Clinical Trials Register

Summary
EudraCT Number:	2017-000151-10
Sponsor's Protocol Code Number:	TAR-PRO
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:	2017-06-12
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

2017-000151-10

A.3

Full title of the trial

Antiretroviral therapy proviral genotype-guided: pilot-proof of concept clinical trial.

Tratamiento antirretroviral guiado por genotipo proviral: ensayo clínico piloto de prueba de concepto.

A.3.1

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

Antiretroviral treatment guiaded by proviral genotype

Tratamiento antirretroviral guiado por genotipo proviral

A.4.1

Sponsor's protocol code number

TAR-PRO

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 para la Investigación Biomédica del Hospital Universitario La Paz
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	Instituto de Salud Carlos III
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	Hospital Universitario La Paz
B.5.2	Functional name of contact point	UCICEC
B.5.3	Address:
B.5.3.1	Street Address	Paseo de la Castellana, 261
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28046
B.5.3.4	Country	Spain
B.5.4	Telephone number	34912071466
B.5.5	Fax number	34912071466
B.5.6	E-mail	guiomar11032016@gmail.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	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	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	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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DOLUTEGRAVIR
D.3.9.3	Other descriptive name	DOLUTEGRAVIR
D.3.9.4	EV Substance Code	SUB35122
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	EPIVIR
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	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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LAMIVUDINE
D.3.9.1	CAS number	134678-17-4
D.3.9.4	EV Substance Code	SUB08392MIG
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	300
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

Human Immunodeficiency Virus

Virus de Inmunodeficiencia Humana

E.1.1.1

Medical condition in easily understood language

HIV

VIH

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

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 evaluate the efficacy of DTG and 3TC for maintenance of virological suppression in patients with a history of treatment with 3TC or emtricitabine (FTC) (with or without M184V / I or K65R / E / N in plasma genotypes) but without presence of M184V / I or K65R / E / N mutations in proviral DNA by population sequencing.

Evaluar la eficacia de DTG y 3TC para el mantenimiento de la supresión virológica en pacientes con historia de tratamiento con 3TC o emtricitabina (FTC) (con o sin M184V/I o K65R/E/N en genotipos poblacionales en plasma) pero sin presencia de mutaciones M184V/I o K65R/E/N en ADN proviral por secuenciación poblacional.

E.2.2

Secondary objectives of the trial

1. Evaluate the frequency of M184V/I or K65R/E/N mutations by NGS in HIV infected patients with suppressed viral replication.
2. Evaluate whether NGS identifies all resistance mutations previously detected in virological failure with the population resistance tests.
3. Evaluate factors related to the frequency of detection of resistance mutations in proviral DNA.
4. Analysis of the impact on the virological response of the mutations detected by NGS only.
5. Evaluate other factors related to virologic rebound during the dual therapy strategy.
6. Evaluate the impact of the dual strategy on the proviral DNA reservoir.
7. Evaluate the pharmacoeconomic impact of the dual strategy.

1. Evaluar la frecuencia de las mutaciones M184V/I o K65R/E/N mediante NGS en pacientes infectados por VIH con replicación viral suprimida.
2. Evaluar si NGS identifica todas las mutaciones de resistencia detectadas previamente en el fracaso virológico con los test de resistencias poblacionales.
3. Evaluar factores relacionados con la frecuencia de detección de mutaciones resistencia en ADN proviral.
4. Análisis del impacto en la respuesta virológica de las mutaciones detectadas sólo por NGS.
5. Evaluar otros factores relacionados con el rebote virológico durante la estrategia de terapia dual.
6. Evaluar el impacto de la estrategia dual sobre el reservorio de ADN proviral.
7. Evaluar el impacto farmacoeconómico de la estrategia dual.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient infected with HIV-1.
2. Age> 18 years.
3. Receiving stable antiretroviral treatment for at least 3 months.
4. Current or historical treatment with 3TC or FTC.
5. Desire to change antiretroviral treatment due to intolerance or interest in simplification.
6. Undetectable viral load (<50 copies/mL) for at least 1 year. A blip (≤500 copies/mL) is allowed within three months prior to inclusion in the study, preceded and followed by undetectable determination.
7. Current CD4 level> 350 cells/μL.
8. Naïve to integrase inhibitors.
9. Able to understand and give written informed consent.
10. For those included in group 1 (20 patients): no history of virological failure with an ART regimen that included 3TC or FTC or at the time of failure had a population genotype without M184V/I or K65R/E/N.
11. For those included in group 2 (20 patients): history of virological failure with TAR guideline including 3TC or FTC and historical genotype with mutations M184V/I or K65R /E/N.

