Clinical Trials Register

Summary
EudraCT Number:	2007-001731-55
Sponsor's Protocol Code Number:	106636
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-06-25
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
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Finland - Fimea

A.2

EudraCT number

2007-001731-55

A.3

Full title of the trial

A phase III/IV, community-randomized, controlled study to evaluate the effectiveness of two vaccination strategies using GlaxoSmithKline Biologicals’ HPV-16/18 L1 VLP AS04 vaccine in reducing the prevalence of HPV-16/18 infection when administered intramuscularly according to a 0, 1, 6-month schedule in healthy female and male study participants aged 12 – 15 years.

A.3.1

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

Evaluation of the effectiveness of two vaccination strategies using GlaxoSmithKline Biologicals’ HPV vaccine administered in healthy adolescents.

A.3.2

Name or abbreviated title of the trial where available

HPV-040 PRI

A.4.1

Sponsor's protocol code number

106636

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00534638

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	GlaxoSmithKline Biologicals
B.1.3.4	Country	Belgium
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	GlaxoSmithKline Biologicals
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline Biologicals
B.5.2	Functional name of contact point	Clinical Disclosure Advisor
B.5.3	Address:
B.5.3.1	Street Address	Rue de l'Institut, 89
B.5.3.2	Town/ city	Rixensart
B.5.3.3	Post code	1330
B.5.3.4	Country	Belgium
B.5.4	Telephone number	442089904466
B.5.5	Fax number	--------
B.5.6	E-mail	GSKClinicalSupportHD@gsk.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	No
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	Prophylactic HPV-16/18 L1 VLP AS04 vaccine
D.3.2	Product code	HPV-16/18 L1 VLP AS04 vaccine
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-16 L1 VLP antigen
D.3.9.3	Other descriptive name	HPV-16 L1 VLP antigen
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-18 L1 VLP antigen
D.3.9.3	Other descriptive name	HPV-18 L1 VLP antigen
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.IMP: 2
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	Engerix B
D.2.1.1.2	Name of the Marketing Authorisation holder	GlaxoSmithKline Biologicals s.a.
D.2.1.2	Country which granted the Marketing Authorisation	Finland
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.3.4	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	Hepatitis B surface antigen
D.3.9.3	Other descriptive name	Hepatitis B surface antigen
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	20
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

For the prevention of high-grade cervical intraepithelial neoplasia (CIN grades 2 and 3) and cervical cancer causally related to human papillomavirus (HPV) types 16 and 18.

E.1.1.1

Medical condition in easily understood language

Cervarix is a vaccine that protects against infection caused by human papillomavirus types 16 and 18. These viruses can infect the skin, the genitals and the oral cavity.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	HLT
E.1.2	Classification code	10008230
E.1.2	Term	Cervix neoplasms malignant
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

CO-PRIMARY OBJECTIVES
• To demonstrate the overall (direct and indirect) effectiveness of GSK Biologicals’ HPV-16/18 vaccine in reducing the prevalence of HPV-16/18 genital infection in females approximately 18.5 years of age following community-based vaccination of 12 - 15 year old females only (Arm B versus Arm C).
• To demonstrate the overall (direct and indirect) effectiveness of GSK Biologicals’ HPV-16/18 vaccine in reducing the prevalence of HPV-16/18 genital infection in females approximately 18.5 years of age, following community-based vaccination of 12 - 15 year old females and males (Arm A versus Arm C).

E.2.2

Secondary objectives of the trial

• Compare overall effectiveness of GSKs HPV-16/18 vaccine in reducing the prevalence of HPV-16/18 genital infection
- In females approx. 18.5 YOA following community-based HPV vaccination of 12-15 yr old females vs. HPV vaccination of 12-15 yr old females and males (Arm A vs. Arm B).
- with oncogenic HPV types in females approx. 18.5 YOA, following community-based vaccination of 12-15 yr old females only (Arm B vs. Arm C) and 12-15 yr old females and males (Arm A vs. Arm C)
• Evaluate the direct effectiveness of GSKs HPV-16/18 vaccine in reducing the prevalence of HPV-16/18 oropharyngeal infection:
- In females following community-based HPV vaccination of 12-15 yr old females/females and males.
- and with oncogenic HPV types in females following community-based HPV vaccination of 12-15 yr old females/females and males.
• To monitor the safety of HPV-16/18 vaccination in males and females and assess the immunogenicity of the HPV-16/18 vaccine in Arm A immuno subset.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria for community selection:•A Finnish urban community including between 1000 and 9000 male and female adolescents when pooling birth cohorts from four consecutive years (1992 - 1995);•Geographically distinct communities;•Minimal distance between communities had to be at least of 50 kilometres (35 kilometers in the Helsinki metropolitan area) (to decrease risk acquisition of HPV infection between adolescents residing in different communities);•Communities with appropriate study personnel available to conduct the trial;•Availability of an HPV vaccine registry, to monitor opportunistic vaccination with a licensed HPV vaccine.

