPV 58 type antigens. Analysis was performed on Per Protocol Set (PPS) for immunogenicity, which included all participants from Exposed Set who met all eligibility criteria, followed the protocol for vaccine administration, adhered to vaccination schedule and blood sampling timings, and had post-vaccination immunogenicity results available for the specified analysis at the specified time points. The PPS excluded those participants with protocol deviations, interfering medications, or intercurrent medical conditions.

End point type

Secondary

End point timeframe

At Day 1, Month 2, Month 3, Month 6, Month 7 (Month 7 data was also reported in primary outcome measure 14, as pre-specified in protocol) and Month 12

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	265	261	264	261
Units: AU/mL
geometric mean (confidence interval 95%)
HPV 6 type antigen, Day 1, (N=264;261;263;261)	3621.58 (3245.94 to 4040.70)	3377.84 (3078.74 to 3705.98)	3124.40 (2891.32 to 3376.27)	2970.65 (2773.07 to 3182.30)
HPV 6 type antigen, Month 2,(N=235;235;234;235)	29701.14 (25289.04 to 34883.02)	29699.92 (25343.87 to 34804.68)	23870.12 (20301.64 to 28065.86)	10488.57 (8707.08 to 12634.56)
HPV 6 type antigen, Month 3,(N=223;232;231;229)	113669.75 (101762.75 to 126969.97)	106471.07 (95221.75 to 119049.37)	100258.49 (88766.41 to 113238.38)	63245.70 (55720.23 to 71787.54)
HPV 6 type antigen, Month 6,(N=225;222;220;212)	42722.37 (37809.13 to 48274.08)	38982.11 (34388.98 to 44188.73)	32792.55 (28876.62 to 37239.51)	18744.02 (15944.74 to 22034.74)
HPV 6 type antigen, Month 7,(N=210;201;206;203)	124141.35 (110854.94 to 139020.20)	117881.81 (103701.90 to 134000.65)	119724.25 (105236.23 to 136206.84)	54710.66 (47259.35 to 63336.80)
HPV 6 type antigen, Month 12,(N=198;200;197;196)	68118.04 (60118.11 to 77182.53)	65112.37 (56605.42 to 74897.80)	59776.32 (51986.07 to 68733.97)	26890.23 (22982.31 to 31462.65)
HPV 11 type antigen, Day 1,(N=265;261;263;261)	2217.95 (1860.09 to 2644.67)	2105.07 (1797.78 to 2464.89)	2013.18 (1725.27 to 2349.12)	1794.54 (1572.94 to 2047.37)
HPV 11 type antigen, Month 2, (N=236;235;230;234)	41618.25 (35124.62 to 49312.39)	37945.17 (32187.34 to 44732.98)	29437.94 (24557.93 to 35287.68)	38760.82 (32890.19 to 45679.30)
HPV 11 type antigen, Month 3, (N=224;232;230;229)	231064.29 (203232.17 to 262707.95)	212805.15 (185957.86 to 243528.46)	192296.18 (167234.40 to 221113.72)	220402.45 (196291.74 to 247474.71)
HPV 11 type antigen, Month 6, (N=226;222;219;212)	77600.50 (68286.55 to 88184.84)	67299.61 (58975.99 to 76798.00)	57076.00 (49315.68 to 66057.49)	68934.35 (59315.95 to 80112.44)
HPV 11 type antigen, Month 7, (N=211;201;205;203)	276225.68 (243524.62 to 313317.91)	250405.46 (217218.09 to 288663.30)	260309.15 (223319.56 to 303425.52)	187507.09 (162968.13 to 215740.99)
HPV 11 type antigen, Month 12, (N=210;209;205;205)	129019.87 (112127.85 to 148456.67)	120984.83 (103575.25 to 141320.73)	117640.77 (100745.01 to 137370.08)	87423.54 (75807.40 to 100819.64)
HPV 16 type antigen, Day 1, (N=258;253;260;254)	684.26 (518.08 to 903.75)	637.99 (490.56 to 829.73)	690.99 (530.87 to 899.40)	525.21 (416.24 to 662.71)
HPV 16 type antigen, Month 2, (N=231;227;230;229)	34918.40 (27711.11 to 44000.21)	31250.65 (24952.39 to 39138.66)	25605.94 (20018.80 to 32752.43)	17397.59 (13647.75 to 22177.73)
HPV 16 type antigen, Month 3,(N=219;224;227;223)	252250.95 (217434.89 to 292641.82)	217440.98 (184257.65 to 256600.37)	201303.15 (171349.89 to 236492.48)	158136.76 (134715.83 to 185629.53)
HPV 16 type antigen, Month 6, (N=219;214;217;208)	101518.07 (87448.85 to 117850.81)	83015.52 (71509.49 to 96372.89)	76558.80 (64740.19 to 90534.95)	56636.27 (47641.12 to 67329.80)
HPV 16 type antigen, Month 7, (N=202;191;202;197)	297480.37 (254936.96 to 347123.34)	272728.60 (231905.67 to 320737.69)	294326.70 (252346.28 to 343290.99)	154844.90 (131166.44 to 182797.86)
HPV 16 type antigen, Month 12,(N=205;202;203;201)	166953.66 (142318.06 to 195853.75)	149269.66 (125174.31 to 178003.24)	168097.78 (142244.20 to 198650.38)	85986.11 (73074.57 to 101178.98)
HPV 18 type antigen, Day 1, (N=265;260;263;260)	1246.54 (1036.67 to 1498.89)	1037.54 (885.47 to 1215.73)	1111.98 (948.66 to 1303.41)	952.51 (830.50 to 1092.44)
HPV 18 type antigen, Month 2, (N=236;233;231;233)	21700.85 (17733.79 to 26555.34)	18029.88 (14988.53 to 21688.36)	16571.70 (13555.92 to 20258.40)	11081.57 (9094.95 to 13502.12)
HPV 18 type antigen, Month 3, (N=224;231;230;229)	137838.37 (118980.92 to 159684.56)	127099.14 (108628.77 to 148710.05)	123342.91 (106423.50 to 142952.21)	79998.43 (68999.00 to 92751.33)
HPV 18 type antigen, Month 6, (N=226;221;219;212)	61676.34 (53576.84 to 71000.30)	51216.03 (44364.44 to 59125.78)	46904.59 (40385.36 to 54476.18)	26774.11 (22940.11 to 31248.90)
HPV 18 type antigen, Month 7,(N=211;200;205;203)	181939.71 (157766.95 to 209816.17)	172862.73 (148117.04 to 201742.65)	183180.47 (156207.11 to 214811.50)	86756.51 (73744.88 to 102063.92)
HPV 18 type antigen, Month 12, (N=210;208;205;205)	84949.48 (72424.07 to 99641.09)	77008.45 (64999.61 to 91235.95)	87334.91 (73919.46 to 103185.10)	36658.81 (31077.43 to 43242.59)
HPV 31 type antigen, Day 1, (N=265;260;264;261)	2748.41 (2441.79 to 3093.53)	2698.81 (2418.57 to 3011.52)	2595.69 (2371.22 to 2841.42)	2358.09 (2189.79 to 2539.33)
HPV 31 type antigen, Month 2,(N=236;234;234;234)	32102.49 (27409.98 to 37598.34)	31733.68 (27111.16 to 37144.34)	27652.57 (23288.94 to 32833.82)	12606.73 (10568.61 to 15037.90)
HPV 31 type antigen, Month 3, (N=224;231;231;229)	161264.11 (142962.02 to 181909.25)	146413.17 (128682.36 to 166587.07)	133818.05 (117762.32 to 152062.83)	89306.66 (79122.92 to 100801.13)
HPV 31 type antigen, Month 6, (N=226;221;220;212)	68516.79 (60395.61 to 77730.00)	61717.39 (54357.98 to 70073.18)	54672.61 (47682.67 to 62687.23)	32131.34 (27928.72 to 36966.36)
HPV 31 type antigen, Month 7, (N=211;200;206;203)	241644.97 (215104.30 to 271460.37)	221590.60 (192869.71 to 254588.41)	230875.63 (202104.78 to 263742.19)	104667.37 (90853.53 to 120581.53)
HPV 31 type antigen, Month 12, (N=205;207;204;204)	137744.87 (120414.00 to 157570.13)	132414.54 (113520.94 to 154452.65)	143396.41 (125201.11 to 164236.01)	55178.34 (47206.87 to 64495.90)
HPV 33 type antigen, Day 1, (N=264;258;260;259)	624.29 (528.02 to 738.12)	578.18 (489.56 to 682.84)	566.26 (487.33 to 657.97)	523.15 (456.49 to 599.54)
HPV 33 type antigen, Month 2,(N=235;231;230;233)	18225.37 (15231.33 to 21807.94)	16873.64 (14013.68 to 20317.26)	14523.05 (12060.26 to 17488.76)	12110.80 (10065.98 to 14571.01)
HPV 33 type antigen, Month 3, (N=220;223;224;223)	124361.59 (108348.67 to 142741.07)	113348.19 (96632.64 to 132955.20)	105284.68 (90915.50 to 121924.92)	87895.71 (76051.15 to 101585.00)
HPV 33 type antigen, Month 6, (N=215;212;201;204)	43736.52 (38187.42 to 50091.97)	41162.19 (35659.00 to 47514.67)	35892.14 (30909.82 to 41677.54)	30563.15 (26208.11 to 35641.88)
HPV 33 type antigen, Month 7, (N=208;200;198;198)	154537.14 (133354.03 to 179085.17)	146931.12 (125717.81 to 171723.90)	150919.88 (128301.37 to 177525.85)	96875.65 (84426.91 to 111159.96)
HPV 33 type antigen, Month 12, (N=209;207;202;203)	79450.21 (68289.18 to 92435.36)	75043.46 (63377.35 to 88857.01)	78826.94 (67275.95 to 92361.18)	46210.95 (40274.75 to 53022.09)
HPV 45 type antigen, Day 1, (N=265;261;264;261)	2431.92 (2233.39 to 2648.10)	2408.58 (2235.09 to 2595.54)	2315.53 (2182.69 to 2456.46)	2217.15 (2109.75 to 2330.02)
HPV 45 type antigen, Month 2, (N=236;235;234;234)	17122.75 (14408.88 to 20347.76)	17097.47 (14406.77 to 20290.70)	14345.03 (12174.35 to 16902.74)	6292.08 (5323.98 to 7436.22)
HPV 45 type antigen, Month 3, (N=224;232;231;229)	137598.43 (121615.96 to 155681.28)	127933.76 (111246.84 to 147123.69)	113479.94 (99528.64 to 129386.85)	55337.26 (48187.68 to 63547.61)
HPV 45 type antigen, Month 6, (N=226;222;220;212)	45691.56 (40155.51 to 51990.83)	41003.12 (35887.26 to 46848.26)	34796.86 (30257.59 to 40017.12)	16153.45 (13858.32 to 18828.69)
HPV 45 type antigen, Month 7, (N=211;201;206;203)	170959.55 (149389.05 to 195644.64)	174740.31 (151200.15 to 201945.41)	174014.45 (150322.39 to 201440.58)	71768.92 (61224.65 to 84129.14)
HPV 45 type antigen, Month 12, (N=210;209;206;205)	78692.83 (68331.72 to 90624.98)	80653.92 (68737.56 to 94636.11)	82021.92 (70210.67 to 95820.12)	29716.61 (25237.04 to 34991.31)
HPV 52 type antigen, Day 1, (N=265;260;264;260)	1641.65 (1464.30 to 1840.48)	1720.51 (1525.62 to 1940.31)	1611.71 (1461.90 to 1776.89)	1549.58 (1410.22 to 1702.72)
HPV 52 type antigen, Month 2,(N=236;233;234;234)	75187.13 (66352.61 to 85197.91)	83557.87 (73382.84 to 95143.74)	73047.67 (63982.97 to 83396.59)	25513.64 (21690.75 to 30010.30)
HPV 52 type antigen, Month 3,(N=224;231;231;228)	185490.54 (166270.48 to 206932.34)	176024.77 (153898.90 to 201331.66)	164122.51 (144482.99 to 186431.62)	95239.18 (84388.59 to 107484.91)
HPV 52 type antigen, Month 6, (N=226;221;220;211)	75353.61 (66851.68 to 84936.78)	77979.01 (68903.19 to 88250.29)	65136.98 (56955.32 to 74493.93)	32359.34 (28207.45 to 37122.36)
HPV 52 type antigen, Month 7, (N=211;200;206;201)	203994.24 (180491.88 to 230556.91)	196454.98 (172561.35 to 223657.02)	204005.75 (178367.04 to 233329.81)	103497.80 (90571.68 to 118268.69)
HPV 52 type antigen, Month 12, (N=207;208;206;203)	123724.49 (107358.59 to 142585.25)	131043.47 (113718.55 to 151007.84)	129678.87 (113220.94 to 148529.14)	54071.66 (46680.66 to 62632.89)
HPV 58 type antigen, Day 1, (N=265;261;263;261)	692.12 (578.03 to 828.72)	615.45 (518.19 to 730.95)	643.72 (548.71 to 755.18)	571.59 (492.66 to 663.17)
HPV 58 type antigen, Month 2, (N=236;235;233;235)	35027.13 (29855.93 to 41094.00)	33438.25 (28322.91 to 39477.45)	30732.28 (26045.95 to 36261.80)	13395.37 (11180.86 to 16048.50)
HPV 58 type antigen, Month 3, (N=224;232;230;229)	158592.29 (139984.81 to 179673.18)	144355.15 (124064.76 to 167963.98)	140028.57 (120462.67 to 162772.43)	79942.78 (69460.78 to 92006.58)
HPV 58 type antigen, Month 6, (N=226;221;219;212)	70466.12 (61803.06 to 80343.50)	66072.77 (57862.76 to 75447.68)	57807.95 (49486.07 to 67529.30)	33188.99 (28367.50 to 38829.98)
HPV 58 type antigen, Month 7, (N=210;199;205;202)	193735.34 (167223.71 to 224450.13)	186513.90 (161169.95 to 215843.18)	190767.16 (162753.08 to 223603.20)	93456.26 (80147.35 to 108975.18)
HPV 58 type antigen, Month 12, (N=202;205;203;204)	114626.18 (98236.18 to 133750.73)	110249.43 (93894.97 to 129452.48)	115765.42 (99881.91 to 134174.76)	51715.19 (44122.31 to 60614.71)