1. Paciente infectado por VIH-1.
2. Edad > 18 años.
3. Recibiendo tratamiento antirretroviral estable durante al menos 3 meses.
4. Tratamiento actual o histórico con 3TC o FTC.
5. Deseo de cambio de tratamiento antirretroviral debido a intolerancia o interés en la simplificación.
6. Carga viral indetectable (<50 cop/mL) desde hace al menos 1 año. Se permite un blip (≤500 copias/mL) antes de los tres meses previos a la inclusión en el estudio, precedido y seguido de una determinación indetectable.
7. Nivel actual de CD4 >350 cel/µL.
8. Naïve a inhibidores de la integrasa.
9. Capaz de entender y dar su consentimiento informado por escrito.
10. Para los incluidos en el grupo 1 (20 pacientes): no historia de fracaso virológico con pauta de TAR que incluyera 3TC o FTC o que en el momento del fracaso presentaban un genotipo poblacional sin las mutaciones M184V/I o K65R/E/N.
11. Para los incluídos en el grupo 2 (20 pacientes): historia de fracaso virológico con pauta de TAR que incluyera 3TC o FTC y genotipo histórico con las mutaciones M184V/I o K65R/E/N.

E.4

Principal exclusion criteria

1. Detection of any of the following mutations in proviral DNA in peripheral blood by conventional sequencing: M184V/I or K65R/E/N.
2. Pregnant, lactating or fertile women who do not commit to using an adequate contraceptive method.

1. Detección de alguna de las siguientes mutaciones en ADN proviral en sangre periférica mediante secuenciación convencional: M184V/I o K65R/E/N.
2. Mujeres embarazadas, lactantes o en edad fértil que no se comprometan a utilizar un método anticonceptivo adecuado.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with undetectable viral load (<50 copies / mL) at 48 weeks follow-up, according to the FDA's "intention-to-treat-exposed" population snapshot algorithm. The intention-to-treat population includes all patients who have received at least one dose of DTG and 3TC.

Proporción de pacientes con carga viral indetectable (<50 copias/mL) a las 48 semanas de seguimiento, según el algoritmo snapshot de la FDA en la población “por intención de tratar-expuesta”. La población por intención de tratar-expuesta incluye a todos los pacientes que hayan recibido por lo menos una dosis de DTG y 3TC.

E.5.1.1

Timepoint(s) of evaluation of this end point

48 weeks

48 semanas

E.5.2

Secondary end point(s)

Effectiveness:
1. Proportion of patients with viral load <50 copies/mL at week 24, according to the FDA's "intention-to-treat-exposed" population snapshot algorithm.
2. Proportion of patients with virological failure at week 48 according to the FDA snapshot algorithm.
3. Median changes in CD4 cell count/μL, relative to the baseline visit, at week 48.
Safety and tolerability:
1. Incidence of adverse events and discontinuation of treatment due to toxicity or intolerance.
Evaluation of the appearance of genotypic resistance mutations
1. Incidence of genotypic resistance mutations in patients with virological failure at week 48.
2. Description and frequency of genotypic resistance mutations.

Eficacia:
1. Proporción de pacientes con carga viral <50 copias/mL en la semana 24, según el algoritmo snapshot de la FDA en la población “por intención de tratar-expuesta”.
2. Proporción de pacientes con fallo virológico en la semana 48 según el algoritmo snapshot de la FDA.
3. Mediana de los cambios en el recuento de células CD4/μL, con respecto a la visita basal, en la semana 48.
Seguridad y tolerabilidad:
1. Incidencia de acontecimientos adversos y de discontinuación del tratamiento por toxicidad o intolerancia.
Evaluación de la aparición de mutaciones genotípicas de resistencia:
1. Incidencia de mutaciones genotípicas de resistencia en los pacientes con fracaso virológico en la semana 48.
2. Descripción y frecuencia de las mutaciones genotípicas de resistencia.

E.5.2.1

Timepoint(s) of evaluation of this end point

24 and 48 weeks

24 y 48 semanas

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

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)

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

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

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

LVLS

Última visita del último sujeto

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)

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

Ninguno

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

2017-08-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-27

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

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