Clinical Trials Register

Summary
EudraCT Number:	2022-000358-26
Sponsor's Protocol Code Number:	BETAF-RED
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:	2022-03-08
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

2022-000358-26

A.3

Full title of the trial

Safety, tolerability, and efficacy of a dose reduction strategy based on bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed HIV-infected adults.

Seguridad, tolerabilidad y eficacia de una estrategia de reducción de dosis basada en bictegravir /emtricitabina / tenofovir alafenamida en adultos infectados por el VIH con
supresión viral

A.3.1

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

Safety, tolerability, and efficacy of a dose reduction strategy based on bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed HIV-infected adults.

Seguridad, tolerabilidad y eficacia de una estrategia de reducción de dosis basada en bictegravir /emtricitabina / tenofovir alafenamida en adultos infectados por el VIH con
supresión viral

A.4.1

Sponsor's protocol code number

BETAF-RED

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	Institut d’Investigacions Biomèdiques August Pi i Sunyer
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 (PI20/869)
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	CTU(clinical Trial Unit)
B.5.2	Functional name of contact point	Anna Cruceta
B.5.3	Address:
B.5.3.1	Street Address	c/ Mallorca 183, planta 1º, despacho 10
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08036
B.5.3.4	Country	Spain
B.5.6	E-mail	acruceta@clinic.cat

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	Biktarvy 50 mg/200 mg/25 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Sciences Ireland UC
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	bictegravir sodium equivalent to 50 mg of bictegravir, 200 mg of emtricitabine, and tenofovir alafen
D.3.2	Product code	J05AR20
D.3.4	Pharmaceutical form	Coated 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	Bictegravir
D.3.9.1	CAS number	1611493-60-7
D.3.9.2	Current sponsor code	Bictegravir
D.3.9.4	EV Substance Code	SUB182699
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	25
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 infection

infección por HIV

E.1.1.1

Medical condition in easily understood language

HIV infection treatment

tratamiento de Infecció por HIV

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	20.1
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

1- Viral efficacy (standard plasma viral load, lower limit of detection HIV RNA 50 copies/mL) of the reduction of BETAF regimen dose per week at 4 weeks.
2- Viral efficacy (standard plasma viral load, lower limit of detection HIV RNA 50 copies/mL) of the reduction of BETAF regimen dose per week at 48 weeks.

1. Eficacia viral (carga viral plasmática estándar, límite inferior de detección de ARN del VIH 50 copias/ml) de la reducción de la dosis del régimen de BETAF por semana a las 4 semanas.
2. Eficacia viral (carga viral plasmática estándar, límite inferior de detección de ARN del VIH 50 copias/ml) de la reducción de la dosis del régimen de BETAF por semana a las 48 semanas.

E.2.2

Secondary objectives of the trial

1-Virological efficacy:
at 0, 4, 12, 24, 36, and 48 weeks
d. Ultrasensitive plasma viral load at 0, 4, and 48 weeks
e. HIV-1 reservoir (total and integrated DNA) in CD4 cells at 0, 4, and 48 weeks.
f. In case of virological failure, ultra-deep sequencing of plasma and intracellular viral load to detect genotypic resistance
2- Immunological safety:
a. CD4 and CD8 cells, CD4/CD8 ratio, inflammation markers at 0, 4, and 48 weeks
3- Subclinical toxicity:
a. Cummulated incidental adverse events at 48 weeks
b. Weight and body mass index (BMI) changes at 4, 12, 24, 36, and 48 weeks
c. Body composition at 0 and 48 weeks
d. sleep quality
e. quality of life
4. Pharmacokinetics of antiretroviral drugs at baseline 4, and 48 weeks:
a. Plasma levels of bictegravir, emtricitabine and tenofovir
b. Intracellular levels of bictegravir and phosphorylated emtricitabine and tenofovir .

1. Eficacia virológica:
a. Carga viral plasmática estándar,l a las 12, 24 y 36 semanas.
b. Blips a las 12, 24, 36 y 48 semanas.
c. Objetivo no detectado con carga viral plasmática estándar a las 0, 4, 12, 24, 36 y 48 semanas
d. Carga viral plasmática ultrasensible (a las 0, 4 y 48 semanas
e. Reservorio de VIH-1 en células CD4 a las 0, 4 y 48 semanas.
f. En caso de fallo virológico, secuenciación del plasma y carga viral resistencia genotípica
2. Seguridad inmunológica:
a. Células CD4 y CD8, relación CD4/CD8 e inflamación inmune a las 0, 4 y 48 semanas.

3. Toxicidad subclínica:
a. Eventos adversos a las 48 semanas
b. Cambios en el peso y (IMC) alas 4, 12, 24, 36 y 48 semanas
Composición corporal por DEXA, a las 0 y 48 semanas.

