Clinical Trials Register

Summary
EudraCT Number:	2015-002932-42
Sponsor's Protocol Code Number:	V501-110-01
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2016-12-14
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2015-002932-42

A.3

Full title of the trial

A Phase IV Open-label, Descriptive Study to Evaluate the Safety and Effectiveness on the Incidence of HPV 6, 11, 16 and 18 Related CIN 2/3 or worse of the Quadrivalent HPV (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) Vaccine in 16- to 26-Year-Old Japanese Women.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Post-marketing study of safety and efficacy of GARDASIL in young Japanese women.

A.3.2

Name or abbreviated title of the trial where available

V501 Safety and Efficacy Study in Japanese Women Aged 16 to 26 Years

A.4.1

Sponsor's protocol code number

V501-110-01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01544478

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	MSD K.K., a subsidiary of Merck & Co., Inc
B.1.3.4	Country	Japan
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MSD K.K., a subsidiary of Merck & Co., Inc
B.4.2	Country	Japan
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	MSD K.K., a subsidiary of Merck & Co., Inc
B.5.2	Functional name of contact point	Shinya Murata
B.5.3	Address:
B.5.3.1	Street Address	Kitanomaru Square
B.5.3.2	Town/ city	1-13-12, Kudan-kita, Chiyoda-Ku
B.5.3.3	Post code	Tokyo, 102-866
B.5.3.4	Country	Japan
B.5.4	Telephone number	+8136272-1639
B.5.5	Fax number	+8136238-9117
B.5.6	E-mail	shinya.murata@merck.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	GARDASIL
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Pasteur MSD
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	GARDASIL
D.3.2	Product code	V501
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HPV 6 TYPE L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
D.3.9.3	Other descriptive name	Human Papillomavirus (HPV) Recombinant Vaccine
D.3.9.4	EV Substance Code	SUB25327
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HPV TYPE 16 L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
D.3.9.3	Other descriptive name	Human Papillomavirus (HPV) Recombinant Vaccine
D.3.9.4	EV Substance Code	SUB25329
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HPV TYPE 11 L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
D.3.9.3	Other descriptive name	Human Papillomavirus (HPV) Recombinant Vaccine
D.3.9.4	EV Substance Code	SUB25330
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HPV TYPE 18 L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
D.3.9.3	Other descriptive name	Human Papillomavirus (HPV) Recombinant Vaccine
D.3.9.4	EV Substance Code	SUB25328
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Human Papillomavirus infection

E.1.1.1

Medical condition in easily understood language

vaccination against HPV infection/related disease

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate the incidence of HPV types 6, 11, 16 and 18 related CIN 2 and 3, AIS and cervical cancer in Japanese women aged 16 to 26 years old who had been vaccinated with the quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine and were PCR negative and seronegative at baseline and PCR negative through Month 7
for the relevant HPV type.

E.2.2

Secondary objectives of the trial

1) To investigate the incidence of HPV types 6, 11, 16 and 18 related external genital lesion (condyloma acuminata, Vulvar Intraepithelial Neoplasia (VIN) 1/2/3, Vaginal Intraepithelial Neoplasia (VaIN) 1/2/3, vulvar cancer and/or vaginal cancer) in Japanese women aged 16 to 26 years old who had been vaccinated with the
quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine and were PCR negative and seronegative at baseline and PCR negative through Month 7 for the relevant HPV type.

2) To demonstrate that a 3-dose regimen of quadrivalent HPV (Types 6, 11,16, 18) L1 VLP vaccine is generally well tolerated.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Healthy Japanese females age 16 to 26 years.
2) Subject (or, for minor subjects, parent/legal guardian and subject) fully understands
study procedures, alternative treatments available, the risks involved with the study
and voluntarily agrees to participate by giving written informed consent.
3) No clinical evidence of gross purulent cervicitis (otherwise postpone until after
treatment or lack of laboratory confirmation of treatable cause).
4) *Must agree to refrain from douching/vaginal cleansing or using vaginal medication or
preparation for 2 calendar days prior to any scheduled visit that includes a pelvic
examination.
5) *Must agree to refrain from sexual activity (including vaginal and anal penetration and
any genital contact) for 2 calendar days prior to any scheduled visit that includes a
pelvic exam, in an attempt to avoid detection of viral DNA which has been deposited in the vagina or on the perineal/perianal area during sexual intercourse and is not the
result of ongoing infection.
6) Not pregnant now (as determined by a urine pregnancy test sensitive to 25 IU hCG),
and must agree to use effective contraception through Month 7 of the study. Effective
contraception will be considered: oral contraceptives or injection contraception IUD,
sterilization, abstinence, condom (male), diaphragm, cervical cap.
7) *Individuals who have had sexual intercourse in the 2 weeks prior to enrollment must
have been using effective contraception as defined above. (Emergency contraception is
not considered effective contraception for enrollment into the study.)
8) Individuals with a lifetime history of 0 to 4 male or female sexual partners. Women
with 0 lifetime male or female sexual partners must be at least 18 years of age and, if
heterosexual or bisexual, they plan to become sexually active within the first 3 months
of the study.
9) Must agree to provide study personnel with a primary telephone number as well as an
alternate telephone number for follow-up purposes.
10) *No temperature ≥37.5°C (oral) within 24 hours prior to injection.