No statistical analyses for this end point

Secondary: Number of participants with seroconversion for anti-HPV IgG antibodies

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End point title

Number of participants with seroconversion for anti-HPV IgG antibodies

End point description

Seroconversion is defined as the appearance of antibodies [i.e., concentration greater than or equal to (>=) the lower limit of quantification (LLOQ) value] in the serum of participants seronegative [i.e, concentrations less than (<) the LLOQ value] before vaccination. The assessed antigens were: HPV 6, HPV 11, HPV 16, HPV 18, HPV 31, HPV 33, HPV 45, HPV 52 and HPV 58 type antigens. The LLOQ values specific to each antigen are as follows: HPV 6 type: LLOQ = 5100 AU/mL; HPV 11 type: LLOQ = 2480 AU/mL; HPV 16 type: LLOQ = 404 AU/mL; HPV 18 type: LLOQ = 1234 AU/mL; HPV 31 type: LLOQ = 3849 AU/mL; HPV 33 type: LLOQ = 617 AU/mL; HPV 45 type: LLOQ = 4079 AU/mL; HPV 52 type: LLOQ = 2352 AU/mL and HPV 58 type: LLOQ = 660 AU/mL. Analysis was performed on Per Protocol Set (PPS) for immunogenicity. The PPS excluded those participants with protocol deviations, interfering medications, or intercurrent medical conditions.

