Clinical Trials Register

Summary
EudraCT Number:	2013-001637-40
Sponsor's Protocol Code Number:	MK-0518-284-01
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:	2014-01-31
Trial results	View 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

2013-001637-40

A.3

Full title of the trial

Switching from regimens consisting of a RTV -boosted protease inhibitor plus TDF/ FTC to a combination of RAltegravir pluis NevIrapine and IAmivudine in HIV patients with suppressed viremia and and impaired renal function (RANIA study)

Passaggio da un regime terapeutico con un inibitore della proteasi potenziato con Ritonavir più Tenofovir/Emtricitabina ad una combinazione di RAltegravir più NevIrapina e lAmivudina nei pazienti affetti da HIV con viremia soppressa e funzionalità renale compromessa”(Studio RANIA)

A.3.1

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

“Passaggio da un regime terapeutico con un inibitore della proteasi potenziato con Ritonavir più Tenofovir/Emtricitabina ad una combinazione di RAltegravir più NevIrapina e lAmivudina nei pazienti affetti da HIV con viremia soppressa e funzionalità renale compromessa”(Studio RANIA)

A.3.2

Name or abbreviated title of the trial where available

RANIA study

Studio RANIA

A.4.1

Sponsor's protocol code number

MK-0518-284-01

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	MSD Italia s.r.l
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MSD Italia S.r.l.
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	MSD Italia s.r.l
B.5.2	Functional name of contact point	Divisione Ricerca Clinica
B.5.3	Address:
B.5.3.1	Street Address	Via Fratelli Cervi-Centro direzionale Milano 2
B.5.3.2	Town/ city	Segrate
B.5.3.3	Post code	20090
B.5.3.4	Country	Italy
B.5.4	Telephone number	0390221018402
B.5.5	Fax number	0390221018629
B.5.6	E-mail	gcto.italy@merck.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	ISENTRESS ®
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	ISENTRESS
D.3.2	Product code	MK0518
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	RALTEGRAVIR
D.3.9.1	CAS number	518048-05-0
D.3.9.2	Current sponsor code	MK0518
D.3.9.4	EV Substance Code	SUB25667
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	EPIVIR
D.2.1.1.2	Name of the Marketing Authorisation holder	ViiV Healthcare UK Limited 980 Great West Road Brentford Middlesex TW8 9GS (Regno Unito)
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	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	LAMIVUDINE
D.3.9.1	CAS number	134678-17-4
D.3.9.4	EV Substance Code	SUB08392MIG
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	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: 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	VIRAMUNE
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH Binger Strasse 173-55216 Ingelheim am Rhein (Germania)
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	VIRAMUNE
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	NEVIRAPINE
D.3.9.1	CAS number	129618-40-2
D.3.9.4	EV Substance Code	SUB09214MIG
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	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

Each subject must be  18 years of age with a diagnosis of HIV Infections

Soggetti adulti di età ≥18 anni affetti da HIV (Virus dell’immunodeficienza umana)

E.1.1.1

Medical condition in easily understood language

Subjects with a diagnosis of HIV infection.

Adulti affetti da HIV

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

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 assess the changes in renal function (e.g. estimated GFR measured by MDRD formula with 6 variables
that is MDRD 4 variables plus blood urea nitrogen and albumin) and the frequency of experiencing a
decline of renal function in HIV-infected patients with an eGFR (MDRD-6 variables) < 60 mL/ min/1.73 m2
at 48 weeks of follow up.

Valutare i cambiamenti nella funzionalità renale (ad esempio, GFR stimato misurato con la formula MDRD a 6 variabili che è caratterizzata da MDRD a 4 variabili più concentrazione di azoto ureico e albumina nel sangue) e la frequenza di un peggioramento della funzionalità renale nei pazienti con infezione da HIV con un eGFR (con formula MDRD a 6 variabili) <60 ml/min/1,73 m2 alla 48ma settimana.

E.2.2

Secondary objectives of the trial

To evaluate changes in eGDR-MDRD during 96 weeks of follow up.
To assess the efficacy (stable suppressed HIV-RNA <50c/ml) after switch from PI/r (LPV/r, ATV/r, DAR/r)+TDF/FTC to RAL + NVP + 3TC in patients with a stable HIV-1 RNA < 50 copies/mL in the previous 12months during 48 and 96 weeks.
To assess laboratory alterations (liver enzymes, lipid profile) after switch from PI/r (LPV/r, ATV/r, DAR/r) +
TDF/FTC to RAL + NVP + 3TC in patients with a stable HIV-1 RNA < 50 copies/mL in the previous 12
months during 48 and 96 weeks

1. Valutare le variazioni nell’eGDR-MDRD nel corso di 96 settimane di trattamento.
2.Valutare l’efficacia alla settimana 48 e 96 (viremia HIV-RNA soppressa stabile <50 c/ml) dopo il passaggio dal regime Pl/r (LPV/r, ATVIr, DARIr) + TDF/FTC al regime RAL + NVP + 3TC in pazienti con HIV-1 RNA stabile <50 copie/ml nei 12 mesi precedenti al cambio di regime.
3.Valutare le alterazioni nei valori di laboratorio, alla settimana 48 e 96, (enzimi epatici, profilo lipidico) dopo il passaggio dal regime Pl/r (LPV/r, ATV/r, DAR/r) + TDF/FTC a RAL + NVP + 3TC in pazienti con HIV-1 RNA stabile <50 copie/ml nei 12 mesi precedenti al cambio di regime.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

