Clinical Trials Register

Summary
EudraCT Number:	2012-005192-14
Sponsor's Protocol Code Number:	HLS03/2012
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:	2012-12-28
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

2012-005192-14

A.3

Full title of the trial

Strategic study of dual-therapy with darunavir/ritonavir and rilpivirine QD versus triple-therapy in patients with suppressed viral load: virological efficacy and evaluation of non-HIV related morbidity.

STUDIO STRATEGICO DI TERAPIA DUPLICE CON DARUNAVIR/rtv E RILPIVIRINA QD VS TERAPIA TRIPLICE IN PAZIENTI CON VIREMIA SOPPRESSA: EFFICACIA VIROLOGICA E VALUTAZIONE DELLA MORBIDITA' NON-HIV CORRELATA.

A.3.1

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

DRV/r + RPV QD: EFFICCY AND TOXICITY REDUCTION.

DRV/r + RPV QD: EFFICACIA E RIDUZIONE TOSSICITÀ.

A.4.1

Sponsor's protocol code number

HLS03/2012

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 L. SACCO (A.O. DI RILIEVO NAZIONALE)
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	Janssen
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	Ospedale Luigi Sacco
B.5.2	Functional name of contact point	U.O. Malattie Infettive III
B.5.3	Address:
B.5.3.1	Street Address	via G.B. Grassi, 74
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20157
B.5.3.4	Country	Italy
B.5.4	Telephone number	02-39042949
B.5.5	Fax number	02-50319758
B.5.6	E-mail	stefano.rusconi@unimi.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	PREZISTA*60CPR RIV 400MG
D.2.1.1.2	Name of the Marketing Authorisation holder	JANSSEN CILAG SpA
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.3.9.4	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	400
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	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	Edurant
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen Cilag International NV
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	rilpivirina
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	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.

Infezione da HIV.

E.1.1.1

Medical condition in easily understood language

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10020161
E.1.2	Term	HIV infection
E.1.2	System Organ Class	10021881 - Infections and infestations

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 evaluate the virologic efficacy of a maintenance regimen with
RPV+DRV/r in HIV+ subjects with a previous antiretroviral treatment and a full HIV-RNA suppression.

Obiettivo primario dello studio è la valutazione dell’efficacia virologica di un regime di mantenimento con RPV + DRV/r in soggetti HIV+ già sottoposti a terapia antiretrovirale e con carica virale soppressa.

E.2.2

Secondary objectives of the trial

• To evaluate VACS index modification in subjects treated in two groups, at Weeks 48
and 96, as compared to the baseline;
• To evaluate differences of markers of tubulopathy (RBP, RBP/creatinine, plasmatic and
urinary phosphate, albuminuria) in two groups at week 12, 48, and 96 as compared to the
baseline; we report urinary RBP abnormalities in some patients treated with tenofovir, in some
studies, and the significance of RBP as an indirect marker of tubular damage;
• To evaluate differences of markers of lipid metabolism (total cholesterol, HDL and LDL cholesterol, triglycerides);
• To evaluate differences of markers of bone metabolism (osteocalcin, CTx) as compared
to baseline;
• To evaluate darunavir and rilpivirine plasma exposure (Ctrough) as a determinant of
virological failure.

• Valutazione della modificazione del VACS index nei due gruppi, confronto tra essi e alle Week 48 e 96 rispetto al baseline;
• Valutazione della differenza in termini di markers di tubulopatia (RBP, RBP/creatinina; fosfato plasmatico; fosfaturia; albuminuria; eGFR) nei due gruppi alle week 12, 48 e 96, confrontato con il baseline; si segnala il riscontro di alterazioni della RBP urinaria (Retinol Binding Protein) in soggetti trattati con tenofovir, e il suo conseguente significato come indicatore indiretto di danno tubulare;
• Valutazione della differenza in termini di markers di metabolismo osseo (osteocalcina, CTx);
• Valutazione della differenza in termini di profilo lipidico (colesterolo totale, HDL, LDL, trigliceridi);
• Valutazione della concentrazione plasmatica (Ctrough) di RPV e DRV nella determinazione di fallimento virologico.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Adult HIV+ subjects (>18 years old), giving and signing an informed consent;
• Any HAART treatment for at least 12 months;
• Current treatment with a PI/r-containing regimen initiated at least 6 months earlier;
• HIV-RNA <50 cp/mL for at least 3 months, without viral blip due to virologic failure at any time;
• Any nadir CD4 lymphocytes;
• Current CD4 count > 100 cell/uL;
• eGFRs >60 mL/min/1,73 m2.