End point type

Secondary

End point timeframe

At Month 2, Month 3, Month 6, Month 7 and Month 12

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	217	216	220	222
Units: Participants
HPV 6 type antigen, Month 2, (N=199;200;209;219)	186	186	189	137
HPV 6 type antigen, Month 3,(N=190;201;207;213)	186	197	201	211
HPV 6 type antigen, Month 6, (N=190;193;198;198)	187	189	191	173
HPV 6 type antigen, Month 7, (N=181;177;184;191)	179	174	178	186
HPV 6 type antigen, Month 12, (N=168;174;178;184)	165	170	174	172
HPV 11 type antigen, Month 2, (N=200;196;195;211)	198	192	190	208
HPV 11 type antigen, Month 3, (N=194;195;196;207)	192	192	191	206
HPV 11 type antigen, Month 6, (N=191;187;188;190)	189	185	183	187
HPV 11 type antigen, Month 7, (N=184;174;174;184)	183	172	169	182
HPV 11 type antigen, Month 12, (N=179;177;174;185)	177	175	171	184
HPV 16 type antigen, Month 2, (N=170;164;171;178)	170	163	169	177
HPV 16 type antigen, Month 3, (N=166;164;172;173)	166	162	170	172
HPV 16 type antigen, Month 6, (N=161;155;166;164)	161	154	165	164
HPV 16 type antigen, Month 7, (N=156;145;152;157)	156	144	152	157
HPV 16 type antigen, Month 12, (N=155;148;152;160)	155	147	151	160
HPV 18 type antigen, Month 2, (N=190;192;188;197)	187	186	185	187
HPV 18 type antigen, Month 3, (N=185;192;188;193)	182	189	185	192
HPV 18 type antigen, Month 6,(N=182;184;181;179)	180	182	178	177
HPV 18 type antigen, Month 7, (N=175;170;167;172)	174	168	164	170
HPV 18 type antigen, Month 12,(N=172;176;166;174)	170	174	163	173
HPV 31 type antigen, Month 2, (N=203;197;196;208)	199	192	189	171
HPV 31 type antigen, Month 3, (N=196;196;196;203)	192	192	191	202
HPV 31 type antigen, Month 6, (N=195;188;189;187)	193	185	185	184
HPV 31 type antigen, Month 7, (N=187;173;174;180)	186	170	170	180
HPV 31 type antigen, Month 12, (N=180;178;173;179)	178	175	171	178
HPV 33 type antigen, Month 2, (N=170;173;171;181)	168	170	168	179
HPV 33 type antigen, Month 3, (N=161;169;169;173)	159	166	166	172
HPV 33 type antigen, Month 6, (N=155;160;155;159)	153	158	152	157
HPV 33 type antigen, Month 7, (N=155;159;151;157)	154	157	148	156
HPV 33 type antigen, Month 12, (N=155;161;153;161)	153	159	151	161
HPV 45 type antigen, Month 2, (N=217;216;220;222)	190	190	191	122
HPV 45 type antigen, Month 3, (N=206;213;218;217)	203	206	213	212
HPV 45 type antigen, Month 6, (N=207;203;208;200)	204	200	203	179
HPV 45 type antigen, Month 7, (N=194;188;194;192)	192	185	189	188
HPV 45 type antigen, Month 12, (N=194;193;194;194)	191	190	190	184
HPV 52 type antigen, Month 2, (N=205;200;200;201)	202	198	197	194
HPV 52 type antigen, Month 3, (N=198;200;199;196)	196	195	195	194
HPV 52 type antigen, Month 6, (N=197;191;190;185)	195	190	187	182
HPV 52 type antigen, Month 7, (N=188;177;177;175)	186	176	175	173
HPV 52 type antigen, Month 12, (N=183;181;177;177)	180	180	174	175
HPV 58 type antigen, Month 2, (N=182;183;173;186)	180	180	170	186
HPV 58 type antigen, Month 3, (N=175;184;174;181)	173	181	170	180
HPV 58 type antigen, Month 6, (N=174;176;167;169)	172	174	163	168
HPV 58 type antigen, Month 7, (N=166;164;155;162)	165	162	152	161
HPV 58 type antigen, Month 12, (N=158;166;153;165)	156	164	151	164

No statistical analyses for this end point

Secondary: Anti-HPV neutralizing titers

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End point title

Anti-HPV neutralizing titers

End point description

Anti-HPV neutralizing titers were determined by pseudovirion-based neutralization (PBNA) assay and expressed as geometric mean titers (GMTs). The assessed antigens were: HPV 6, HPV 11, HPV 16, HPV 18, HPV 31, HPV 33, HPV 45, HPV 52 and HPV 58 type antigens. Analysis was performed on Per Protocol Set (PPS) for immunogenicity, which included all participants from Exposed Set who met all eligibility criteria, followed the protocol for vaccine administration, adhered to vaccination schedule and blood sampling timings, and had post-vaccination immunogenicity results available for the specified analysis at the specified time points. The PPS excluded those participants with protocol deviations, interfering medications, or intercurrent medical conditions.

