Clinical Trials Register

Summary
EudraCT Number:	2011-001871-37
Sponsor's Protocol Code Number:	LTN0001
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-05-31
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

Denmark - DHMA

A.2

EudraCT number

2011-001871-37

A.3

Full title of the trial

Immune Response to Bivalent or Tetravalent Human Papillomavirus Vaccine in HIV infected Adults

A.3.1

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

Comparison of vaccine effects of two different vaccines against Human Papillomavirus in HIV infected people

A.3.2

Name or abbreviated title of the trial where available

HIPAVAC study

A.4.1

Sponsor's protocol code number

LTN0001

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	Department of Infectious Diseases - Aarhus University Hospital
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Department of Infectious Diseases, Aarhus University Hospital
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Infectious Diseases, Aarhus University Hospital
B.5.2	Functional name of contact point	Research Department
B.5.3	Address:
B.5.3.1	Street Address	Brendstrupgaardsvej 100
B.5.3.2	Town/ city	Aarhus N
B.5.3.3	Post code	8200
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4589498491
B.5.5	Fax number	+45 89498490
B.5.6	E-mail	larsnise@rm.dk

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 SNC
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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.3.4	Pharmaceutical form	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.3.9.3	Other descriptive name	HUMAN PAPILLOMAVIRUS TYPE 16 L1 PROTEIN ADSORBED ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE
D.3.9.4	EV Substance Code	SUB25252
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
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.3.9.3	Other descriptive name	HUMAN PAPILLOMAVIRUS TYPE 6 L1 PROTEIN ADSORBED ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE
D.3.9.4	EV Substance Code	SUB25358
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	HUMAN PAPILLOMAVIRUS TYPE 11 L1 PROTEIN ADSORBED ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE
D.3.9.4	EV Substance Code	SUB25352
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
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.3.9.3	Other descriptive name	HUMAN PAPILLOMAVIRUS TYPE 18 L1 PROTEIN ADSORBED ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE
D.3.9.4	EV Substance Code	SUB25253
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
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	No
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	Cervarix
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	Denmark
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	Cervarix
D.3.4	Pharmaceutical form	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.3.9.3	Other descriptive name	HUMAN PAPILLOMAVIRUS VACCINE [TYPES 16, 18] (RECOMBINANT, ADJUVANTED, ADSORBED)
D.3.9.4	EV Substance Code	SUB27633
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
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	No
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

HIV
Human Papilloma Virus

E.1.1.1

Medical condition in easily understood language

HIV
Human Papilloma Virus

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
E.1.2	Level	LLT
E.1.2	Classification code	10020443
E.1.2	Term	Human immunodeficiency virus syndrome
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
E.1.2	Level	LLT
E.1.2	Classification code	10063001
E.1.2	Term	Human papilloma virus infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
E.1.2	Level	LLT
E.1.2	Classification code	10046859
E.1.2	Term	Vaccination
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

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 compare induction of anti-HPV-16 and -18 antibodies in the bivalent HPV vaccine group vs. the Tetravalent HPV vaccine group as measured by pseudovirion neutralization titer.

E.2.2

Secondary objectives of the trial

- To evaluate and compare induction of cross protection against other HPV-serotypes in the bivalent HPV vaccine group vs. the Tetravalent HPV vaccine group.
- To evaluate tolerance and safety of Bivalent and Tetravalent HPV vaccines in HIV infected adults.
- To compare the induction of immunological memory against HPV-6, -11, -16 and -18 in the bivalent HPV vaccine group vs. the Tetravalent HPV vaccine group.
- To screen study participants for prevalent HPV-infection and investigate for serological evidence of previous HPV-infection
- To compare antibody responses to HPV vaccination in patients receiving HAART and patients not receiving HAART.
- To compare induction of cellular immunity against vaccine-specific HPV-types in the bivalent HPV vaccine group vs. the Tetravalent HPV vaccine group.
- To assess induction of innate immune activation after vaccination with either of the HPV-vaccines.
- To assess if HAART-treatment can predict vaccine response.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Written informed consent and authority statement provided according to local regulatory and ethical practice using a participant information sheet and informed consent form approved by the responsible Ethics Committee.
2) Male or female participants ≥ 18 years.
3) HIV-seropositive individuals.

E.4

Principal exclusion criteria

1) Pregnancy as determined by a positive urine beta-hCG (if female)
2) Participants unwilling to use reliable contraception for the duration of the trial (if female). Reliable methods of birth control include: pharmacologic contraceptives including oral, parenteral and transdermal delivery, surgical sterilization, vaginal ring, intrauterine device, abstinence and post-menopause (if female).
3) Currently breast-feeding (if female)
4) Viral load (HIV-RNA) > 50 copies/mL if on HAART
5) Previous enrolment in the study
6) Any medical, psychiatric, social or occupational condition that, in the judgement of the Principal Investigator (PI) would interfere with the evaluation of study objectives (such as severe alcohol abuse, severe drug abuse and dementia)
7) Unable to follow protocol regimen
8) Previous HPV-vaccination
9) Planned participation in other vaccination trials during the time of the study.
10) Cancer, autoimmune disease or chronic administration of systemic immunosuppressive drugs.

E.5 End points

E.5.1

Primary end point(s)

- Quantitative measurement of Serum Neutralization titer of anti-HPV-16 and -18 antibodies

E.5.1.1

Timepoint(s) of evaluation of this end point

- Day 210 from first vaccination

E.5.2

Secondary end point(s)

- Number and intensity of adverse and serious adverse events.
- Induction of antibodies cross reactive to toher HPV serotypes
- HPV specific B-cell analyses.
- B-cell phenotype specific analyses.
- HPV specific T-cell analyses.
- T-cell phenotype specific analyses.
- HPV specific cell mediated immune response: Secretion of IFN gamma, TNF alfa and IL-2 when stimulated with HPV antigen.
Quantitative measures of cytokine producing T-cells with subsequent
flow cytometry.
- Changes in HPV-DNA from material obtained from cervix (females), rectum and tonsils.
- Non-specific innate immune activation and responsivity.

E.5.2.1

Timepoint(s) of evaluation of this end point

- Safety issues are evaluated after each vaccination.
- Other outcomes are evaluated at day 0, day 45, day 180, day 210 and day 360

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

Yes

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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

Yes

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

LVLS

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

F.1.1

Number of subjects for this age range:

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

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

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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.4.1

In the member state

100

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)

Normal HIV treatment

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

2011-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-05-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-12-03

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