Inclusion criteria for study participants during the immunisation phase:
• Study participants who the investigator believes that they and/or their parents/legally acceptable representative can and will comply with the requirements of the protocol (should be enrolled in the study.
•A male or female between, and including, 12 and 15 years of age at the time of the first vaccination.
•A written informed consent/assent must be obtained from all study participants prior to enrolment. In addition, for study participants below legal age of consent (15 years) a written informed consent must be obtained from the parent or legally acceptable representative.
•A written informed assent must be obtained from all study participants prior to enrolment. In addition, a written informed consent must be obtained from the study participants’ parent or legally acceptable representative. As according to the Finnish law legal age of consent is 15 years, a written informed consent form can be obtained from study participants aged 15 years old and their parent(s)/legally acceptable representative(s) will receive a letter informing them of their child participation to the study.
•Healthy male and female study participants as established by medical history before entering into the study. If needed, an history-directed clinical examination will be performed by the investigator or delegate (e.g. study nurse).
•Subjects should not be pregnant. Absence of pregnancy should be verified (e.g. urine pregnancy test) as per investigator’s clinical judgement.
•If the study participant is female, she must be of non-childbearing potential, i.e. be abstinent, have a current tubal ligation, hysterectomy, ovariectomy or be post-menopausal or pre-menarcheal, or if she is of childbearing potential and has not practiced adequate contraception for 30 days prior to vaccination, she must have a negative pregnancy test and continue adequate contraception for 2 months after completion of the vaccination series.

E.4

Principal exclusion criteria

Immunization phase:
•Previous vaccination against HPV or Hepatitis B virus.
•History of allergic disease or reactions likely to be exacerbated by any component of the vaccines.
•Acute disease at the time of enrolment. (Acute disease is defined as the presence of a moderate or severe illness with or without fever. All vaccines can be administered to persons with a minor illness such as diarrhoea, mild upper respiratory infection with or without low-grade febrile illness, i.e. Oral temperature <37.5°C (99.5°F) / Axillary temperature <37.5°C (99.5°F) / Rectal temperature <38°C (100.4°F).)
•Pregnant or lactating female.

E.5 End points

E.5.1

Primary end point(s)

• Genital HPV-16 and/or HPV-18 DNA positivity (by PCR) in females approximately 18.5 years of age in Arm B vs C.
•Genital HPV-16 and/or HPV-18 DNA positivity (by PCR) in females approximately 18.5 years of age in Arm A vs C.

E.5.1.1

Timepoint(s) of evaluation of this end point

At final analysis.

E.5.2

Secondary end point(s)

•Genital HPV-16 and/or HPV-18 DNA positivity (by PCR) in females approximately 18.5 years of age in Arm A vs B.
•Genital oncogenic HPV DNA positivity (by PCR) (overall and individually) in females approximately 18.5 years of age. •Oropharyngeal HPV-16 and/or HPV-18 DNA positivity (by PCR) in females in Arms A, B and C.
•Oropharyngeal oncogenic HPV DNA positivity (by PCR) in females in Arms A, B, and C.
•Occurrence, intensity and causal relationship to vaccination of solicited (local and general) symptoms within 7 days (Days 0 - 6) after any vaccination (study participants in the Diary Card subset).
•Occurrence, intensity and causal relationship to vaccination of unsolicited symptoms within 30 days (Days 0 - 29) after any vaccination (study participants in the Diary Card subset).
•Occurrence of rash and urticaria within 30 minutes following vaccination (study participants in the Diary Card subset).
•Occurrence of medically significant conditions from dose 1 until Month 12 (study participants in the Diary Card subset).
•Occurrence and causal relationship to vaccination of SAEs from dose 1 until Month 12 (male study participants in the Diary Card subset and remaining Arm A male study participants)
•Occurrence of SAEs assessed by the investigator as possibly related to vaccination reported during the entire study period up to Visit 5 (all study participants)
•Occurrence of new onset of autoimmune diseases between Visit 1 and Visit 5 retrieved from Care Register for Social Welfare and Health (HILMO) (all study participants)
•Occurrence of pregnancies with onset between Visit 1 and Visit 5, and their outcomes, retrieved from medical birth registry (all female study participants).
•Anti-HPV-16/18 antibody levels and quality assessed at the time of serum withdrawal (Visits 1, 4, and 5) (study participants in the immunogenicity subset).

E.5.2.1

Timepoint(s) of evaluation of this end point

At interim analysis of immunogenicity and safety and/or at final analysis.

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

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

Yes

E.6.13.1

Other scope of the trial description

Effectiveness, immunogenicity.

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)

Yes

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Partially blind

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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 the final analysis of effectiveness, a study participant who returns for the concluding visit (Visit 5, 18.5 years of age) is considered to have completed the study.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

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:

36000

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:

36000

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2007-06-25.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

Yes

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.4.1

In the member state

36000

F.4.2

For a multinational trial

F.4.2.1

In the EEA

36000

F.4.2.2

In the whole clinical trial

36000

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)

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2007-08-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-06-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-12-17

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