Clinical Trials Register

Summary
EudraCT Number:	2017-000447-40
Sponsor's Protocol Code Number:	FARM12FEXH(TESS)
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:	2020-11-04
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

2017-000447-40

A.3

Full title of the trial

IMPACT ON BONE MINERAL DENSITY (BMD) OF TDF-SPARING ANTIRETROVIRAL REGIMENS IN HIV-POSITIVE MENOPAUSAL WOMEN AFFECTED BY OSTEOPENIA: THE TENOFOVIR SPARING STRATEGY (TESS) STUDY

Impatto dei regimi antiretrovirali Tenofovir-sparing sulla densita' minerale ossea (BMD) in donne HIV-positive con osteopenia in menopausa: lo studio TESS (TEnofovir Sparing Strategy)

A.3.1

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

n.a.

A.3.2

Name or abbreviated title of the trial where available

TESS

A.4.1

Sponsor's protocol code number

FARM12FEXH(TESS)

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	ASST SANTI PAOLO E CARLO
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	AIFA - Italian Medicines Agency
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	ASST Santi Paolo e Carlo
B.5.2	Functional name of contact point	Clinica Malattie Infettive Tropical
B.5.3	Address:
B.5.3.1	Street Address	Via A. di Rudin¿, 8
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20142
B.5.3.4	Country	Italy
B.5.4	Telephone number	0281843061
B.5.5	Fax number	0281843046
B.5.6	E-mail	esther.merlini@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	CELSENTRI - 150 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	[xxxxxxx]
D.3.4	Pharmaceutical form	Film-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	MARAVIROC
D.3.9.1	CAS number	376348-65-1
D.3.9.2	Current sponsor code	n.a.
D.3.9.3	Other descriptive name	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	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: 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	PREZISTA - 800 MG - COMPRESSE RIVESTITE - 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.3.1	Product name	darunavir
D.3.2	Product code	[xxxxxxxx]
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	n.a.
D.3.9.3	Other descriptive name	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.3.11 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	RITONAVIR SANDOZ - "100 MG COMPRESSE RIVESTITE CON FILM" 30 COMPRESSE IN FLACONE HDPE
D.2.1.1.2	Name of the Marketing Authorisation holder	SANDOZ S.P.A.
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	ritonavir
D.3.2	Product code	xxxx
D.3.4	Pharmaceutical form	Film-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	RITONAVIR
D.3.9.1	CAS number	155213-67-5
D.3.9.2	Current sponsor code	n.a.
D.3.9.3	Other descriptive name	RITONAVIR
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	100
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: 4
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	EPIVIR - 300 MG 1 FLACONE 30 COMPRESSE RIVESTITE CON FILM USO ORALE
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	lamivudina
D.3.2	Product code	[xxxxxxxx]
D.3.4	Pharmaceutical form	Film-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	LAMIVUDINA
D.3.9.1	CAS number	134678-17-4
D.3.9.2	Current sponsor code	n.a.
D.3.9.3	Other descriptive name	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	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: 5
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	PREZISTA - 800 MG - COMPRESSE RIVESTITE - 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.3.1	Product name	darunavir
D.3.2	Product code	xxxx
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	n.a.
D.3.9.3	Other descriptive name	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.3.11 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: 6
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	RITONAVIR SANDOZ - "100 MG COMPRESSE RIVESTITE CON FILM" 30 COMPRESSE IN FLACONE HDPE
D.2.1.1.2	Name of the Marketing Authorisation holder	SANDOZ S.P.A.
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	ritonavir
D.3.2	Product code	[xxxxx]
D.3.4	Pharmaceutical form	Film-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	RITONAVIR
D.3.9.1	CAS number	155213-67-5
D.3.9.2	Current sponsor code	n.a.
D.3.9.3	Other descriptive name	RITONAVIR
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	100
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-positive women affected by osteopenia.

donne HIV positive affette da osteopenia.

E.1.1.1

Medical condition in easily understood language

n.a.

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	PT
E.1.2	Classification code	10049088
E.1.2	Term	Osteopenia
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

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	10008922
E.1.2	Term	Chronic infection with HIV
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

The primary objective of the study is to evaluate whether in menopausal HIV-positive women affected by osteopenia switch from a TDF-containing cART to a TDF-sparing strategy (TSS) based on darunavir/ritonavir and maraviroc (DRV/r+MRV) is superior in terms of increasing BMD at the spine or femur site to a TSS based on DRV/r and lamivudine (DRV/r+3TC).