End point type

Secondary

End point timeframe

At Day 1, Month 3 and Month 7

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	266	261	264	261
Units: Titers
geometric mean (confidence interval 95%)
HPV 6 type antigen, Day 1 (N=266;261;264;261)	328.72 (265.51 to 406.99)	280.37 (232.07 to 338.73)	242.72 (206.00 to 286.00)	230.40 (196.29 to 270.43)
HPV 6 type antigen, Month 3 (N=223;229;227;226)	45690.44 (39581.97 to 52741.61)	41126.63 (35026.80 to 48288.74)	39346.74 (33229.37 to 46590.30)	21637.85 (18354.48 to 25508.56)
HPV 6 type antigen, Month 7 (N=149;140;147;141)	82061.27 (70437.95 to 95602.62)	75228.75 (61603.93 to 91866.94)	71805.19 (57989.96 to 88911.69)	33651.69 (27317.93 to 41453.96)
HPV 11 type antigen, Day 1 (N=266;261;264;261)	225.65 (193.18 to 263.58)	210.97 (183.33 to 242.77)	204.12 (178.72 to 233.13)	189.59 (168.38 to 213.47)
HPV 11 type antigen, Month 3 (N=224;231;228;228)	13233.27 (11647.45 to 15035.00)	12081.23 (10600.08 to 13769.35)	10838.85 (9463.76 to 12413.73)	11547.59 (10251.71 to 13007.27)
HPV 11 type antigen, Month 7 (N=149;140;147;142)	17321.54 (14965.94 to 20047.91)	16793.17 (14214.38 to 19839.80)	16315.93 (13807.32 to 19280.31)	12607.96 (10724.69 to 14821.94)
HPV 16 type antigen, Day 1 (N=266;261;264;261)	361.27 (291.97 to 447.02)	325.48 (270.30 to 391.92)	356.83 (294.43 to 432.46)	277.19 (236.97 to 324.24)
HPV 16 type antigen, Month 3 (N=224;232;231;229)	35416.74 (29603.66 to 42371.29)	31018.79 (26065.77 to 36912.98)	29774.15 (24560.51 to 36094.53)	21870.13 (18225.32 to 26243.85)
HPV 16 type antigen, Month 7 (N=149;140;147;142)	83674.41 (68253.56 to 102579.36)	75779.10 (59852.62 to 95943.55)	81101.64 (64972.49 to 101234.78)	37820.19 (29988.35 to 47697.42)
HPV 18 type antigen, Day 1 (N=266;261;264;261)	73.24 (61.47 to 87.27)	63.14 (54.42 to 73.25)	64.18 (55.86 to 73.73)	57.05 (50.67 to 64.22)
HPV 18 type antigen, Month 3 (N=225;232;230;229)	3994.46 (3295.05 to 4842.33)	3610.97 (3001.43 to 4344.30)	3528.45 (2908.77 to 4280.15)	1705.98 (1394.09 to 2087.65)
HPV 18 type antigen, Month 7 (N=149;140;147;142)	9236.06 (7400.65 to 11526.67)	9539.94 (7507.03 to 12123.35)	9756.59 (7610.84 to 12507.29)	3518.33 (2745.04 to 4509.45)
HPV 31 type antigen, Day 1 (N=266;261;264;261)	86.49 (72.60 to 103.02)	85.98 (71.95 to 102.75)	86.03 (73.71 to 100.41)	76.01 (66.25 to 87.22)
HPV 31 type antigen, Month 3 (N=225;232;231;229)	22472.04 (19266.57 to 26210.81)	21241.61 (17729.34 to 25449.67)	18317.84 (15540.80 to 21591.12)	9156.79 (7772.33 to 10787.86)
HPV 31 type antigen, Month 7 (N=149;140;147;142)	69730.78 (56719.94 to 85726.14)	64413.46 (49797.87 to 83318.69)	59252.25 (46942.33 to 74790.26)	17581.92 (14014.44 to 22057.53)
HPV 33 type antigen, Day 1 (N=266;261;264;261)	207.88 (185.90 to 232.47)	216.99 (191.26 to 246.17)	200.17 (181.73 to 220.49)	186.32 (172.16 to 201.64)
HPV 33 type antigen, Month 3 (N=225;232;230;229)	17034.78 (14730.51 to 19699.52)	15199.08 (12954.60 to 17832.44)	12923.25 (10949.50 to 15252.79)	9132.50 (7752.49 to 10758.18)
HPV 33 type antigen, Month 7 (N=149;140;147;142)	33246.87 (27979.03 to 39506.53)	30752.43 (25717.48 to 36773.13)	27855.80 (22482.02 to 34514.06)	18696.71 (15656.33 to 22327.51)
HPV 45 type antigen, Day 1 (N=266;261;264;261)	55.65 (48.99 to 63.21)	61.43 (53.20 to 70.94)	53.80 (48.31 to 59.93)	49.89 (45.89 to 54.25)
HPV 45 type antigen, Month 3 (N=225;232;230;229)	13822.73 (11844.34 to 16131.59)	13197.57 (11085.72 to 15711.73)	11113.74 (9429.52 to 13098.77)	3488.90 (2963.94 to 4106.83)
HPV 45 type antigen, Month 7 (N=149;139;146;142)	25204.55 (20693.56 to 30698.90)	24537.36 (20030.78 to 30057.86)	22748.14 (18260.65 to 28338.42)	7853.20 (6210.60 to 9930.24)
HPV 52 type antigen, Day 1 (N=266;261;264;261)	78.63 (68.76 to 89.92)	85.37 (73.69 to 98.89)	75.58 (67.66 to 84.43)	72.37 (64.86 to 80.75)
HPV 52 type antigen, Month 3 (N=225;232;231;229)	18288.04 (16184.95 to 20664.41)	15548.20 (13427.71 to 18003.57)	14606.62 (12634.89 to 16886.04)	7903.98 (6883.36 to 9075.93)
HPV 52 type antigen, Month 7 (N=149;140;147;142)	21604.03 (18522.86 to 25197.74)	20617.17 (17543.87 to 24228.84)	20285.76 (17088.28 to 24081.54)	10904.65 (9006.10 to 13203.43)
HPV 58 type antigen, Day 1 (N=266;261;264;261)	87.31 (72.70 to 104.85)	87.15 (72.02 to 105.46)	82.06 (69.30 to 97.16)	73.81 (63.25 to 86.13)
HPV 58 type antigen, Month 3 (N=225;232;231;229)	31623.27 (27319.75 to 36604.69)	27936.10 (23519.92 to 33181.47)	27246.89 (22979.23 to 32307.15)	11650.18 (9904.82 to 13703.09)
HPV 58 type antigen, Month 7 (N=149;140;147;142)	51354.94 (42792.24 to 61631.03)	46896.70 (38584.84 to 56999.07)	46983.15 (37929.98 to 58197.15)	22245.13 (18114.56 to 27317.58)

No statistical analyses for this end point

Secondary: Anti-HPV neutralizing titers in a subset of participants

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End point title

Anti-HPV neutralizing titers in a subset of participants

End point description

Anti-HPV neutralizing titers were determined by PBNA assay and expressed as GMTs. The assessed antigens were: HPV 6, HPV 11, HPV 16, HPV 18, HPV 31, HPV 33, HPV 45, HPV 52 and HPV 58 type antigens. Analysis was performed on a subset of participants from Per Protocol Set (PPS) for immunogenicity with post-vaccination immunogenicity results available for the specified analysis at the specified time point.

End point type

Secondary

End point timeframe

At Month 2

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	92	91	89	88
Units: Titers
geometric mean (confidence interval 95%)
HPV 6 type antigen (N=84;82;82;80)	13438.35 (9145.74 to 19745.74)	11275.45 (7643.73 to 16632.69)	6658.75 (4614.67 to 9608.24)	3364.11 (2041.48 to 5543.64)
HPV 11 type antigen (N=92;91;89;88)	2592.37 (1870.39 to 3593.02)	2441.65 (1755.07 to 3396.81)	1531.82 (1119.26 to 2096.46)	2912.25 (2156.54 to 3932.76)
HPV 16 type antigen (N=92;91;89;88)	5888.86 (3547.05 to 9776.79)	4711.97 (2939.99 to 7551.96)	2947.73 (1742.01 to 4987.98)	2987.06 (1757.29 to 5077.45)
HPV 18 type antigen (N=92;91;89;88)	603.31 (365.97 to 994.56)	447.98 (286.20 to 701.20)	379.32 (237.94 to 604.69)	259.14 (161.99 to 414.56)
HPV 31 type antigen (N=92;91;89;88)	4005.68 (2737.23 to 5861.95)	3612.79 (2463.24 to 5298.82)	2193.35 (1620.34 to 2969.00)	1183.70 (775.15 to 1807.59)
HPV 33 type antigen (N=92;91;89;88)	1830.91 (1260.56 to 2659.31)	1782.19 (1234.63 to 2572.59)	1097.86 (810.20 to 1487.66)	1182.00 (818.69 to 1706.55)
HPV 45 type antigen (N=92;91;89;88)	1382.24 (973.72 to 1962.14)	1657.88 (1178.35 to 2332.56)	1119.04 (824.21 to 1519.32)	369.17 (267.20 to 510.05)
HPV 52 type antigen (N=92;91;89;88)	9664.68 (7775.37 to 12013.06)	9081.81 (7013.61 to 11759.89)	8379.90 (6544.29 to 10730.38)	4052.45 (3070.88 to 5347.77)
HPV 58 type antigen (N=92;91;89;88)	5169.27 (3769.39 to 7089.05)	5519.36 (3960.66 to 7691.47)	3848.83 (2823.14 to 5247.19)	1569.91 (1070.81 to 2301.63)

