Clinical Trials Register

Summary
EudraCT Number:	2011-002071-42
Sponsor's Protocol Code Number:	HIV-IMMUNESARTAN
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-01-11
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

Spain - AEMPS

A.2

EudraCT number

2011-002071-42

A.3

Full title of the trial

Effects of losartan and antiretroviral regimen containing raltegravir in fibrosis inflammation mediators, cardiovascular risk and neurocognitive disorders in HIV infected patients previously effectively treated.

Efectos de Losartán y de un régimen antiretroviral conteniendo raltegravir en los mediadores de fibrosis-inflamación, en el riesgo cardiovascular y en los trastornos neurocognitivos, en pacientes infectados por HIV con tratamiento previo eficaz.

A.3.1

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

N/A

A.3.2

Name or abbreviated title of the trial where available

N/A

A.4.1

Sponsor's protocol code number

HIV-IMMUNESARTAN

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	Fundació Clínic de Recerca Biomèdica
B.1.3.4	Country	Spain
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	N/A
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fundació Clinic per a la Recerca Biomèdica
B.5.2	Functional name of contact point	CTU clinic-Farmacología clinica
B.5.3	Address:
B.5.3.1	Street Address	villarroel 170
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08036
B.5.3.4	Country	Spain
B.5.4	Telephone number	+349322754004380
B.5.5	Fax number	+34932279877
B.5.6	E-mail	acruceta@clinic.ub.es

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	Cozaar 50 mg comprimidos recubiertos con película Cozaar 100 mg comprimidos recubiertos con película
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme de España, S. A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Cozaar 50 mg comprimidos recubiertos con película
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	losartan potassium
D.3.9.1	CAS number	124750-99-8
D.3.9.3	Other descriptive name	LOSARTAN POTASSIUM
D.3.9.4	EV Substance Code	SUB02974MIG
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	50
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	Isentress 400 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	ISENTRESS
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RALTEGRAVIR POTASSIUM
D.3.9.1	CAS number	871038-72-1
D.3.9.3	Other descriptive name	RALTEGRAVIR POTASSIUM
D.3.9.4	EV Substance Code	SUB25668
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	400
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: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	ATRIPLA
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb and Gilead Sciences Limited
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	ATRIPLA
D.3.2	Product code	efavirenz 600 mg, emtricitabina 200 mg, tenofovir
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATRIPLA
D.3.9.1	CAS number	J05AR06
D.3.9.2	Current sponsor code	ATRIPLA
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	400
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: 4
D.1.2 and D.1.3	IMP Role	Comparator
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	TRUVADA
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Sciences International Limited
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	TRUVADA
D.3.2	Product code	emtricitabine 200/tenofovir 245
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TRUVADA
D.3.9.1	CAS number	J05AF09
D.3.9.2	Current sponsor code	TRUVADA
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	245
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.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 seropositive

Seropositivo para el HIV

E.1.1.1

Medical condition in easily understood language

HIV seropositive

seropositivo para el VIH

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10008919
E.1.2	Term	Chronic HIV infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10058315
E.1.2	Term	HIV disease progression
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Proportion of patients with decreased collagen deposition in TL equal to or greater than 50%.

Proporción de pacientes con disminución del deposito de colágeno en TL igual o mayor al 50%

E.2.2

Secondary objectives of the trial

1. Changes in markers of fibrosis and immune recovery TL: the ratio of MMP-9/TIMP-1 and MMP-2 / TIMP-2 in the TL, Changes in the count of CD4 + T cells in peripheral blood and LT changes the CD4/CD8 ratio in peripheral blood, changes in the value of HIV viral load in peripheral blood and LT.
2. Changes in markers of atherosclerosis: To determine the levels of IL-6, D-dimer and CRP in the different groups and changes in the diameter of the carotid intima as a marker of atherosclerosis.
3. Changes in markers of dementia and CNS inflammation: measuring levels of metalloproteinases and their inhibitors in cerebrospinal fluid, as well as beta2-microglobulin levels and levels of cells and proteins. Changes in neuropsychological test diagnosis of CDS.
4. Adverse Events.

1. Cambios en los marcadores de fibrosis de TL y de recuperación inmunológica: el cociente MMP-9/TIMP-1 y MMP-2/ TIMP-2 en el TL, Cambios en el recuento de linfocitos T CD4+ en sangre periférica y TL, Cambios en el cociente CD4/CD8 en sangre periférica, Cambios en el valor de la carga vírica del VIH en sangre periférica y TL.