Valutare se, nelle donne sieropositive in menopausa e affette da osteopenia, il passaggio da una Terapia Antiretrovirale Combinata (cART) includente Tenofovir (TDF) ad una strategia TDF-priva (TSS) costituita da darunavir/ritonavir e maraviroc (DRV/r + MRV) sia superiore, in termini di aumento della Densità Minerale Ossea (BMD) a livello della colonna vertebrale o del femore, rispetto al passaggio dalla stessa verso una terapia TSS costituita da darunavir/ritonavir e lamivudina (DRV/r + 3TC).

E.2.2

Secondary objectives of the trial

Secondary objectives of the study are to compare the two TSS with regard to the following:
•viroimmunologic response, by plasma HIV-RNA and CD4+ T-cell count;
•change of bone turnover markers and of osteoclastogenic cytokines between baseline and the end of the study (18 months);
•change in the 10 year probability of fracture (hip and/or major osteoporotic fracture); assessed by WHO fracture risk assessment tool (FRAX¿) between baseline and the end of the study (18 months);
•change in the amount of CD4+ T-lymphocytes HIV-DNA after 18 months of therapy;
•to assess the change of inflammation markers involved in bone homeostasis and of T-cell immune-activation markers after 18 months of treatment;
•to assess the change of glomerular filtration rate, estimated by MDRD formula, after 18 months of treatment (eGFR);
•plasma trough concentration of antiretroviral drugs (MRV, DRV and ritonavir);
•study of tropism change in case of virological failure.

Paragonare i due regimi TSS riguardo a quanto segue:
•risposta viroimmunologica attraverso la quantità plasmatica di HIV-RNA e della conta delle cellule-T CD4+
•variazioni dei markers del turnover osseo e di citochine osteoclastogeniche tra il basale e la fine dello studio (18 mesi)
•variazione della probabilità di frattura ossea in 10 anni (e/o grave frattura da osteoporosi dell'anca) calcolata attraverso l’indice di rischio di frattura WHO (FRAX’’) tra il basale e la fine dello studio (18 mesi)
•variazioni nella quantità dell’HIV-DNA intracellulare nei linfociti-T CD4+, dopo 18 mesi di terapia
•variazione markers di infiammazione coinvolti nell’omeostasi dell’osso e dei markers di infiammazione t-cellulare dopo 18 mesi trattamento
•variazione della Velocità di Filtrazione Glomerulare, calcolata con formula MDRD (eFGR)
•concentrazione plasmatica minima dei farmaci antiretrovirali (maraviroc, darunavir, ritonavir)
•studio della variazione del tropismo in caso di fallimento virologico

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.HIV-positive menopausal women with age between 40 and 75 years (menopausal state: patient-reported absent menstrual cycle since a minimum of 12 months);
2.affected by osteopenia at spine and/or femur site defined by T score = -1 SD and > -2,5. SD at DXA scan performed within 3 months prior to enrolment (see “DXA quality assurance program” in Annex 4, page 52 – Lab. 3);
3.ART with TDF+3TC or emtricitabine in association with either a boosted protease inhibitor or a non-nucleoside reverse transcriptase inhibitor unchanged for at least 6 months;
4.viroimmunological markers (performed within 3 months prior to enrolment): HIV-RNA < 40 copies/ml in at least two determinations from at least 6 months and CD4 counts > 200 cells/mmc;
5.eGFR >50 ml/min (estimated by MDRD formula);
6.patients harbouring a CCR5-tropic virus. In case of tropism data available in patient’s clinical history, there is no need to repeat the test: consider the last result as inclusion criteria. In case of missing data, testing must be conducted on HIV-DNA c/o Virology Lab Tor Vergata, on frozen blood sample collected within 6 months from screening (see Annex 4, page 53 – Lab. 4);
7.HBsAg negative by test performed within 6 months before enrolment;
8.willing to comply with all study procedures and be available for the duration of the study;
9.provide signed and dated informed consent form.

1.donne HIV-positive in menopausa di età compresa tra i 40 e i 75 anni (menopausa: assenza del ciclo mestruale, riportata dalla paziente, da un minimo di 12 mesi);
2.affette da osteopenia alla colonna o al femore definita da un T-score = -1 SD e > -2,5. SD alla DXA eseguita entro i 3 mesi precedenti l’arruolamento;
3.ART con TDF+3TC o emtricitabina in associazione con altri inibitori della proteasi o inibitori non nucleosidici della trascrittasi inversa, non modificata da almeno 6 mesi;
4.markers viroimmunologici (eseguita entro i 3 mesi precedenti l’arruolamento): HIV-RNA < 40 copie/ml in almeno due determinazioni da almeno 6 mesi e la conta dei CD4 > 200 cell/mmc;
5.eGFR > 50 ml/min (calcolata con la formula MDRD);
6.pazienti con tropismo di HIV CCR5;
7.HBsAg negativo (test eseguito entro i 6 mesi precedenti l’arruolamento);
8.volontà di completare tutte le procedure dello studio e disponibilità per la durata dello studio;
9.ottenimento del consenso informato firmato e datato.