No statistical analyses for this end point

Secondary: Number of participants with seroconversion for anti-HPV neutralizing antibodies

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End point title

Number of participants with seroconversion for anti-HPV neutralizing antibodies

End point description

Seroconversion is defined as the appearance of antibodies (i.e., titer >=LLOQ value) in the serum of participants seronegative (i.e, titer <LLOQ value) before vaccination. The assessed antigens were: HPV 6, HPV 11, HPV 16, HPV 18, HPV 31, HPV 33, HPV 45, HPV 52 and HPV 58 type antigens. The LLOQ values specific to each antigen are as follows: HPV 6 type: LLOQ = 269 titers; HPV 11 type: LLOQ = 279 titers; HPV 16 type: LLOQ = 339 titers; HPV 18 type: LLOQ = 84 titers; HPV 31 type: LLOQ = 96 titers; HPV 33 type: LLOQ = 323 titers; HPV 45 type: LLOQ = 76 titers; HPV 52 type: LLOQ = 104 titers and HPV 58 type: LLOQ = 95 titers. Analysis was performed on Per Protocol Set (PPS) for immunogenicity. The PPS excluded those participants with protocol deviations, interfering medications, or intercurrent medical conditions.

End point type

Secondary

End point timeframe

At Month 3 and Month 7

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	208	211	216	217
Units: Participants
HPV 6 type antigen, Month 3 (N=173;182;186;194)	172	179	181	192
HPV 6 type antigen, Month 7 (N=112;111;120;120)	112	109	116	119
HPV 11 type antigen, Month 3 (N=199;200;203;208)	195	196	198	206
HPV 11 type antigen, Month 7 (N=132;121;132;129)	130	118	128	127
HPV 16 type antigen, Month 3 (N=189;188;191;199)	187	185	187	196
HPV 16 type antigen, Month 7 (N=125;111;115;123)	124	109	114	121
HPV 18 type antigen, Month 3 (N=195;204;198;203)	192	199	193	195
HPV 18 type antigen, Month 7 (N=131;122;123;123)	129	119	120	120
HPV 31 type antigen, Month 3 (N=190;188;187;192)	189	184	186	192
HPV 31 type antigen, Month 7 (N=120;109;116;118)	120	107	116	118
HPV 33 type antigen, Month 3 (N=208;211;216;217)	204	206	210	215
HPV 33 type antigen, Month 7 (N=139;123;140;132)	136	121	135	131
HPV 45 type antigen, Month 3 (N=187;188;192;188)	185	184	189	186
HPV 45 type antigen, Month 7 (N=124;113;122;117)	122	111	119	116
HPV 52 type antigen, Month 3 (N=188;191;193;194)	186	188	189	193
HPV 52 type antigen, Month 7 (N=121;112;119;118)	120	111	118	116
HPV 58 type antigen, Month 3 (N=195;192;195;195)	193	188	190	193
HPV 58 type antigen, Month 7 (N=128;116;121;118)	126	114	118	116

No statistical analyses for this end point

Secondary: Correlation between anti-HPV IgG antibody concentration and anti-HPV neutralizing antibody titers

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End point title

Correlation between anti-HPV IgG antibody concentration and anti-HPV neutralizing antibody titers

End point description

The Pearson coefficient of correlation between anti-HPV IgG antibody concentration and anti-HPV neutralizing antibody titers was calculated for each study group and for each antigen. The Pearson correlation was computed by the log10-transformation of specific antibody concentrations. Analysis was performed on a subset of participants from Per Protocol Set for analysis of immunogenicity, which included participants with both concentration and titer values available for the specified analysis at the specified time points. Participants with values below the LLOQ or above ULOQ in either assay were excluded from the analysis.

End point type

Secondary

End point timeframe

At Day 1, Month 2, Month 3 and Month 7

End point values	HPV9 High Group	HPV9 Med Group	HPV9 Low Group	Gar9 Group
Number of subjects analysed	211	223	213	225
Units: Correlation coefficient
number (not applicable)
HPV 6, Day 1 (N=42;37;28;21)	0.850	0.818	0.756	0.830
HPV 6, Month 2 (N=61;66;70;48)	0.824	0.851	0.766	0.786
HPV 6, Month 3 (N=175;185;190;203)	0.813	0.790	0.789	0.867
HPV 6, Month 7 (N=95;81;89;118)	0.820	0.810	0.786	0.892
HPV 11, Day 1 (N=30;30;32;26)	0.907	0.921	0.951	0.932
HPV 11, Month 2 (N=73;72;73;75)	0.840	0.831	0.807	0.820
HPV 11, Month 3 (N=173;176;182;187)	0.806	0.808	0.820	0.856
HPV 11, Month 7 (N=91;79;86;104)	0.659	0.839	0.787	0.820
HPV 16, Day 1 (N=49;51;54;40)	0.934	0.927	0.918	0.951
HPV 16, Month 2 (N=80;79;70;73)	0.965	0.951	0.880	0.958
HPV 16, Month 3 (N=211;223;213;225)	0.871	0.862	0.827	0.904
HPV 16, Month 7 (N=143;133;138;135)	0.866	0.893	0.894	0.894
HPV 18, Day 1 (N=38;31;39;30)	0.903	0.863	0.896	0.920
HPV 18, Month 2 (N=61;65;64;54)	0.885	0.885	0.811	0.866
HPV 18, Month 3 (N=203;212;203;213)	0.881	0.880	0.860	0.884
HPV 18, Month 7 (N=130;127;117;133)	0.899	0.871	0.881	0.905
HPV 31, Day 1 (N=34;38;42;25)	0.751	0.811	0.708	0.344
HPV 31, Month 2 (N=83;84;83;77)	0.768	0.820	0.824	0.745
HPV 31, Month 3 (N=194;207;208;218)	0.800	0.800	0.798	0.845
HPV 31, Month 7 (N=107;96;101;127)	0.814	0.824	0.806	0.842
HPV 33, Day 1 (N=22;23;20;15)	0.664	0.843	0.831	0.886
HPV 33, Month 2 (N=65;69;68;63)	0.794	0.790	0.672	0.711
HPV 33, Month 3 (N=184;188;194;203)	0.811	0.767	0.783	0.859
HPV 33, Month 7 (N=80;78;77;114)	0.649	0.807	0.789	0.768
HPV 45, Day 1 (N=19;23;18;14)	0.721	0.885	0.692	0.557
HPV 45, Month 2 (N=78;77;73;57)	0.834	0.859	0.740	0.805
HPV 45, Month 3 (N=192;193;199;220)	0.846	0.863	0.799	0.882
HPV 45, Month 7 (N=86;74;87;127)	0.869	0.870	0.737	0.882
HPV 52, Day 1 (N=31;37;39;28)	0.809	0.790	0.847	0.804
HPV 52, Month 2 (N=77;76;78;78)	0.748	0.832	0.606	0.767
HPV 52, Month 3 (N=149;151;172;203)	0.797	0.821	0.754	0.861
HPV 52, Month 7 (N=77;70;67;113)	0.777	0.834	0.829	0.831
HPV 58, Day 1 (N=40;35;38;31)	0.632	0.816	0.791	0.831
HPV 58, Month 2 (N=79;77;85;80)	0.666	0.733	0.666	0.803
HPV 58, Month 3 (N=169;172;171;210)	0.831	0.721	0.789	0.852
HPV 58, Month 7 (N=63;69;67;121)	0.851	0.860	0.825	0.851

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited AEs: during the 7-day follow-up period after any vaccination. Unsolicited AEs: during the 28-day follow-up period after any vaccination. All-cause mortality, SAEs and pIMDs: from first vaccination (Day 1) up to study end (Month 12).