E.4

Principal exclusion criteria

1) Individuals concurrently enrolled in clinical studies of investigational agents or studies involving collection of cervical specimens.
2) Subject has received a marketed HPV vaccine, or has participated in an HPV vaccine clinical trial and has received active agent.
3) *Receipt of inactivated vaccines within 14 days prior to enrollment or receipt of live virus vaccines within 28 days prior to enrollment.
4) Individuals with any prior abnormal Pap test showing squamous intraepithelial lesion (SIL), ASC-US, ASC-H, Class III or worse (Papanicolaou's classification), or biopsy showing cervical intraepithelial neoplasia (CIN).
5) Subject has a history of a positive test for HPV.
6) Individuals with genital warts or any prior history of, or treatment for genital warts.
7) History of severe allergic reaction (e.g., swelling of the mouth and throat, difficulty breathing, hypotension or shock) that required medical intervention.
8) Individuals allergic to any vaccine component, including aluminum, yeast, or BENZONASE™ (nuclease, Nycomed [used to remove residual nucleic acids from this and other vaccines]). For the purpose of this exclusion criterion, an allergy to vaccine components is defined as an allergic reaction that met the criteria for serious adverse experiences defined in Section 3.4.
9) Individuals who have received any immune globulin or blood derived products within the 6 months prior to the first injection, or plan to receive any through Month 7 of the study.
10) Individuals with history of splenectomy, known immune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis), or receiving immunosuppressives (e.g., substances or treatments known to diminish the immune response such as radiation therapy, administration of antimetabolites, antilymphocytic sera, systemic
corticosteroids). Individuals who have received periodic treatments with immunosuppressives, defined as at least 3 courses of oral corticosteroids each lasting at least 1 week in duration for the year prior to enrollment, will be excluded. Subjects using topical steroids (i.e., inhaled, or nasal, or topical) will be eligible for vaccination.
11) Individuals who are immunocompromised or have been diagnosed as having HIV infection.
12) Individuals with known thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections.
13) History of recent (within 1 year from the date of enrollment) or ongoing alcohol abuse
or other drug abuse.
14) Any condition which in the opinion of the investigator might interfere with the
evaluation of the study objectives.
15) Any plans to permanently relocate from the area prior to the completion of the study or
to leave for an extended period of time when study visits would need to be scheduled.
16) Individuals with >4 lifetime male or female sexual partners.
17) *Subject is having menses.
18) Subject does not have an intact cervix uteri or has more than one cervix uteri

E.5 End points

E.5.1

Primary end point(s)

Incidence of HPV 6-, 11-, 16- or 18-related CIN 2/3 or worse

E.5.1.1

Timepoint(s) of evaluation of this end point

In the primary per-protocol analysis, follow-up for efficacy begins following the Month 7 visit and efficacy is assessed to end of the study (Month 48 visit).

E.5.2

Secondary end point(s)

Efficacy Endpoints:
• Incidence of HPV 6-, 11-, 16- or 18-related EGLs
• Incidence of any grade CIN1 or worse due to any HPV type
• Incidence of any grade EGLs due to any HPV type
Safety Endpoints:
• Incidence of vaccine-related serious adverse experiences occurring any time during the study,
• Non-serious adverse experiences occurring Day 1 through Day 15 following any vaccination
• Serious adverse experiences occurring Day 1 through Day 15 following any vaccination
• New medical condition occurring any time during the study

E.5.2.1

Timepoint(s) of evaluation of this end point

In the primary per-protocol analysis, follow-up for efficacy begins following the Month 7 visit and efficacy is assessed to end of the study (Month 48 visit). Safety is assessed from Day 1 to Month 48.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

Japan

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

For purposes of analysis and reporting, the overall trial ends when the Sponsor receives the last assay results (e.g. serum, swab, and biopsy) or patient data from the last study-related phone-call or visit.

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

1030

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

1028

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

1000

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	Japan

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