4. Farmacocinética de los fármacos antirretrovirales al inicio y a las 4 y 48 semanas:
a. Niveles plasmáticos de bictegravis, emtricitabina y tenofovir
b. Niveles intracelulares de bictegravir y emtricitabina fosforilada y tenofovir.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Stable and asymptomatic HIV-infected adults (≥18 years) on BETAF once daily for at least the previous 6 months.
2) Plasma HIV-1 RNA less than 50 copies/mL for at least the previous 6 months
3) CD4 cell counts greater than 350 cells/mL at the time of consideration for the study
4) Women of child-bearing potential must have a negative pregnancy test in serum before the inclusion in the study and agree to use highly effective contraceptive methods
5) Patients agreed to participate

- Adultos infectados por el VIH estables y asintomáticos (≥18 años) que recibieron BETAF una vez al día durante al menos los 6 meses anteriores.
- ARN plasmático del VIH-1 inferior a 50 copias/ml durante al menos los 6 meses anteriores
- Recuentos de células 3CD4 superiores a 350 células/ml en el momento de la consideración para el estudio
- Las mujeres en edad fértil deben tener una prueba de embarazo negativa en suero antes de la inclusión en el estudio y aceptar el uso de métodos anticonceptivos altamente efectivos
- Pacientes aceptaron participar

E.4

Principal exclusion criteria

1) Prior virological failure to any antiretroviral regimen or documented resistance mutations to bictegravir, emtricitabine, or tenofovir
2) Any diagnosis of psychiatric illness
3) Alcohol abuse or illicit drug consumption (based on their past medical history and specific questions at the time of recruitment)
4) Patients co-infected with HIV and active hepatitis B or C virus
5) Any other condition at the doctor's discretion that did not allow ensuring a correct adherence.

- - Fracaso virológico anterior a cualquier régimen antirretroviral o mutaciones de resistencia documentadas a bictegravir, emtricitabina o tenofovir.
- cualquier diagnóstico de enfermedad psiquiátrica
- Abuso de alcohol o consumo de drogas ilícitas (basado en su historial médico pasado y preguntas específicas en el momento del reclutamiento)
- Pacientes coinfectados con VIH y virus de la hepatitis B o C
- Cualquier otra condición a discreción del médico que no permitiera asegurar una correcta adherencia.

E.5 End points

E.5.1

Primary end point(s)

Primary outcomes will be defined as:
Patients with VL <50 copies at 4 weeks (FDA snapshot algorithm) in the intention-to-treat (ITT) population.
- Patients with VL <50 copies at 48 weeks (FDA snapshot algorithm) in the intention-to-treat (ITT) population.
1-Virological efficacy:
a. Standard plasma viral load, lower limit of detection HIV RNA 50 copies/mL) at 12, 24, and 36 weeks
b. Blips (VL ≥50 copies/mL followed by VL <50 copies/mL) at 12, 24, 36, and 48 weeks.
c. Target not detected with standard plasma viral load (lower limit of detection HIV RNA 50 copies/mL) at 0, 4, 12, 24, 36, and 48 weeks
d. Ultrasensitive plasma viral load (lower limit of detection 5 copies/mL) at 0, 4, and 48 weeks
e. HIV-1 reservoir (total and integrated DNA) in CD4 cells at 0, 4, and 48 weeks.
f. In case of virological failure, ultra-deep sequencing of plasma and intracellular viral load to detect genotypic resistance
2- Immunological safety:
a. CD4 and CD8 cells, CD4/CD8 ratio at 0, 4, and 48 weeks
b. Inflammation (hsCRP, IL-6, adiponectin) and immune
activation (sCD14, CD163) markers at 0, 4, and 48 weeks
3- Subclinical toxicity:
a. Cummulated incidental adverse events at 48 weeks
b. Weight and body mass index (BMI) changes at 4, 12,
24, 36, and 48 weeks
c) Body composition (fat, fat-free mass, and bone by
DEXA,) at 0 and 48 weeks
d. Impact on sleep quality (Pittsburg Sleep Quality Index) at 0 and 48 weeks
e. Impact on quality of life (EQ-5D-5L) at 0 and 4,12,24,36,
48 weeks
4- Pharmacokinetics of antiretroviral drugs at baseline and at 4, and 48 weeks
a. Plasma levels of bictegravir, emtricitabine and tenofovir
b. Intracellular levels of bictegravir, phosphorylated emtricitabine
and phosphorylated tenofovir .

1. Los pacientes con VL <50 copias/ml con VL <50 copias a las 4 semanas (algoritmo de instantánea de la FDA) en la población por intención de tratar (ITT).
2. Los pacientes con VL <50 copias a las 48 semanas (algoritmo de instantánea de la FDA) en la población por intención de tratar (ITT).

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients with VL <50 copies at 4 weeks (FDA snapshot algorithm) in the intention-to-treat (ITT) population.
- Patients with VL <50 copies at 48 weeks (FDA snapshot algorithm) in the intention-to-treat (ITT) population.