Adverse event reporting additional description

All events presented in the Serious Adverse Events and Non Serious Adverse Events modules are reported for the Exposed Set population during the specified time frames.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

HPV9 High Group

Reporting group description

Participants received 3 doses of the high formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Reporting group title

HPV9 Low Group

Reporting group description

Participants received 3 doses of the low formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Reporting group title

Gar9 Group

Reporting group description

Participants received 3 doses of the marketed Human Papilloma Virus (HPV) vaccine (Gardasil 9) at Day 1, Month 2, and Month 6.

Reporting group title

HPV9 Med Group

Reporting group description

Participants received 3 doses of the medium formulation of Human Papilloma Virus 9-valent (HPV9) investigational adjuvanted vaccine at Day 1, Month 2, and Month 6.

Serious adverse events	HPV9 High Group	HPV9 Low Group	Gar9 Group	HPV9 Med Group
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 270 (0.37%)	2 / 269 (0.74%)	7 / 270 (2.59%)	4 / 270 (1.48%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Tibia fracture
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (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
Joint injury
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (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
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Nasal septal operation
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
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 / 0
Gastric bypass
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
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 / 0
Pregnancy, puerperium and perinatal conditions
Ruptured ectopic pregnancy
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis ulcerative
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
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 / 0
Reproductive system and breast disorders
Endometriosis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
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 / 0
Psychiatric disorders
Personality disorder
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Affective disorder
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infectious mononucleosis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic tonsillitis
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (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
Bartholin's abscess
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
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 / 0
Appendiceal abscess
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	HPV9 High Group	HPV9 Low Group	Gar9 Group	HPV9 Med Group
Total subjects affected by non serious adverse events
subjects affected / exposed	260 / 270 (96.30%)	262 / 269 (97.40%)	254 / 270 (94.07%)	265 / 270 (98.15%)
Vascular disorders
Haematoma
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Hot flush
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Hypertension
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
General disorders and administration site conditions
Injection site haematoma
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	2 / 270 (0.74%)	0 / 270 (0.00%)
occurrences all number	1	0	2	0
Administration site erythema
subjects affected / exposed	126 / 270 (46.67%)	139 / 269 (51.67%)	89 / 270 (32.96%)	131 / 270 (48.52%)
occurrences all number	211	224	130	217
Administration site pain
subjects affected / exposed	255 / 270 (94.44%)	256 / 269 (95.17%)	235 / 270 (87.04%)	262 / 270 (97.04%)
occurrences all number	636	654	528	656
Administration site swelling
subjects affected / exposed	113 / 270 (41.85%)	106 / 269 (39.41%)	59 / 270 (21.85%)	99 / 270 (36.67%)
occurrences all number	188	183	80	161
Asthenia
subjects affected / exposed	2 / 270 (0.74%)	1 / 269 (0.37%)	1 / 270 (0.37%)	2 / 270 (0.74%)
occurrences all number	2	1	1	2
Axillary pain
subjects affected / exposed	0 / 270 (0.00%)	2 / 269 (0.74%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	2	1	0
Chest pain
subjects affected / exposed	2 / 270 (0.74%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	2	1	0	0
Chills
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	3	0	0
Fatigue
subjects affected / exposed	213 / 270 (78.89%)	192 / 269 (71.38%)	192 / 270 (71.11%)	205 / 270 (75.93%)
occurrences all number	458	373	379	402
Induration
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	1 / 270 (0.37%)	3 / 270 (1.11%)
occurrences all number	1	0	2	4
Influenza like illness
subjects affected / exposed	2 / 270 (0.74%)	0 / 269 (0.00%)	4 / 270 (1.48%)	0 / 270 (0.00%)
occurrences all number	2	0	5	0
Injection site bruising
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	2 / 270 (0.74%)	0 / 270 (0.00%)
occurrences all number	1	0	2	0
Injection site granuloma
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	1 / 270 (0.37%)
occurrences all number	0	0	1	2
Injection site induration
subjects affected / exposed	4 / 270 (1.48%)	1 / 269 (0.37%)	3 / 270 (1.11%)	0 / 270 (0.00%)
occurrences all number	5	1	5	0
Vaccination site induration
subjects affected / exposed	1 / 270 (0.37%)	4 / 269 (1.49%)	2 / 270 (0.74%)	3 / 270 (1.11%)
occurrences all number	1	4	4	4
Injection site nodule
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	2	0	0
Injection site pain
subjects affected / exposed	2 / 270 (0.74%)	0 / 269 (0.00%)	2 / 270 (0.74%)	1 / 270 (0.37%)
occurrences all number	3	0	2	1
Injection site pruritus
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	1	0	0
Injection site reaction
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Malaise
subjects affected / exposed	0 / 270 (0.00%)	2 / 269 (0.74%)	0 / 270 (0.00%)	3 / 270 (1.11%)
occurrences all number	0	2	0	4
Mucosal inflammation
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Pain
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Peripheral swelling
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	1 / 270 (0.37%)	2 / 270 (0.74%)
occurrences all number	1	0	1	2
Pyrexia
subjects affected / exposed	34 / 270 (12.59%)	25 / 269 (9.29%)	33 / 270 (12.22%)	37 / 270 (13.70%)
occurrences all number	38	31	37	37
Swelling
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	1	0	0
Thirst
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Vaccination site bruising
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	1	0	0	1
Injection site mass
subjects affected / exposed	0 / 270 (0.00%)	2 / 269 (0.74%)	1 / 270 (0.37%)	1 / 270 (0.37%)
occurrences all number	0	2	1	1
Vaccination site nodule
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Vaccination site pruritus
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Vaccination site swelling
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Vaccination site pain
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	1	0	0	1
General symptom
Additional description: Other symptoms/illnesses or reactions
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Hypersensitivity
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	1	0	1	0
Seasonal allergy
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	1 / 270 (0.37%)
occurrences all number	0	0	1	1
Uterine pain
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Menstruation irregular
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Menstruation delayed
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	1	0	0	2
Dysmenorrhoea
subjects affected / exposed	13 / 270 (4.81%)	11 / 269 (4.09%)	9 / 270 (3.33%)	11 / 270 (4.07%)
occurrences all number	13	17	9	14
Vaginal discharge
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Dyspnoea
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Dyspnoea exertional
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Epistaxis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	1 / 270 (0.37%)	3 / 269 (1.12%)	4 / 270 (1.48%)	3 / 270 (1.11%)
occurrences all number	1	3	4	3
Rhinitis allergic
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	1	1	0
Rhinorrhoea
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	1	1	0	1
Sinus congestion
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	1	0	1	0
Sinus pain
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Cough
subjects affected / exposed	2 / 270 (0.74%)	1 / 269 (0.37%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	2	1	1	0
Psychiatric disorders
Sleep disorder
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Insomnia
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	1 / 270 (0.37%)
occurrences all number	0	0	1	1
Depression
subjects affected / exposed	3 / 270 (1.11%)	1 / 269 (0.37%)	0 / 270 (0.00%)	3 / 270 (1.11%)
occurrences all number	3	1	0	3
Bipolar disorder
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Anxiety disorder
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	1	0	1
Anxiety
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	2 / 270 (0.74%)	1 / 270 (0.37%)
occurrences all number	1	0	2	1
Affective disorder
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	1	0	0	1
Investigations
Platelet count increased
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Human papilloma virus test positive
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Body temperature decreased
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Blood prolactin increased
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	2 / 270 (0.74%)	0 / 270 (0.00%)
occurrences all number	0	0	2	0
Procedural headache
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Limb injury
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Ligament sprain
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	1	0	1
Joint injury
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Joint dislocation
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Infusion related reaction
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Foot fracture
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Contusion
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	1	0	0
Clavicle fracture
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Arthropod bite
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Cardiac disorders
Supraventricular extrasystoles
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Tachycardia
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Tension headache
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	1	0	1	0
Presyncope
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	2	1	0	0
Paraesthesia
subjects affected / exposed	0 / 270 (0.00%)	2 / 269 (0.74%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	2	0	0
Neuralgia
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	1 / 270 (0.37%)	1 / 270 (0.37%)
occurrences all number	1	0	1	1
Multiple sclerosis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Migraine