E.4

Principal exclusion criteria

1.previous diagnosis of AIDS dementia complex;
2.virological failure to prior DRV/r containing regimens;
3.history of mutations conferring resistance to DRV or 3TC;
4.CXCR4 or CCR5/CXCR4 dual tropic HIV tropism or a non-reportable tropism result;
5.previous virological failure to MRV;
6.HCV active infection with ongoing or planned treatment with DAA drugs known to show interactions with ART drugs in study;
7.previous (within 1 year) or ongoing biphosfonate therapy;
8.ongoing estro-progestinic therapy;
9.ongoing or less than 30 days prior corticosteroids or immunosuppressive therapy;
10.history of pathologic fracture;
11.known allergic reactions to study drugs;
12.treatment with any other investigational drug;
13.anything that, in the opinion of the investigator, would place the subject at increased risk or reclude the subject’s full
compliance with or completion of the study;
14. patients with decompensated liver diseases (Child Pugh Score: B9).

1.diagnosi pregressa di AIDS dementia complex;
2.fallimento virologico a precedenti regimi contenenti DRV/r;
3.storia di mutazioni conferenti resistenza a DRV o 3TC;
4.virus HIV CXCR4 tropico o CCR5/CXCR4 dual tropico o risultato non-reportable;
5.precedente fallimento virologico a MRV;
6.infezione attiva da HCV con trattamento in corso o pianificato con farmaci DAA noti per le interazioni con farmaci ART in studio;
7.terapia con bifosfonati precedente (entro 1 anno) o attiva;
8.terapia con estroprogestinici in atto;
9.terapia corticosteroidea o immunosoppressiva in atto o nei precedenti 30 giorni;
10.storia di fratture patologiche;
11.allergia nota ai farmaci in studio;
12.trattamento con qualsiasi altro farmaco sperimentale;
13.qualsiasi cosa che, nell’opinione dello sperimentatore, possa porre la paziente maggiormente a rischio o precludere la piena
conformità del soggetto con lo studio o il completamento dello stesso;
14. pazienti con malattie epatiche decompensate (Child Pugh Score: B9).

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

18 months

18 mesi

E.5.2

Secondary end point(s)

Secondary objectives of the study are to compare the two TSS with regard to the following:
•viroimmunologic response, by plasma HIV-RNA and CD4+ T-cell count;
•change of bone turnover markers and of osteoclastogenic cytokines between baseline and 18 months of follow-up;
•change in the 10 year probability of fracture (hip and/or major osteoporotic fracture) assessed by WHO fracture risk assessment tool (FRAX¿) between baseline and 18 months of follow-up;
•change in the amount of CD4+ T-lymphocytes HIV-DNA after 18 months of therapy;
•to assess the change of inflammation markers involved in bone homeostasis and of T-cell immune-activation markers after 18 months of treatment;
•to assess the change of glomerular filtration rate, estimated by MDRD formula, after 18 months of treatment (eGFR);
•plasma trough concentration of antiretroviral drugs (MRV, DRV and ritonavir);
•study of tropism change in case of virological failure.

Paragonare i due regimi TSS riguardo a quanto segue:
•risposta viroimmunologica attraverso la quantità plasmatica di HIV-RNA e della conta delle cellule-T CD4+;
•variazioni dei markers del turnover osseo e di citochine osteoclastogeniche tra il basale e il follow-up dopo 18 mesi di trattamento;
•variazione della probabilità di frattura ossea in 10 anni (e/o grave frattura da osteoporosi dell'anca) calcolata attraverso l’indice di
rischio di frattura WHO (FRAX’’) tra il basale e i 18 mesi di follow-up;
•variazioni nella quantità dell’HIV-DNA intracellulare nei linfociti-T CD4+, dopo 18 mesi di terapia
•variazione dei markers di infiammazione coinvolti nell’omeostasi dell’osso e dei markers di infiammazione t-cellulare dopo 18 mesi di trattamento;
•variazione della Velocità di Filtrazione Glomerulare, calcolata con la formula MDRD (eFGR);
•concentrazione plasmatica minima dei farmaci antiretrovirali (maraviroc, darunavir e ritonavir);
•studio della variazione del tropismo in caso di fallimento virologico.

E.5.2.1

Timepoint(s) of evaluation of this end point

18 months

18 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

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

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

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

194

F.4.2

For a multinational trial

F.4.2.1

In the EEA

194

F.4.2.2

In the whole clinical trial

194

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)

n.a.

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

2017-07-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-12

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

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