E.5.2

Secondary end point(s)

1-Virological efficacy:
a. Standard plasma viral load, lower limit of detection HIV RNA 50 copies/mL) at 12, 24, and 36 weeks
b. Blips (VL ≥50 copies/mL followed by VL <50 copies/mL) at 12, 24, 36, and 48 weeks.
c. Target not detected with standard plasma viral load (lower limit of detection HIV RNA 50 copies/mL) at 0, 4, 12, 24, 36, and 48 weeks
d. Ultrasensitive plasma viral load (lower limit of detection 5 copies/mL) at 0, 4, and 48 weeks
e. HIV-1 reservoir (total and integrated DNA) in CD4 cells at 0, 4, and 48 weeks.
f. In case of virological failure, ultra-deep sequencing of plasma and intracellular viral load to detect genotypic resistance
2- Immunological safety:
a. CD4 and CD8 cells, CD4/CD8 ratio at 0, 4, and 48 weeks
b. Inflammation (hsCRP, IL-6, adiponectin) and immune
activation (sCD14, CD163) markers at 0, 4, and 48 weeks
3- Subclinical toxicity:
a. Cummulated incidental adverse events at 48 weeks
b. Weight and body mass index (BMI) changes at 4, 12,
24, 36, and 48 weeks
c) Body composition (fat, fat-free mass, and bone by
DEXA,) at 0 and 48 weeks
d. Impact on sleep quality (Pittsburg Sleep Quality Index) at 0 and 48 weeks
e. Impact on quality of life (EQ-5D-5L) at 0 and 4,12,24,36,
48 weeks
4- Pharmacokinetics of antiretroviral drugs at baseline and at 4, and 48 weeks
a. Plasma levels of bictegravir, emtricitabine and tenofovir
b. Intracellular levels of bictegravir, phosphorylated emtricitabine
and phosphorylated tenofovir .

1. Eficacia virológica:
a. Carga viral plasmática estándar , límite inferior de detección de ARN del VIH 50 copias/ml) a las 12, 24 y 36 semanas
b. Blips (VL ≥50 copias/mL seguido de VL <50 copias/mL) a las 12, 24, 36 y 48 semanas.
c. Objetivo no detectado con carga viral plasmática estándar (límite inferior de detección de ARN del VIH 50 copias/ml) a las 0, 4, 12, 24, 36 y 48 semanas
d. Carga viral plasmática ultrasensible (límite inferior de detección 5 copias/ml) a las 0, 4 y 48 semanas
e. Reservorio de VIH-1 (ADN total e integrado) en células CD4 a las 0, 4 y 48 semanas.
f. En caso de fallo virológico, secuenciación ultra profunda del plasma y carga viral intracelular para detectar resistencia genotípica
2. Seguridad inmunológica:
a. Células CD4 y CD8, relación CD4/CD8 a las 0, 4 y 48 semanas
b. Inflamación (hsCRP, IL-6, adiponectina) e inmune marcadores de activación (sCD14, CD163) a las 0, 4 y 48 semanas
3. Toxicidad subclínica:
a. Eventos adversos incidentales acumulados a las 48 semanas
b. Cambios en el peso y el índice de masa corporal (IMC) a los 4, 12, 24, 36, y 48 semanas.
c. Composición corporal (grasa y masa libre de grasa por DEXA, single-tc abdominal en rodajas L2-L3) a las 0 y 48 semanas.
d. Impacto en la calidad del sueño ((Pittsburg Sleep Quality Index) en 0 y 48 semanas)
e. Impacto en la calidad de vida (EQ-ED-5L) a las 0 y 48 semanas.
4. Farmacocinética de los fármacos antirretrovirales al inicio y a las semanas 4 y 48:
a. Niveles plasmáticos de bictegravir, emtricitabina y tenofovir
b. Niveles intracelulares de bictegravir y emtricitabina fosforilada y tenofovir

E.5.2.1

Timepoint(s) of evaluation of this end point

The patient may also discontinue study participation in the following instances:
1. If the investigator considers in the interest of the subject (i.e intercurrent illness, occurrence of adverse events) that it is best for them to stop study medication.
2. The subject fails to comply with the protocol requirements or fails to cooperate with investigator.
3.If a female subject becomes pregnant along the study, she will discontinue the study treatment

El paciente también puede interrumpir la participación en el estudio en los siguientes casos:
1. Si el investigador considera en interés del sujeto (es decir, enfermedad intercurrente, ocurrencia de eventos adversos) que es mejor para él suspender la medicación del estudio.
2. El sujeto no cumple con los requisitos del protocolo o no coopera con el investigador.
3. Si una mujer queda embarazada durante el estudio, interrumpirá el tratamiento del estudio.

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

Yes

E.8.2.3.1

Comparator description

TARV

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

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

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

2022-05-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-05-09

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

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