Clinical Trials Register

Summary
EudraCT Number:	2016-003741-29
Sponsor's Protocol Code Number:	MARAND-X
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-06-08
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-003741-29

A.3

Full title of the trial

MARAND-X Study: MARaviroc-based Treatment Switch in HIV-positive Patients with HAND: Consequences of Reducing Antiretroviral-associated NeurotoXicity

Studio MARAND-X: Switch Basato su Maraviroc in Pazienti HIV-positivi con Disturbi Neurocognitivi (HAND): Conseguenze della Riduzione di Neurotossicit¿ Associata a Farmaci Antiretrovirali

A.3.1

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

Study of the use of anti_HIV drugs with reduced neuronal toxicity (including maraviroc) in patients with neurocogntive disorders

Utilizzo di farmaci per il trattamento dell'infezione da HIV a ridotta tossicit¿ sui neuroni (incluso maraviroc) in pazienti con disturbi neurocognitivi

A.3.2

Name or abbreviated title of the trial where available

MARAND-X

A.4.1

Sponsor's protocol code number

MARAND-X

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	A.S.L. TO 2
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	Viiv Healthcare
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	A.S.L. TO2
B.5.2	Functional name of contact point	CU 1p
B.5.3	Address:
B.5.3.1	Street Address	C.so Svizzera 164
B.5.3.2	Town/ city	TORINO
B.5.3.3	Post code	10149
B.5.3.4	Country	Italy
B.5.4	Telephone number	0114393856
B.5.5	Fax number	0114393942
B.5.6	E-mail	andrea.calcagno@unito.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	CELSENTRI - 300 MG COMPRESSA RIVESTITA CON FILM - USO ORALE BLISTER (PVC/ALU) 60 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	VIIV HEALTHCARE UK LTD
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	CELSENTRI
D.3.2	Product code	MARAVIROC
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.3.9.1	CAS number	376348-65-1
D.3.9.2	Current sponsor code	MARAVIROC
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	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	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	REZOLSTA - 800 MG/ 150 MG- COMPRESSA RIVESTITA CON FILM- USO ORALE-FLACONE (HDPE)- 30 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	JANSSEN-CILAG INTERNATIONAL N.V.
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.3.4	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	DARUNAVIR
D.3.9.1	CAS number	206361-99-1
D.3.9.2	Current sponsor code	DARUNAVIR
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.3.9.2	Current sponsor code	COBICISTAT
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	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	No
D.IMP: 3
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	EMTRIVA - 30 CAPSULE RIGIDE IN FLACONE DA 200 MG
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD SCIENCE INTERNATIONAL LIMITED
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	EMTRIVA
D.3.2	Product code	EMTRIVA
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	EMTRICITABINA
D.3.9.1	CAS number	143491-57-0
D.3.9.2	Current sponsor code	EMTRICITABINA
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.3.11 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	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, HIV-associated neurocognitive disorders

Infezione da HIV, disordini neurocognitivi HIV-correlati

E.1.1.1

Medical condition in easily understood language

HIV-infection with neurocognitive problems

Infezione da HIV con problemi neurocognitivi

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10001516
E.1.2	Term	AIDS-dementia complex
E.1.2	System Organ Class	100000004862

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	10002725
E.1.2	Term	Anti-HIV positive
E.1.2	System Organ Class	100000004848

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The change in neurocognitive function in patients randomized to a less neurotoxic regimen (maraviroc, emtricitbaine, darunavir)

la valutazione della variazione della funzionalit¿ neurocognitiva in pazienti HIV-positivi con HAND randomizzati a un regime contenente farmaci a ridotta neurotossicit¿ (maraviroc, emtricitabina, darunavir);

E.2.2

Secondary objectives of the trial

The change in surrogate markers of cerebral function (MRI with resting state fMRI, EEG, lumbar puncture) in patients randomized to a less neurotoxic regimen (maraviroc, emtricitbaine, darunavir); The correlation of such effect to plasma and CSF concentrations of antiretorvirals.

la valutazione della variazione di marcatori surrogati di funzionalit¿ cerebrale (tramite RMN, EEG, marcatori plasmatici e liquorali) in pazienti HIV-positivi con HAND randomizzati a un regime contenente farmaci a ridotta neurotossicit¿ (maraviroc, emtricitabina, darunavir); e la correlazione di tali effetti con le concentrazioni plasmatiche e liquorali dei farmaci antiretrovirali.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age above >18 years;
• Confirmed HIV-positivity;
• Diagnosed with HAND according to the Frascati Criteria;
• On combination antiretroviral treatment;
• No evidence of major resistance associated mutations on previous plasma or CSF samples;
• Plasma and CSF HIV RNA <50 copies/mL;