subjects affected / exposed	1 / 270 (0.37%)	5 / 269 (1.86%)	3 / 270 (1.11%)	0 / 270 (0.00%)
occurrences all number	1	5	3	0
Hypoaesthesia
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Headache
subjects affected / exposed	194 / 270 (71.85%)	187 / 269 (69.52%)	179 / 270 (66.30%)	180 / 270 (66.67%)
occurrences all number	384	354	337	319
Dizziness postural
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Dizziness
subjects affected / exposed	3 / 270 (1.11%)	3 / 269 (1.12%)	4 / 270 (1.48%)	0 / 270 (0.00%)
occurrences all number	3	3	4	0
Carpal tunnel syndrome
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Thoracic radiculopathy
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Lymph node pain
subjects affected / exposed	0 / 270 (0.00%)	2 / 269 (0.74%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	2	0	0
Lymphadenitis
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Lymphadenopathy
subjects affected / exposed	3 / 270 (1.11%)	3 / 269 (1.12%)	1 / 270 (0.37%)	5 / 270 (1.85%)
occurrences all number	3	6	1	6
Ear and labyrinth disorders
Ear inflammation
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Ear congestion
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Ear pain
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Tinnitus
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Vertigo
subjects affected / exposed	3 / 270 (1.11%)	2 / 269 (0.74%)	3 / 270 (1.11%)	1 / 270 (0.37%)
occurrences all number	3	2	4	1
Eye disorders
Eyelid oedema
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Chalazion
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Eye inflammation
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Lacrimation increased
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	12 / 270 (4.44%)	15 / 269 (5.58%)	7 / 270 (2.59%)	5 / 270 (1.85%)
occurrences all number	14	21	7	5
Abdominal pain lower
subjects affected / exposed	2 / 270 (0.74%)	3 / 269 (1.12%)	1 / 270 (0.37%)	1 / 270 (0.37%)
occurrences all number	2	3	1	1
Abdominal pain upper
subjects affected / exposed	3 / 270 (1.11%)	1 / 269 (0.37%)	3 / 270 (1.11%)	5 / 270 (1.85%)
occurrences all number	3	1	3	5
Anal fissure
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Constipation
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Diarrhoea
subjects affected / exposed	4 / 270 (1.48%)	2 / 269 (0.74%)	5 / 270 (1.85%)	6 / 270 (2.22%)
occurrences all number	4	2	5	6
Dry mouth
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Dyspepsia
subjects affected / exposed	3 / 270 (1.11%)	3 / 269 (1.12%)	1 / 270 (0.37%)	1 / 270 (0.37%)
occurrences all number	3	3	1	1
Gastritis
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	1	0	1
Gastrointestinal pain
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 270 (0.00%)	2 / 269 (0.74%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	2	0	0
Haemorrhoidal haemorrhage
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Haemorrhoids
subjects affected / exposed	2 / 270 (0.74%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	2	0	0	0
Abdominal pain
subjects affected / exposed	5 / 270 (1.85%)	5 / 269 (1.86%)	9 / 270 (3.33%)	3 / 270 (1.11%)
occurrences all number	5	5	10	4
Odynophagia
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Vomiting
subjects affected / exposed	5 / 270 (1.85%)	2 / 269 (0.74%)	1 / 270 (0.37%)	2 / 270 (0.74%)
occurrences all number	5	4	1	2
Toothache
subjects affected / exposed	3 / 270 (1.11%)	2 / 269 (0.74%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	3	2	0	2
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Dermatitis
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	1	1	0
Dermatitis allergic
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	1 / 270 (0.37%)	2 / 270 (0.74%)
occurrences all number	0	1	1	2
Eczema
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Erythema
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	2	0
Haemorrhage subcutaneous
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Hyperhidrosis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Lipohypertrophy
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Pityriasis rosea
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Pruritus
subjects affected / exposed	2 / 270 (0.74%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	2	0	0	1
Psoriasis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Rash
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	1 / 270 (0.37%)	3 / 270 (1.11%)
occurrences all number	0	1	1	3
Rash erythematous
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Rash pruritic
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Rosacea
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Skin burning sensation
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Skin discolouration
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Macule
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Endocrine disorders
Polycystic ovarian syndrome
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Autoimmune thyroiditis
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	137 / 270 (50.74%)	126 / 269 (46.84%)	118 / 270 (43.70%)	133 / 270 (49.26%)
occurrences all number	228	213	178	231
Pain in extremity
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	2 / 270 (0.74%)	0 / 270 (0.00%)
occurrences all number	1	1	2	0
Muscle spasms
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	1	0	0	1
Enthesopathy
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Back pain
subjects affected / exposed	1 / 270 (0.37%)	4 / 269 (1.49%)	5 / 270 (1.85%)	2 / 270 (0.74%)
occurrences all number	1	4	5	2
Arthritis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Arthralgia
subjects affected / exposed	55 / 270 (20.37%)	47 / 269 (17.47%)	45 / 270 (16.67%)	44 / 270 (16.30%)
occurrences all number	75	65	56	60
Musculoskeletal chest pain
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Pain in jaw
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Tendonitis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Synovial cyst
subjects affected / exposed	2 / 270 (0.74%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	2	0	0	0
Spinal pain
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Infections and infestations
Enterovirus infection
subjects affected / exposed	0 / 270 (0.00%)	2 / 269 (0.74%)	1 / 270 (0.37%)	2 / 270 (0.74%)
occurrences all number	0	2	1	2
Acute sinusitis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	2 / 270 (0.74%)	1 / 270 (0.37%)
occurrences all number	0	0	2	1
Bacterial vaginosis
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	1	0	0
Bronchitis
subjects affected / exposed	4 / 270 (1.48%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	4	0	0	0
Chlamydial infection
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Chronic sinusitis
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Conjunctivitis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	2 / 270 (0.74%)	0 / 270 (0.00%)
occurrences all number	0	0	2	0
COVID-19
subjects affected / exposed	6 / 270 (2.22%)	2 / 269 (0.74%)	7 / 270 (2.59%)	5 / 270 (1.85%)
occurrences all number	6	2	7	5
Cystitis
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	3 / 270 (1.11%)	9 / 270 (3.33%)
occurrences all number	1	1	3	9
Fungal infection
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	1	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	1	0	1
Gastrointestinal infection
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Gastrointestinal viral infection
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	1	1	0	1
Genitourinary tract infection
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Helicobacter infection
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Lyme disease
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Herpes zoster
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	1	1	0
Impetigo
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Infectious mononucleosis
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Influenza
subjects affected / exposed	2 / 270 (0.74%)	1 / 269 (0.37%)	0 / 270 (0.00%)	3 / 270 (1.11%)
occurrences all number	2	1	0	3
Laryngitis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Herpes virus infection
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	1	1	0
Nasopharyngitis
subjects affected / exposed	10 / 270 (3.70%)	10 / 269 (3.72%)	6 / 270 (2.22%)	5 / 270 (1.85%)
occurrences all number	11	11	6	6
Oral herpes
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	1	3	1	0
Pharyngitis
subjects affected / exposed	2 / 270 (0.74%)	2 / 269 (0.74%)	1 / 270 (0.37%)	2 / 270 (0.74%)
occurrences all number	2	2	1	2
Pharyngitis streptococcal
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Pulpitis dental
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	1 / 270 (0.37%)
occurrences all number	0	0	1	1
Pyelonephritis
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Respiratory tract infection
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	1 / 270 (0.37%)	1 / 270 (0.37%)
occurrences all number	1	1	1	2
Respiratory tract infection viral
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	0 / 270 (0.00%)	4 / 270 (1.48%)
occurrences all number	1	3	0	4
Rhinitis
subjects affected / exposed	3 / 270 (1.11%)	6 / 269 (2.23%)	5 / 270 (1.85%)	4 / 270 (1.48%)
occurrences all number	3	6	5	4
Sinusitis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Tonsillitis
subjects affected / exposed	1 / 270 (0.37%)	1 / 269 (0.37%)	0 / 270 (0.00%)	2 / 270 (0.74%)
occurrences all number	1	1	0	2
Tracheitis
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0
Upper respiratory tract infection
subjects affected / exposed	17 / 270 (6.30%)	11 / 269 (4.09%)	15 / 270 (5.56%)	11 / 270 (4.07%)
occurrences all number	17	15	16	11
Urinary tract infection
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	2 / 270 (0.74%)	1 / 270 (0.37%)
occurrences all number	0	1	2	1
Otitis externa
subjects affected / exposed	0 / 270 (0.00%)	1 / 269 (0.37%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	0	1	0	0
Vaginal infection
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	1 / 270 (0.37%)	1 / 270 (0.37%)
occurrences all number	1	0	1	1
Viral infection
subjects affected / exposed	3 / 270 (1.11%)	1 / 269 (0.37%)	0 / 270 (0.00%)	2 / 270 (0.74%)
occurrences all number	3	1	0	2
Vulvovaginitis
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Vulvovaginal candidiasis
subjects affected / exposed	1 / 270 (0.37%)	2 / 269 (0.74%)	2 / 270 (0.74%)	0 / 270 (0.00%)
occurrences all number	2	2	2	0
Metabolism and nutrition disorders
Vitamin D deficiency
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	0 / 270 (0.00%)	1 / 270 (0.37%)
occurrences all number	0	0	0	1
Folate deficiency
subjects affected / exposed	0 / 270 (0.00%)	0 / 269 (0.00%)	1 / 270 (0.37%)	0 / 270 (0.00%)
occurrences all number	0	0	1	0
Decreased appetite
subjects affected / exposed	1 / 270 (0.37%)	0 / 269 (0.00%)	0 / 270 (0.00%)	0 / 270 (0.00%)
occurrences all number	1	0	0	0

