Clinical Trials Register

Summary
EudraCT Number:	2018-001158-82
Sponsor's Protocol Code Number:	GESIDA10418
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:	2018-08-02
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

2018-001158-82

A.3

Full title of the trial

Phase IV, Open Label, Randomized, Clinical Trial to Evaluate the Reversibility of abacavir/lamivudine/dolutegravir CNS-Related Neurotoxicity After Switching to tenofovir alafenamide/emtricitabine/darunavir/cobicistat

Ensayo clínico fase IV, abierto, aleatorizado diseñado para evaluar la reversibilidad de la neurotoxicidad asociada al uso de abacavir/lamivudina/dolutegravir en el sistema nervioso central tras el cambio a una pauta de tratamiento antirretroviral basada en alafenamida/emtricitabina/darunavir/cobicistat

A.3.1

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

DETOX Study

Estudio DETOX

A.3.2

Name or abbreviated title of the trial where available

DETOX

A.4.1

Sponsor's protocol code number

GESIDA10418

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 SEIMC-GESIDA
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	JANSSEN CILAG S.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	Fundación SEIMC-GESIDA
B.5.2	Functional name of contact point	Marta de Miguel
B.5.3	Address:
B.5.3.1	Street Address	C/ Agustín de Betancourt nº 13 - entreplanta
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28003
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034915568025
B.5.5	Fax number	0034915542283
B.5.6	E-mail	mdemiguel@f-sg.org

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	Symtuza
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag SpA
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	Symtuza
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	TENOFOVIR ALAFENAMIDA
D.3.9.1	CAS number	379270-37-8
D.3.9.3	Other descriptive name	TENOFOVIR ALAFENAMIDE
D.3.9.4	EV Substance Code	SUB121761
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EMTRICITABINA
D.3.9.1	CAS number	143491-57-0
D.3.9.3	Other descriptive name	EMTRICITABINE
D.3.9.4	EV Substance Code	SUB01882MIG
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	200
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DARUNAVIR
D.3.9.1	CAS number	206361-99-1
D.3.9.3	Other descriptive name	DARUNAVIR
D.3.9.4	EV Substance Code	SUB25394
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	800
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	COBICISTAT
D.3.9.1	CAS number	1004316-88-4
D.3.9.3	Other descriptive name	COBICISTAT
D.3.9.4	EV Substance Code	SUB33760
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	150
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	Triumeq
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.3.4	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 sodium
D.3.9.3	Other descriptive name	DOLUTEGRAVIR SODIUM
D.3.9.4	EV Substance Code	SUB130591
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.3.8 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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Abacavir sulfate
D.3.9.1	CAS number	188062-50-2
D.3.9.3	Other descriptive name	ABACAVIR SULFATE
D.3.9.4	EV Substance Code	SUB00231MIG
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	600
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

VIH

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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10001509
E.1.2	Term	AIDS
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

Compare at week 4 changes in the proportion of patients who self-reported insomnia, between HIV-suppressed patients who continue abacavir/lamivudine/dolutegravir (ABC/3TC/DTG)and those who switched to tenofovir alafenamide/emtricitabine/darunavir/cobicistat (TAF/FTC/DRV/c)

Comparar en semana 4 los cambios en la proporción de pacientes que reportaron insomnio asociado al uso de abacavir/lamivudina/dolutegravir (ABC/3TC/DTG) y los aleatorizados a instaurar el cambio del tratamiento antirretroviral alafenamida/emtricitabina/darunavir/cobicistat (TAF/FTC/DRV/c)

E.2.2

Secondary objectives of the trial

- Compare at week 4 changes in the proportion and severity of neuropsychiatric symptoms, between HIV-suppressed patients who continue abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) and those who switched to tenofovir alafenamide/emtricitabine/darunavir/cobicistat (TAF/FTC/DRV/c)
- To evaluate changes in the proportion and severity of neuropsychiatric symptoms potentially associated with the use of abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) after switching to tenofovir alafenamide/emtricitabine/darunavir/cobicistat (TAF/FTC/DRV/c)
- To evaluate the percentages of virologic failure after switching antiretroviral therapy from abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) to tenofovir alafenamide/emtricitabine/darunavir/cobicistat (TAF/FTC/DRV/c).

