Clinical Trials Register

Summary
EudraCT Number:	2018-004885-32
Sponsor's Protocol Code Number:	DOBINeuro
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-05-20
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-004885-32

A.3

Full title of the trial

THE EFFECTS OF SWITCHING FROM DOLUTEGRAVIR/LAMIVUDINE/ABACAVIR (D/L/A) TO BICTEGRAVIR/EMTRICITABINE/TENOFOVIR ALAFENAMIDE (B/F/TAF) IN PATIENTS WITH SUPPRESSED VIRAL LOAD ON NEUROPSYCHIATRIC SIDE EFFECTS AND NEUROCOGNITIVE FUNCTION

L’IMPATTO DEL PASSAGGIO DA DOLUTEGRAVIR/LAMIVUDINA/ABACAVIR (D/L/A) A BICTEGRAVIR/EMTRICITABINA/TENOFOVIR ALAFENAMIDE (B/F/TAF) NEI PAZIENTI IN TERAPIA ANTIRETROVIRALE CON HIVRNA SOPPRESSO SUGLI EVENTI AVVERSI NEUROPSICHIATRICI E SULLE FUNZIONI NEUROCOGNITIVE

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

DOBINeuro

A.4.1

Sponsor's protocol code number

DOBINeuro

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	AZIENDA OSPEDALIERA UNIVERSITARIA SENESE
B.1.3.4	Country	Italy
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	Gilead Sciences
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Azienda Ospedaliera Universitaria Senese
B.5.2	Functional name of contact point	UOC Malattie Infettive
B.5.3	Address:
B.5.3.1	Street Address	Viale Bracci 16
B.5.3.2	Town/ city	Siena
B.5.3.3	Post code	53100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0577586347
B.5.5	Fax number	0577586155
B.5.6	E-mail	barbara.rossetti@ao-siena.toscana.it

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
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD Sciences
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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/emtricitabina/tenofovir alafenamide
D.3.2	Product code	[GS-9883-01]
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	bictegravir/emtricitabina/tenofovir alafenamide
D.3.9.2	Current sponsor code	bictegravir/emtricitabina/tenofovir alafenamide - GS-9883-01
D.3.9.3	Other descriptive name	bictegravir/emtricitabina/tenofovir alafenamide
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Antiretrovirale
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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	TRIUMEQ
D.3.2	Product code	[dolutegravir/abacavir/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	dolutegravir/abacavir/lamivudina
D.3.9.2	Current sponsor code	dolutegravir/abacavir/lamivudina
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	49
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	antiretrovirale

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-1 infection

Infezione da HIV-1

E.1.1.1

Medical condition in easily understood language

Human immunodeficiency virus type 1 (HIV-1) infection

Infezione da virus dell'immunodeficienza umana acquisita 1 (HIV-1)

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	10068341
E.1.2	Term	HIV-1 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

To determine frequence and to compare the severity of neuropsychiatric symptoms in HIV-infected patients treated with antiretroviral therapy with dolutegravir / lamivudine / abacavir switching to bictegravir / emtricitabine / tenofovir alafenamide or continue dolutegravir / lamivudine / abacavir after 3 months

Determinare l’incidenza e confrontare la severità dei sintomi neuropsichiatrici nei pazienti con infezione da HIV virosoppressi in terapia antiretrovirale con dolutegravir/lamivudina/abacavir dopo 3 mesi dallo switch a bictegravir/emtricitabina/tenofovir alafenamide o dalla prosecuzione di dolutegravir/lamivudina/abacavir

E.2.2

Secondary objectives of the trial

To compare between the two study arms:
- severity and incidence of neuropsychiatric symptoms after 12 months in patients switching to bictegravir/emtricitabina/tenofovir alafenamide or continuing dolutegravir/lamivudina/abacavir
- severity and incidence of neurocognitive impairment after 12 months in patients switching to bictegravir/emtricitabina/tenofovir alafenamide or continuing dolutegravir/lamivudina/abacavir
- virological failure rates and resistance mutation selection
- adverse effects rate
- symptoms reported by patients, adherence, quality of life, satisfaction with treatment
- to correlate the plasma concentrations of drugs with the severity of neuropsychiatric symptoms and with neurocognitive performances

Confrontare tra i due bracci di studio:
• severità ed incidenza dei sintomi neuropsichiatrici a 12 mesi dallo switch a bictegravir/emtricitabina/tenofovir alafenamide o dalla prosecuzione di dolutegravir/lamivudina/abacavir
• severità ed incidenza della compromissione neurocognitiva a 12 mesi dallo switch a bictegravir/emtricitabina/tenofovir alafenamide o dalla prosecuzione di dolutegravir/lamivudina/abacavir
• tasso di fallimento virologico e sviluppo di resistenze ai farmaci
• tasso di effetti avversi
• sintomi riferiti dai pazienti, aderenza, qualità della vita, soddisfazione al trattamento
• correlare le concentrazioni plasmatiche dei farmaci con la severità dei sintomi neuropsichiatrici e con le performance neurocognitive

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age >18 years
- HIV-1 infection
- HIV RNA <50 copies/mL >12 months (including patients with 1 blip 50-200 cp/ml before screening not confirmed)
- On treatment with dolutegravir/abacavir/lamivudine >6 months

- Età superiore ai 18 anni
- Infezione da HIV-1
- HIV RNA< 50 copie/mL da almeno 12 mesi (ammesso prima dello screening 1 blip viremico tra 50 e 200 cp/ml non confermato da una successiva determinazione)
- Terapia antiretrovirale con dolutegravir/abacavir/lamivudina in corso da almeno 6 mesi