2. Cambios en los marcadores de arteriosclerosis: Determinar los niveles de IL-6, D-dímero y PCR ultrasensible en los diferentes grupo y los cambios en el diámetro de la íntima carotídea como marcador de arteriosclerosis.

3. Cambios en los marcadores de demencia e inflamación de SNC: medición de los niveles de metaloproteasas y sus inhibidores en liquido cefalorraquídeo, además de niveles de beta2-microglobulina y niveles de células y proteinas . Cambios en test neuropsicológicos diagnósticos de CDS.

4. Efectos adversos.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients older than 18 years.
2. Patients with HIV infection in antiretroviral treatment with EFV / FTC / TDF with undetectable viral load (VL <37 copies) for at least 48 weeks.
3. Nadir CD4 +> 250 cells/mm3.
4. Patients, properly informed, give their written consent to participate in the study.

1. Pacientes con edad superior a 18 años.
2. Pacientes con infección por HIV en tratamiento antiretroviral con EFV/FTC/TDF y con carga viral indetectable (CV < 37 copias) durante al menos 48 semanas.
3. Nadir de CD4+ > 250 cel/mm3 (se permitirá una determinación < 250 cel/mm3 si se trata de una sola determinación aislada)
4. Pacientes que, adecuadamente informados, otorguen su consentimiento por escrito para participar en el estudio y someterse a las pruebas y exploraciones que ello comporta.

E.4

Principal exclusion criteria

1. Criteria for patients with AIDS.
2. Patients with active opportunistic diseases.
3. Patients coinfected with HCV.
4. Patients without tonsillar tissue.
5. Treatment with other drugs receptor antagonists or angiotensin II converting enzyme inhibitors, angiotensin II.
6. Kidney failure.(Glomerular Filtration Rate (GFR < 60 mL/mn)
7. Severe liver failure (PT> 60% ).
8. Pregnant women
9. Known hypersensitivity or contraindication to any study drug.
10. determination of blood pressure (BP) <100/60 mmHg
11. Hyponatremia with serum Na numbers <132 Meq / l
12. History of chronic vomiting the last 6 months
13. History of chronic diarrhea the last 6 months

1. Pacientes con criterios de SIDA.
2. Pacientes con enfermedades oportunistas activas.
3. Pacientes coinfectados por VHC.
4. Pacientes sin tejido amigdalar.
5. Tratamiento con otros fármacos antagonistas del receptor de la angiotensina II o con inhibidores de la enzima convertidora de la angiotensina II (ANEXO 3)
6. Insuficiencia renal (filtrado glomerular calculado con la fórmula MDRD) < 60 mL/min).
7. Insuficiencia hepática grave (tiempo de protrombina < 60%).
8. Embarazadas
9. Hipersensibilidad conocida o contraindicación a algún fármaco del estudio.
10. Cifras de Tensión arterial (TA) < 100/60 mmHg
11. Hiponatremia con cifras de Na sérico < 132 Meq/l
12. Antecedentes de vómitos de repetición los últimos 6 meses
13. Antecedentes de diarrea crónica los últimos 6 meses.

E.5 End points

E.5.1

Primary end point(s)

Proporción de pacientes con disminución del 50% de fibrosis en TL.

E.5.1.1

Timepoint(s) of evaluation of this end point

N/A

E.5.2

Secondary end point(s)

- Proporción de pacientes con cambios en los niveles de IL-6, D-dímero y PCR ultrasensible en los diferentes grupos.

- Proporción de pacientes con aumento de CD4 en sangre periférica y en TL en los diferentes grupos.

- Proporción de pacientes con carga viral indetectable en plasma y disminuida en TL en los diferentes grupos

- Proporción de pacientes con cambios en el cociente CD4/CD8 en sangre periférica en los diferentes grupos.

- Proporción de pacientes con disminución del complejo íntima media en la ecografía carotídea en los diferentes grupos.

- Proporción de pacientes con cambios en niveles de metaloproteasas y sus inhibidores , beta2 -microglobulina y células y proteínas en LCR.

- Proporción de pacientes con mejoría de los test neuropsicologicos de CDS

- Incidencia y tipos de efectos adversos clínicos y alteraciones analíticas en los diferentes grupos.

E.5.2.1

Timepoint(s) of evaluation of this end point

N/A

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

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

Yes

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

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

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.1.1.1

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)

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)

N/A

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

2012-01-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-12-16

P. End of Trial
P.	End of Trial Status	Completed

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