Clinical Trials Register

Summary
EudraCT Number:	2013-004747-23
Sponsor's Protocol Code Number:	BPC01-001
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:	2014-01-17
Trial 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

2013-004747-23

A.3

Full title of the trial

An Open Phase I/IIa Study to Evaluate the Safety and Effect of Therapeutic HIV-1 Immunization using Vacc-4x + rhuGM-CSF, and HIV-1 Reactivation using Romidepsin, on the Viral Reservoir in Virologically Suppressed HIV-1 Infected Adults on cART

A.3.1

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

Safety and Effect of the Histone Deacetylase Inhibitor Romidepsin and the Therapeutic Vaccine Vacc-4x for Reduction of the Latent HIV Reservoir

A.3.2

Name or abbreviated title of the trial where available

REDUC

A.4.1

Sponsor's protocol code number

BPC01-001

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	Bionor Pharma ASA
B.1.3.4	Country	Norway
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	Bionor Pharma ASA
B.4.2	Country	Norway
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	KLIFO A/S
B.5.2	Functional name of contact point	Joris Wilms
B.5.3	Address:
B.5.3.1	Street Address	Fruebjergvej 3
B.5.3.2	Town/ city	Copenhagen O
B.5.3.3	Post code	DK-2100
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4539 17 99 26
B.5.5	Fax number	+4539 20 90 45
B.5.6	E-mail	jow@klifo.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	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	VACC4X
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intradermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Vacc-10
D.3.9.2	Current sponsor code	Vacc-10
D.3.9.3	Other descriptive name	VACC-10
D.3.9.4	EV Substance Code	SUB96362
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.9
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Vacc-11
D.3.9.2	Current sponsor code	Vacc-11
D.3.9.3	Other descriptive name	Vacc-11
D.3.9.4	EV Substance Code	SUB96362
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.9
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Vacc-12
D.3.9.2	Current sponsor code	Vacc-12
D.3.9.3	Other descriptive name	Vacc-12
D.3.9.4	EV Substance Code	SUB96362
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.9
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Vacc-13
D.3.9.2	Current sponsor code	Vacc-13
D.3.9.3	Other descriptive name	Vacc-13
D.3.9.4	EV Substance Code	SUB96362
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.9
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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)	No
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	Istodax
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	romidepsin
D.3.4	Pharmaceutical form	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ROMIDEPSIN
D.3.9.1	CAS number	128517-07-7
D.3.9.4	EV Substance Code	SUB26362
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	Yes
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: 3
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	Leukine®,
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis U.S. LLC
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Leukine (R)
D.3.2	Product code	Sargramostim (GM-CSF)
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intradermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SARGRAMOSTIM
D.3.9.1	CAS number	123774-72-1
D.3.9.3	Other descriptive name	GM-CSF
D.3.9.4	EV Substance Code	SUB10450MIG
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	250
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

HIV-infection

E.1.1.1

Medical condition in easily understood language

HIV-infection

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10008919
E.1.2	Term	Chronic HIV infection
E.1.2	System Organ Class	100000004862

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 ensure that the chosen dose and dosing schedule of romidepsin is both safe and able to induce HIV-1 expression in latently infected CD4+ T cells, the study is planned in two parts with the following specific objectives:
Part A
1. The primary objective is to evaluate the safety and tolerability of romidepsin at a reduced dosing of 5 mg/m2 in HIV- infected patients.
Part B
2.The primary objective is to measure the effect of treatment with Vacc-4x + rhuGM-CSF and cyclic romidepsin treatment on the HIV-1 latent reservoir in HIV-infected patients virologically suppressed on cART.
The main hypothesis is that therapeutic use of a potent HDACi will lead to short-term increases in HIV-1 transcription and long-term reductions in the HIV-1 reservoir size due to increased levels and responsiveness of HIV-1-specific cytotoxic T lymphocytes in Vacc-4x immunized subjects.

E.2.2

Secondary objectives of the trial

PartA
1. The secondary objective is to determine the effect of romidepsin treatment on HIV-1 transcription in HIV-infected patients virologically suppressed on cART.
Part B secondary objectives:
- to evaluate the safety and tolerability of romidepsin and vacc4x in combination with GM-CSF
-to evaluate the treatment induced effect on virological control of HIV-infection following a monitoring antiretroviral pause.
- to determine the effect of Vacc-4x and romidepsin treatment on HIV-1 transcription in HIV-infected patients virologically suppressed on cART.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Age >18 years
2) Currently receiving cART and having received cART for a minimum of 1 year
3) HIV-1 plasma RNA <50 copies/mL for at least 1 year (excluding viral load blips)
4) CD4 T-cell count ≥500 cells/mm3 at screening

E.4

Principal exclusion criteria

1) CD4 T cell count nadir <200 cells/mm3
2) Previous treatment with an HDACi (Histone deacetylase inhibitor) within the previous 6 months
3) Any evidence of an active AIDS-defining opportunistic infection, active HBV or HCV co-infection, significant cardiac disease, malignancy, transplantation, insulin dependent diabetes mellitus or other protocol defined excluded medical condition
4) Use of any protocol defined contraindicated medication or vaccination
5) Unacceptable values of the hematologic and clinical chemistry parameters as defined in the protocol.
6) Males or females who are unwilling or unable to use protocol defined methods of contraception

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoints PART A
1) Safety and tolerability evaluation as measured by adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR), serious unexpected adverse reactions (SUSAR)

Primary Endpoints PART B
Latent reservoir size measured in CD4+ T cells by:
a) HIV-1 viral outgrowth assay (HIV-1 RNA per 106 in resting memory CD4+ T cells (RUPM))
b) Integrated HIV-1 DNA (copies per 106 CD4+ T cells)
c) Total HIV-1 DNA (copies per 106 CD4+ T cells)

E.5.1.1

Timepoint(s) of evaluation of this end point

Part A after 16 weeks
Part B after 45 weeks

E.5.2

Secondary end point(s)

Secondary Endpoints PART A
1) HIV transcription measured as cell associated unspliced HIV-1 RNA (copies per 106 CD4+ T cells)
2) HIV transcription measured as plasma HIV RNA (by NAT screen and standard HIV RNA)
3) Histone H3 acetylation in lymphocytes
4) Size of the latent HIV-1 reservoir as measured in CD4+ T cells as measured by
a) HIV-1 viral outgrowth assay (HIV-1 RNA per 106 in resting memory CD4+ T cells (RUPM))
b) Integrated HIV-1 DNA (copies per 106 CD4+ T cells)
c) Total HIV-1 DNA (copies per 106 CD4+ T cells)

Secondary Endpoints PART B
1) Safety: Safety and tolerability evaluation as measured by adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR), suspected unexpected serious adverse reactions (SUSAR) and dose-limiting toxicity
2) Time to re-initiation of cART
3) Time to detectable viremia (>50copies/mL) during cessation of cART
4) HIV transcription measured as cell associated unspliced HIV-1 RNA (copies per 10⁶ CD4+ T cells)
5) HIV-specific T-cell responses as measured by ELISpot, T cell proliferation and probably also intracellular cytokine staining
6) Plasma HIV-1 viral load
7) Histone H3 acetylation as measured in lymphocytes
8) T cell count and phenotype
9) Antibody titer to Vacc-4x peptides and to p24 as measured by
10) Change in antibody titer to C5 as measured by ELISA.

E.5.2.1

Timepoint(s) of evaluation of this end point

Part A: week 16
Part B: week 45

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Exploratory

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

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

Yes

E.8.1.7.1

Other trial design description

Study is split in part A and B. See objectives

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

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-01-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-05-29

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