Clinical Trials Register

Summary
EudraCT Number:	2016-005226-11
Sponsor's Protocol Code Number:	FIS-TAR-01-2016
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-01-25
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

2016-005226-11

A.3

Full title of the trial

Phase 4 clinical trial, randomized to evaluate the effect on immune recovery of triple antiretroviral maintenance therapy (elvitegravir / cobicistat 150/150 mg + tenofovir + emtricitabine alapenamide 10 mg 200 mg) versus simplification of combination therapy (dolutegravir + lamivudine or darunavir / Cobicistat + lamivudine) in HIV-infected patients with sustained undetectable viremia.

Ensayo clínico de fase 4, aleatorizado para evaluar el efecto sobre la recuperación inmune de la terapia de mantenimiento antiretroviral triple (elvitegravir / cobicistato 150/150 mg + tenofovir + emtricitabina alafenamida 10 mg 200 mg) versus simplificación de la terapia combinada (dolutegravir más lamivudina o darunavir / Cobicistat más lamivudina ) en pacientes con infección por VIH con viremia indetectable sostenida.

A.3.1

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

Phase 4 clinical trial to evaluate the effect on immune recovery of antiretroviral treatment of three drugs versus two in in HIV-infected patients but not dectactable in blood.

Ensayo clínico de fase 4 para evaluar el efecto sobre la recuperación inmunológica del tratamiento antiretroviral de tres fármacos frente a dos en pacientes con infección por VIH pero no dectactable en sangre.

A.4.1

Sponsor's protocol code number

FIS-TAR-01-2016

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	Fundación Pública Andaluza para la Gestión en Salud de Sevilla (FISEVI)
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	Own funding
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	Unidad de Investigación Clínica y ensayos Clínicos
B.5.2	Functional name of contact point	UICEC-HUVR
B.5.3	Address:
B.5.3.1	Street Address	AVENIDA MANUEL SIUROT S/N
B.5.3.2	Town/ city	SEVILLA
B.5.3.3	Post code	41013
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034955013414
B.5.5	Fax number	0034954232992
B.5.6	E-mail	claram.rosso.sspa@juntadeandalucia.es

D. IMP Identification
D.IMP: 1
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	Tivicay®
D.2.1.1.2	Name of the Marketing Authorisation holder	ViiV Healthcare UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Dolutegravir
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.3.11 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	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	Lamivudina Teva
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva B.V.
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	Lamivudina
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.3.11 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	Rezolsta®
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International NV
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Darunavir
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.3.11 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	Rezolsta®
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International NV
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Cobicistat
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.3.11 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

Adult patients with HIV infection on stable therapy (≥ 6 months) with triple therapy and undetectable viremia for ≥ 1 year.

Pacientes adultos con infección por el VIH en tratamiento estable (≥ 6 meses) con triple terapia y viremia indetectable durante ≥ 1 año.

E.1.1.1

Medical condition in easily understood language

Adult HIV-infected patients on treatment of ≥ 6 months with triple therapy and no virus in the blood for ≥ 1 year.

Pacientes adultos con infección por el VIH en tratamiento de ≥ 6 meses con triple terapia y sin presencia del virus en sangre durante ≥ 1 año.

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10049838
E.1.2	Term	HIV viral load undetectable
E.1.2	System Organ Class	100000004848

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	PT
E.1.2	Classification code	10077716
E.1.2	Term	HIV viraemia
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

Evaluate the effect on immune recovery maintaining a triple antiretroviral therapy (elvitegravir / cobicistat 150/150 mg + tenofovir + emtricitabine alafenamide 10 mg 200 mg) versus combination therapy simplification (dolutegravir plus lamivudine or darunavir / cobicistat plus lamivudine) after 48 weeks Of treatment in HIV-infected patients with sustained undetectable viremia.

Evaluar el efecto en la recuperación inmunológica del mantenimiento de una terapia antirretroviral triple (elvitegravir/cobicistat 150/150 mg + tenofovir alafenamide 10 mg + emtricitabina 200 mg) versus simplificación a biterapia (dolutegravir más lamivudina o darunavir/cobicistat más lamivudina) tras 48 semanas de tratamiento en pacientes con infección por el VIH con viremia indetectable de forma mantenida.

E.2.2

Secondary objectives of the trial

Evaluate whether a triple therapy based on (elvitegravir / cobicistat 150/150 mg + tenofovir alafenamide 10 mg + emtricitabine 200 mg) will lead to a greater decrease in immune activation and inflammation compared to simplification to bitherapy (dolutegravir plus lamivudine or darunavir / Cobicistat plus lamivudine) in HIV-infected patients and sustained undetectable viremia.

Evaluar si una triple terapia basada en (elvitegravir/cobicistat 150/150 mg + tenofovir alafenamide 10 mg + emtricitabina 200 mg) dará lugar a una disminución mayor de la activación inmunológica e inflamación comparado con la simplificación a biterapia (dolutegravir más lamivudina o darunavir/cobicistat más lamivudina) en pacientes con infección por el VIH y viremia indetectable de forma mantenida.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients with HIV infection and age ≥ 18 years.
- Initiation of antiretroviral treatment after 01/01/2013
- Undetectable viremia (<20 copies / ml for at least one year) with triple therapy.
- Nadir and CD4 + T lymphocyte count ≥200 / μl at the time of inclusion.
Informed written consent.