E.4

Principal exclusion criteria

- Previous AIDS events
- Pregnancy or pregnancy plan
- Decompensated cirrhosis (Child B or C)
- Intake of alcohol, substances, other drugs that may affect neurocognitive performance
- Necessity to receive drugs that may require dosing adjustment of dolutegravir or bictegravir
- Certified diagnosis of major depression, psychosis, history of suicidal attempts
- Treatment with antidepressants or antipsychotic drugs
- History of virological failure with integrase inhibitors
- Lack of knowledge of italian language
- Impossibility to obtain informed written consent
- HBsAg positivity
- Estimated glomerular filtration rate by CK-EPI <50 ml/min per 1.73m2

- Pregressi eventi AIDS-definenti
- Donna in gravidanza o che pianifichi una gravidanza
- Cirrosi scompensata (stadio Child B o C)
- Uso di alcol, sostanze stupefacenti, altri farmaci che possono alterare le capacità neurocognitive
- Necessità di assumere altri farmaci che possono richiedere aggiustamenti di dose di dolutegravir o bictegravir
- Diagnosi accertata di depressione maggiore, psicosi, storia di tentativi di suicidio
- Trattamento con farmaci antidepressivi o antipsicotici
- Storia di fallimento virologico con inibitori dell’integrasi
- Mancata conoscenza della lingua italiana
- Incapacità di fornire consenso libero e informato
- Positività HBsAg
- Clearance creatinina sec CK-EPI <50 ml/min per 1.73m2

E.5 End points

E.5.1

Primary end point(s)

To verify difference in neuropsychiatric symptoms severity, using the Symptom Checklist-90-R, 3 months after switching to bictegravir or continuing dolutegravir (on treatment analysis).

Differenza nella gravità dei sintomi neuropsichiatrici, usando la Checklist-90-R dei sintomi, 3 mesi dopo lo switch a bictegravir o continuando dolutegravir (analisi on-treatment).

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months

3 mesi

E.5.2

Secondary end point(s)

Difference in neuropsychiatric symptoms severity, each of the 10 symptoms analyzed separately using the Symptom Checklist-90-R, 3 and 12 months after switching to bictegravir or dolutegravir (on treatment analysis); Changes in self-reported symptoms, adherence and HR-QoL (using validated questionnaires) during the first year of follow up (ITT-exposed, using LOCF).; Difference in neuropsychiatric symptoms severity, using the Mini International Neuropsychiatric Interview Plus subscale for suicide risk, 3 and 12 months after switching to bictegravir or dolutegravir (on treatment analysis); Difference in neurocognitive performance, using a comprehensive and validated neuropsychological battery, 12 months after switching to bictegravir or dolutegravir (on treatment analysis); Correlation between symptoms (neuropsychiatric and other), drug exposure and HR-QoL during the first year of follow up.; Proportion of adverse events and serious adverse events and of patients discontinuing due to side effects in both arms; Proportion of virological failures and antiretrovirals resistance at virological failure; Differences in Treatment Satisfaction between arms as per specific questionnaire; Comparison of the inter-arm and intra-arm incidence of neurocognitive impairment (on the basis of Frascati criteria) at 12 months and neuropsychiatric symptoms (using the Symptom Checklist-90-R) at 3 (on treatment analysis) and 12 months (ITT-exposed, using LOCF)

Differenza dei sintomi neuropsichiatrici tra i due bracci di trattamento, ciascuno dei 10 sintomi analizzati separatamente utilizzando la Checklist-90-R dei sintomi, 3 e 12 mesi dopo il passaggio a bictegravir o continuando dolutegravir (analisi on-treatment); Cambiamenti nei sintomi auto-riportati, aderenza e qualità della vita HR-Qol (utilizzando questionari validati) durante il primo anno di follow-up (ITT-esposti, utilizzando il criterio “Last Observation Carried Forward”); Differenza nella gravità dei sintomi neuropsichiatrici, utilizzando la sottoscala Mini International Neuropsychiatric Interview Plus per il rischio di suicidio, 3 e 12 mesi dopo il passaggio a bictegravir o continuando dolutegravir (analisi on-treatment); Differenza nelle prestazioni neurocognitive, utilizzando una batteria neuropsicologica completa e validata, 12 mesi dopo il passaggio a bictegravir o continuando dolutegravir (analisi on-treatment); correlazione tra sintomi (neuropsichiatrici e altro), livelli plasmatici di farmaci INSTI e qualità della vita durante il primo anno di follow-up (ITT-esposti, utilizzando il criterio “Last Observation Carried Forward”); Proporzione di eventi avversi ed eventi avversi severi e di pazienti che cessano la terapia a causa di effetti collaterali in entrambi i bracci; Percentuale di fallimenti virologici e di resistenze ai farmaci in caso di fallimento virologico; Differenze nella soddisfazione al trattamento tra i bracci come da questionario specifico; Confronto dell’incidenza nel braccio e tra bracci di danno neurocognitivo (sulla base dei criteri di Frascati) a 12 mesi e dei sintomi neuropsichiatrici (usando la Checklist-90-R dei sintomi) a 3 mesi (analisi on-treatment) e 12 mesi ( ITT esposti, utilizzando il criterio “Last Observation Carried Forward”)

E.5.2.1

Timepoint(s) of evaluation of this end point

3 and 12 months; 12 months; 3 and 12 months; 12 months; 12 months; 12 months; 12 months; 12; 3 and 12 months

3 e 12 mesi; 12 mesi; 3 e 12 mesi; 12 mesi; 12 mesi; 12 mesi; 12 mesi; 12; 3 e 12 mesi

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

Yes

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)

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

Yes

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

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

100

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)

Continuation antiretroviral therapy

Prosecuzione terapia farmacologica antiretrovirale

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

2019-08-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-24

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

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