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Were there any global substantial amendments to the protocol? Yes

23 Jun 2022

This is a country-specific amendment for Germany to clarify that only adults between and including 18 to 26 years of age would be included in the study in this country.

23 Sep 2022

The purpose of this amendment was to allow for additional iSRC review(s) in case of enrollment delay to mitigate the risk that the iSRC for all 48 Step 1 participants may occur after the allowed interval range for their second vaccination dose. Additionally, the country-specific amendment for Germany (Protocol Amendment 1/DEU-1) to clarify that only adults between and including 18 to 26 years of age would be included in the study in Germany was incorporated. Further updates (as summarized below) were made to clarify the study procedures.

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

Clinical Trial Results: A Phase 1/2 randomized, observer-blinded, multi-country study to evaluate safety and immunogenicity of investigational adjuvanted human papillomavirus vaccine in females (16 to 26 years of age)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 1

Primary: Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 1

Primary: Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 2

Primary: Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 2

Primary: Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 3

Primary: Number of participants reporting Grade 3 solicited administration site events after vaccine Dose 3

Primary: Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 1

Primary: Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 1

Primary: Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 2

Primary: Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 2

Primary: Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 3

Primary: Number of participants reporting Grade 3 solicited systemic events after vaccine Dose 3

Primary: Number of participants reporting Grade 3 unsolicited adverse events (AEs) after vaccine Dose 1

Primary: Number of participants reporting Grade 3 unsolicited adverse events (AEs) after vaccine Dose 1

Primary: Number of participants reporting Grade 3 unsolicited AEs after vaccine Dose 2

Primary: Number of participants reporting Grade 3 unsolicited AEs after vaccine Dose 2

Primary: Number of participants reporting Grade 3 unsolicited AEs after vaccine Dose 3

Primary: Number of participants reporting Grade 3 unsolicited AEs after vaccine Dose 3

Primary: Number of participants reporting serious adverse events (SAEs)

Primary: Number of participants reporting serious adverse events (SAEs)

Primary: Number of participants in Step 1 subset with clinically relevant biochemical abnormalities

Primary: Number of participants in Step 1 subset with clinically relevant biochemical abnormalities

Primary: Number of participants in Step 1 subset with clinically relevant hematological abnormalities

Primary: Number of participants in Step 1 subset with clinically relevant hematological abnormalities

Primary: Number of participants in Step 1 subset with clinically relevant abnormalities in hemoglobin change from baseline levels

Primary: Number of participants in Step 1 subset with clinically relevant abnormalities in hemoglobin change from baseline levels

Primary: Anti-HPV immunoglobulin G (IgG) antibody concentrations

Primary: Anti-HPV immunoglobulin G (IgG) antibody concentrations

Secondary: Number of participants reporting any solicited administration site events

Secondary: Number of participants reporting any solicited administration site events

Secondary: Number of participants reporting any solicited systemic events

Secondary: Number of participants reporting any solicited systemic events

Secondary: Number of participants reporting any unsolicited AEs

Secondary: Number of participants reporting any unsolicited AEs

Secondary: Number of participants reporting potential immune-mediated diseases (pIMDs)

Secondary: Number of participants reporting potential immune-mediated diseases (pIMDs)

Secondary: Number of participants reporting pregnancies

Secondary: Number of participants reporting pregnancies

Secondary: Number of participants with outcomes of reported pregnancies

Secondary: Number of participants with outcomes of reported pregnancies

Secondary: Anti-HPV IgG antibody concentrations

Secondary: Anti-HPV IgG antibody concentrations

Secondary: Number of participants with seroconversion for anti-HPV IgG antibodies

Secondary: Number of participants with seroconversion for anti-HPV IgG antibodies

Secondary: Anti-HPV neutralizing titers

Secondary: Anti-HPV neutralizing titers

Secondary: Anti-HPV neutralizing titers in a subset of participants

Secondary: Anti-HPV neutralizing titers in a subset of participants

Secondary: Number of participants with seroconversion for anti-HPV neutralizing antibodies

Secondary: Number of participants with seroconversion for anti-HPV neutralizing antibodies

Secondary: Correlation between anti-HPV IgG antibody concentration and anti-HPV neutralizing antibody titers

Secondary: Correlation between anti-HPV IgG antibody concentration and anti-HPV neutralizing antibody titers

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 1/2 randomized, observer-blinded, multi-country study to evaluate safety and immunogenicity of investigational adjuvanted human papillomavirus vaccine in females (16 to 26 years of age)