• Soggetti con infezione da HIV, di età >18 anni, in grado di comprendere e firmare un consenso informato;
• HAART da almeno 12 mesi;
• HAART in corso comprendente un PI/r da almeno 6 mesi;
• Carica virale < 50 cp/mL da almeno 3 mesi, senza blip virali;
• Qualsiasi valore di CD4 al nadir;
• eGFR > 60 mL/min/1,73 m2.

E.4

Principal exclusion criteria

• Previous drug resistance genotypic test showing the presence of any RPV (RT: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C, M230I/L) or DRV (protease: V11I, V32I, L33F, I47V, I50V, I54M/L, T74P, L76V, I84V, L89V) resistance associated mutation (RAM), according to the November 2011 IAS-USA list;
• Child-Pugh C or grade 3-4 AST or ALT values;
• Acute cardiovascular event within 6 months;
• AIDS event within 6 months;
• Current IVDU;
• HBsAg + ;
• Pregnancy or lactation.

• Pregresso test genotipico con presenza di qualsiasi mutazione (RAM) associata a RPV o DRV, secondo l’elenco 2011 IAS-USA (RT: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C, M230I/L; proteasi: V11I, V32I, L33F, I47V, I50V, I54M/L, T74P, L76V, I84V, L89V);
• Child-Pugh C o grado 3-4 alle transaminasi;
• Evento cardiovascolare acuto negli ultimi 6 mesi;
• Evento AIDS-definente negli ultimi 6 mesi;
• Attuale uso di sostanze stupefacenti per via endovenosa;
• Positività per HBsAg;
• Gravidanza o allattamento.

E.5 End points

E.5.1

Primary end point(s)

HIV+ subjects with HIV-RNA < 50 cp/mL at week 48 according to the intention-to-treat (ITT-TLOVR) approach.

Valutazione della percentuale di soggetti con HIV-RNA<50 cp/mL alla week 48 secondo l’approccio Intention to Treat.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 48.

Settimana 48.

E.5.2

Secondary end point(s)

Safety will be assessed through the number of ACTG grade III and IV in the specified safety parameters.

 Calcolo della percentuale dei soggetti con riduzione di 3 punti del VACs index alle weeks 48 e 96;
 Calcolo della mediana dei valori di RBP e RBP/creatinina urinarie alle weeks 12, 48, e 96, e confronto rispetto al baseline;
 Calcolo della mediana dei valori osteocalcina e CTx alle weeks 12, 48 e 96, e confronto con il baseline;
 Calcolo dei TLOVR (VL > 50 cp/mL in 2 misurazioni consecutive) alle week 48 e 96, nell'analisi Intention to Treat;
 Calcolo della percentuale di soggetti con VL<50 cp/mL alla week 96, secondo AT e PP analisi;
 Calcolo della mediana dell'incremento dei CD4 (conta sia assoluta che percentuale) durante il periodo di studio);
 Ricerca di modificazioni statisticamente significative del profilo lipidico (colesterolo totale, HDL, LDL, trigliceridi), durante il periodo di studio;
 Ricerca di modificazioni statisticamente significative in termini di glicemia e insulinemia durante il periodo di studio;
 Percentuale di concentrazioni Ctrough di rilpivirina e darunavir inferiori al range atteso in entrambi i bracci e relazione con il fallimento virologico;
 Valutazione della concentrazione plasmatica di darunavir e rilpivirina (Ctrough) nella determinazione del fallimento virologico.

E.5.2.1

Timepoint(s) of evaluation of this end point

Weeks 12, 48 and 96.

Settimane 12, 48 e 96.

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

Yes

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

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

Number of subjects for this age range:

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:

120

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

132

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)

Subjects will be followed according to the current GCP.

I soggetti verranno seguiti secondo la migliore pratica clinica.

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

2013-01-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-19

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

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