- Comparar en semana 4 los cambios en proporción y la intensidad de síntomas neuro-psiquiátricos entre los pacientes que continúan con el uso de abacavir/lamivudina/dolutegravir (ABC/3TC/DTG) y los que cambian a alafenamida/emtricitabina/darunavir/cobicistat (TAF/FTC/DRV/c)
- Evaluar cambios en la proporción e intensidad de síntomas neuro-psiquiátricos asociados con el uso de abacavir/lamivudina/dolutegravir (ABC/3TC/DTG) tras el cambio a alafenamida/emtricitabina/darunavir/cobicistat (TAF/FTC/DRV/c)
- Evaluar los porcentajes de fallo virológico tras el cambio del tratamiento antirretroviral de abacavir/lamivudina/dolutegravir (ABC/3TC/DTG) por alafenamida/emtricitabina/darunavir/cobicistat (TAF/FTC/DRV/c)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

* Patient ≥ 18 years of age diagnosed with HIV using conventional serology techniques.
* Current antiretroviral therapy with ABC/3TC/DTG for at least 4 weeks.
* HIV viral load < 50 copies/mL for at least 12 weeks prior to signing the consent form (confirmed by two assays at least 12 weeks apart with viremia < 50 copies/mL between both). If the patient has a recent routine blood test available (≤ 4 weeks) that includes determining HIV viral load, these results may be used for the screening visit. If this test is not available, or the test is more than four weeks old, viral load will be determined on the day of screening in order to confirm that the patient meets this criterion.
* A positive screening test for sleep disorders detected using the sleep quality index (Pittsburgh ).

•Paciente >18 años diagnosticado de VIH mediante técnicas serológicas habituales.
•Tratamiento antirretroviral actual con ABC/3TC/DTG durante al menos 4 semanas.
•Carga viral VIH < 50 copias/mL durante al menos 12 semanas anteriores a la firma del consentimiento confirmada mediante dos determinaciones separadas por al menos 12 semanas con viremia < 50 copias/mL entre ambas). Si el paciente dispone de una analítica de rutina reciente (≤ 4 semanas) que incluya la determinación de la carga viral VIH, estos resultados se podrán utilizar para la visita de selección. En caso de no disponer de dicha analítica, o que la analítica supere las 4 semanas de antigüedad, se procederá, el día de la selección a una determinación de la carga viral para confirmar que el paciente cumple con este criterio.
•Valoración positiva de trastorno del sueño en el cuestionario de calidad del sueño (Pittsburg).

E.4

Principal exclusion criteria

* Determination of at least one HIV viral load ≥ 50 copies/mL in the last 12 weeks.
* Allergy, intolerance or existence of resistance mutations to any of the components of TAF/FTC/DRV/c.
* History of active CNS infections.
* Active psychosis, major depression with psychotic symptoms or autolytic ideation.
* Dementia or mental retardation.
* Drug use with a diagnosis of abuse or dependence according to DSM-5 criteria.
* Illnesses that may interfere with the study procedures.
* Presence of magnetisable devices in the body.
* Inability to complete any of the study procedures.
* Pregnant or nursing women, as well as women of childbearing age who do not agree to use an adequate birth control method.

•Determinación de al menos, una carga viral de VIH ≥50 copias/mL en las últimas 12 semanas.
•Alergia, intolerancia o existencia de mutaciones de resistencia a cualquiera de los componentes de TAF/FTC/DRV/c
•Historia de infecciones activas del SNC
•Psicosis activa, depresión mayor con síntomas psicóticos o ideación autolítica
•Demencia o retraso mental
•Consumo de drogas con diagnóstico de abuso o dependencia de acuerdo con los criterios del DSM-5
•Enfermedades que puedan interferir con los procedimientos del estudio
•Inhabilidad para completar cualquiera de los procedimientos del estudio
•Mujeres embarazadas o lactantes, así como mujeres en edad fértil que no se comprometan a utilizar un método anticonceptivo adecuado.

E.5 End points

E.5.1

Primary end point(s)

The ACTG adverse effects scale, the Pittsburg sleep quality index and the hospital anxiety and depression scale

Escala ACTG de efectos adversos, la escala de calidad del sueño de Pittsburg y la escala hospitalaria de ansiedad y depresión

E.5.1.1

Timepoint(s) of evaluation of this end point

Basal visit and week 4

Visita Basal y semana 4

E.5.2

Secondary end point(s)

- The ACTG adverse effects scale, the Pittsburg sleep quality index and the hospital anxiety and depression scale
- Viral load

- Escala ACTG de efectos adversos, la escala de calidad del sueño de Pittsburg y la escala hospitalaria de ansiedad y depresión
- Carga Viral

E.5.2.1

Timepoint(s) of evaluation of this end point

Weeks 4 and 8 after the change

Semanas 4 y 8 tras el cambio

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

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

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

Ultima visita del ultimo paciente

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:

110

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

110

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 according the clinical practic

Tratamiento de acuerdo a la práctica clínica habitual

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

2018-09-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-09-06

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

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