- Pacientes con infección por el VIH y edad ≥ 18 años.
- Inicio de tratamiento antirretroviral después del 01/01/2013
- Viremia indetectable (<20 copias/ml durante al menos un año) con triple terapia.
- Nadir y recuento de linfocitos T CD4+ ≥200/μl en el momento de la inclusión.
- Consentimiento informado por escrito.

E.4

Principal exclusion criteria

- Presence of major resistance mutations to any of the study drugs.
- Opportunistic infections active at the time of inclusion.
- Pregnancy at the time of inclusion or during the follow-up period.
- Active co-infection with B or C virus of hepatitis.
- Cirrhosis, portal hypertension and / or hypersplenism of any etiology.
- Past or current neoplasms of steroid treatment, immunomodulators, or chemotherapy
- Laboratory abnormalities grade 3 or 4.
- Concomitant use of drugs with higher drug interactions with study drugs, according to respective product data sheets.
- Estimated creatinine clearance <50ml / min.
- Withdrawal of informed consent.
- Patients who do not complete the follow-up period or with virological failure, defined as viremia> 200 copies in two consecutive determinations, during follow-up will be excluded from the analysis.

- Presencia de mutaciones de resistencia mayores a cualquiera de los fármacos del estudio.
- Infecciones oportunistas activas en el momento de la inclusión.
- Embarazo en el momento de la inclusión o durante el periodo de seguimiento.
- Co-infección active por virus B o C de la hepatitis.
- Cirrosis, hipertensión portal y/o hiperesplenismo de cualquier etiología.
- Neoplasias pasadas o actuales subsidiarias de tratamiento con esteroides, inmunomoduladores o quimioterapia
- Anomalías de laboratorio grado 3 o 4.
- Utilización concomitante de fármacos con interacciones farmacológicas mayores con los fármacos de estudio, según las respectivas fichas técnicas de los productos.
- Aclaramiento estimado de creatinina <50ml/min.
- Retirada del consentimiento informado.
- Asimismo, se excluirán del análisis aquellos pacientes que no completen el periodo de seguimiento o con fracaso virológico, definido como viremia >200 copiasen dos determinaciones consecutivas, durante el seguimiento.

E.5 End points

E.5.1

Primary end point(s)

Changes in the CD4 + / CD8 + T lymphocyte ratio after 48 weeks of treatment.

Cambios en el cociente de linfocitos T CD4+/CD8+ tras 48 semanas de tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 48 weeks of treatment.

Tras 48 semanas de tratamiento.

E.5.2

Secondary end point(s)

Changes in CD4 + / CD8 + T lymphocyte ratio after 96 weeks of treatment.
Changes after 48 and 96 weeks of treatment in:
Immunoactivation measured as HLA-DR and CD38 expression on CD4 + and CD8 + T lymphocytes and plasma levels of sCD14.
Expression of the following markers on CD4 + and CD8 + T lymphocytes: Ki67, PD-1, CD57, TRAIL, Annexin V and CD31.
Concentrations of the following proinflammatory mediators: IL-1β, IL-1ra, IL-2, IL-6, IL-10, IL-17, IFN-α and γ, IP-10, MIP-1 / 1β and dimers D.
Changes in microbial translocation measured by plasma concentrations of LPS and 16S rDNA.
Changes in proviral DNA (HIV-DNA) in PBMCs.

Cambios en el cociente de linfocitos T CD4+/CD8+ tras 96 semanas de tratamiento.
Cambios tras 48 y 96 semanas de tratamiento en:
Inmuno-activación medida como expresión de HLA-DR y CD38 en linfocitos TCD4+ y CD8+y niveles plasmáticos de sCD14.
Expresión de los siguientes marcadores en linfocitos T CD4+ y CD8+: Ki67, PD-1, CD57, TRAIL, Anexina V y CD31.
Concentraciones de los siguientes mediadores pro-inflamatorios: IL-1β, IL-1ra, IL-2, IL-6, IL-10, IL-17, IFN-α y γ, IP-10, MIP-1/1β y dímeros D.
Cambios en la translocación microbiana medida mediante concentraciones plasmáticas de LPS y 16S rDNA.
Cambios en ADN proviral (HIV-DNA)en PBMCs.

E.5.2.1

Timepoint(s) of evaluation of this end point

Changes after 48 and 96 weeks of treatment according to variable.

Cambios tras 48 y 96 semanas de tratamiento según variable.

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)

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

Final visit of the last patient included.

El día de la visita final del último paciente incluido.

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:

160

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

180

F.4.2

For a multinational trial

F.4.2.1

In the EEA

180

F.4.2.2

In the whole clinical trial

180

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)

Treatment after study as per investigators juice according to GCP

A juicio del investigador de acuerdo a BPCs

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

2017-04-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-31

P. End of Trial
P.	End of Trial Status	Ongoing

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