* Età > 18 anni;
* Positività confermata per HIV;
* Diagnosi di HAND secondo i criteri di Frascati;
* In terapia antiretrovirale di combinazione;
* Nessuna evidenza di mutazioni maggiori associate a resistenza su campioni plasmatici e/o liquorali;
* HIV RNA plasmatico e liquorale <50 copie/mL;

E.4

Principal exclusion criteria

• the use of drugs having major drug-to-drug interaction with maraviroc (for instance rifampicin);
• the use of efavirenz- or darunavir-containing regimens at baseline;
• confounding comorbidities that may influence or affect the diagnosis of HAND including developmental disability, history of traumatic brain injury or of cerebrovascular accident;
• a previous diagnosis of central nervous system opportunistic, autoimmune, neurodegenerative or neoplastic disease;
• severe untreated depression;
• active alcohol or recreational substance abuse (in the previous 3 months);
• not fluent in Italian or unable to complete the neurocognitive tests.
• the presence of CXCR4 or dual mixed tropic virus;

* Utilizzo di regimi contenenti efavirenz e/o darunavir alla visita di screening;
* Virus CXCR4-tropico, CCR5&CXCR4 dual-tropico o un test indeterminato identificato tramite un test genotipico o fenotipico prima dell’inizio di una HAART continuativamente efficace o genotipico eseguito su DNA provirale negli ultimi 6 mesi.
* Presenza di comorbidità che possano influenzare in maniera significativa la diagnosi di HAND compresi: ritardo mentale, traumi cerebrali, eventi cerebrovascolari, cirrosi epatica, insufficienza renale con clearance stimata della creatinina inferiore a 50 ml/min, malattie sistemiche in corso di eziologia infettiva, autoimmune o neoplastica.
* Presenza di una precedente diagnosi di processo infettivo, autoimmune, neurodegenerativo o neoplastico a carico del sistema nervoso centrale;
* Presenza di sindrome ansioso-depressiva grave e non in trattamento;
* Presenza di abuso di alcool o di sostanze stupefacenti nei tre mesi precedenti;
* Assenza di corretta comprensione della lingua italiana o incapacità a eseguire i test neurocognitivi;
* Necessità di farmaci proibiti in co-somministrazione con gli antiretrovirali utilizzati nello studio. Tali farmaci includono:
o farmaci direttamente attivi contro HCV;
o rifampicina, rifabutina;
o quetiapina, terfenadina, astemizolo, cisapride, chinidina, amiodarone, midazolam, triazolam, pimozide, bepridil, sildenafil;
o alcaloidi della segale cornuta (ad es. ergotamina, diidroergotamina, ergonovina e metilergonovina);
o voriconazolo, ketoconazolo, itraconazolo, posaconazolo;
o preparati erboristici contenenti l’erba di San Giovanni;
o simvastatina, lovastatina, atorvastatina;
o fenobarbital, fenitoina e carbamazepina;
o fluticasone e budesonide per via inalatoria.

E.5 End points

E.5.1

Primary end point(s)

6-month variation in global deficit score in NPZ-8 complete neurocognitive tests according to the study arm;

il confronto della variazione di global deficit score (GDS, definito nel capitolo sui metodi) nei test neurocognitivi nei due bracci di trattamento a 6 mesi dall’inizio dello studio.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

E.5.2

Secondary end point(s)

change in neuronal integrity, perfusion and connectivity using MRI and resting state fMRI in the two arms; change in EEG waves using a EEG with LIORETA software in the two arms; change in CSF HIV RNA in the two arms; change in CSF biomarkers (neuronal damage, immune activation and astrocytosis) in the two arms; change in intima media thickness in the two arms; change in serum TMA/TMAO in thw two arms; Association of changes in primary and secondary endpoints with plasma and CSF concentrations of antiretrovirals

variazione nei marcatori di integrit¿ neuronale, perfusione e connettivit¿ alla RMN con tecniche di spettroscopia e RMN funzionale a riposo nei due bracci; variazione nell'ampiezza delle onde utilizzando un EEG con software LORETA nei due bracci; variazione nell'HIV RNA liquorale nei due bracci; variazione nei marcatori liquorali di danno neuronale, immunoattivazione e astrocitosi nei due bracci; variazione dello spessore miointimale nei due bracci; variazione in TMA/TMAO plasmatico nei due bracci; Associazione dei cambiamenti negli endpoint primari e secondari in base alle concentrazioni plasmtiche e liquorali dei farmaci antiretrovirali in studio.

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months; 6 months; 6 months; 6 months; 6 months; 6 months; 6 months

6 mesi; 6 mesi; 6 mesi; 6 mesi; 6 mesi; 6 mesi; 6 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

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)

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

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.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.5.1

Number of sites anticipated in the EEA

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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

According to routine clinical care. Subjects will be allowed to continue the experimentale combination of re-start their previous regimens.

Assistenza secondo pratica clinica. Ai soggetti verr¿ conentito di continuare la terapia sperimentale o ritornare alla precedente.

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

2017-01-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-04-05

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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