PK Substudy (Pharmacocinetic Substudy),MK-0518-284 -01 Amendment dated 17 Dec 2013

Sottostudio di farmacocinetica,MK-0518-284 -01 Amendment dated 17 Dec 2013

E.3

Principal inclusion criteria

1. Each subject must be  18 years of age.
2. Each subject must be male or non-pregnant, non-breastfeeding female
3. Each subject must have diagnosis of HIV infection.
4. Each subject must have no history of previous virological failure (defined as 2 consecutive plasma HIV-1 RNA >200 copies/mL while on previous or current ARV therapy)
5. Each subject must have no history of previous exposure to NNRTIs or INIs prior to entering the study
6. Each subject must have no history of previous intolerance to Lamivudine
7. Each subject must have at least 2 documented plasma HIV-1 RNA <50 copies/mL and no HIV-1 RNA >50 copies/mL in the 12 months prior to the screening visit
8. Each subject must be taking the same PI/r + TDF/FTC based ARV combination for at least 6 months before screening
9. Each subject mustn't have major IAS-USA mutations on genotypic testing performed before starting ARV treatment.

1.Ogni soggetto deve avere un’età pari o superiore a 18 anni.
2. Ogni soggetto deve essere di sesso maschile o, se di sesso femminile, non deve essere in gravidanza o in allattamento.
3.Ogni soggetto deve avere una diagnosi di infezione da HIV.
4.Ogni soggetto non deve avere nessuna storia di pregresso fallimento virologico (definito come 2 analisi consecutive con livelli plasmatici di HIV-1 RNA >200 copie/ml, durante la precedente o attuale terapia ARV).
5.Ogni soggetto non deve avere nessuna storia di pregressa esposizione a NNRTl o INl prima di entrare nello studio.
6.Ogni soggetto non deve avere nessuna storia di pregressa intolleranza alla Lamivudina.
7.Ogni soggetto deve avere almeno 2 analisi documentate con livelli plasmatici di HIV-1 RNA <50 copie/ml e nessuna evidenza di HIV-1 RNA >50 copie/ml nei 12 mesi precedenti alla visita di screening.
8.Ogni soggetto deve assumere la stessa combinazione ARV con Pl/r + TDF/FTC per almeno 6 mesi prima dello screening.
9.Ogni soggetto non deve avere mutazioni maggiori IAS-USA sul test genotipico eseguito prima di iniziare la terapia ARV.

E.4

Principal exclusion criteria

1.The subject has HBsAg+ or anticipated need for HCV-treatment
2. The subject has grade 2-4 laboratory abnormality of liver transaminases (ALT and AST)
3. The subject has experiencing liver cirrhosis
4. The subject has an allergy/sensitivity to investigational product or its/their excipients.
5. The female subject is nursing.
6. The female subject is pregnant or intending to become pregnant.
7. The subject has any clinically significant condition or situation, other than the condition being studied that,
in the opinion of the investigator, would interfere with the trial evaluations or optimal participation in the
trial.
8. The subject has active AIDS-defining event (CDC-C), exception for stable Kaposi Sarcoma, HIV Wasting
Syndrome.

1.Il soggetto è HBsAg+ o si prevede che necessiterà di trattamento per HCV
2.Il soggetto presenta un’anomalia di laboratorio di grado 2-4 delle transaminasi epatiche (ALT e AST)
3.Il soggetto soffre di cirrosi epatica
4.Il soggetto è allergico/sensibile al prodotto sperimentale o ai rispettivi eccipienti.
5.Il soggetto di sesso femminile sta allattando.
6.Il soggetto di sesso femminile è in gravidanza o intende intraprendere una gravidanza.
7.Il soggetto ha una condizione o una situazione clinicamente significativa, diversa dalla condizione oggetto di studio che, a giudizio dello sperimentatore, potrebbe interferire con le valutazioni della sperimentazione o con una partecipazione ottimale alla sperimentazione.
8.Il soggetto presenta un evento attivo che definisce l’AIDS (CDC-C), fatta eccezione per il sarcoma di Kaposi stabile e della sindrome da deperimento da HIV.

E.5 End points

E.5.1

Primary end point(s)

The primary end-point will be the change from BL in eGFR (MDRD) at Week 48.

L’endpoint primario dello studio sarà il cambiamento tra il BL e la settimana 48 dell’ eGFR (MDRD).

E.5.1.1

Timepoint(s) of evaluation of this end point

The detection time is between baseline and week 48

Il tempo di rilevazione è compreso tra il basale e la settimana 48.

E.5.2

Secondary end point(s)

The Main Secondary Efficacy End-point will be the proportion of subjects with HIV-RNA < 50 cp/ml at 48 weeks according to intent-to-treat (ITT) analysis.

L’endpoint secondario di efficacia principale sarà la percentuale di soggetti con HIV-RNA < 50 cp/ml alla settimana 48 in base all’analisi di Intent to Treat (ITT).

E.5.2.1

Timepoint(s) of evaluation of this end point

The detection time is between baseline and week 48

Il tempo di rilevazione è compreso tra il basale e la settimana 48.

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.2.3.1

Comparator description

regime terapeutico a base di PI/r ovvero Inibitore della Proteasi boosted (Lopinavir-boosted OPPURE

regimen consisting of PI / r or boosted protease inhibitor (lopinavir-boosted atazanavir-boosted OR

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.1.1.1

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

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)

When an / a patient has completed participation in the study, the experimental drug will no longer be made available to / the patient, and any other future care will be provided to / from the patient to his personal physician / healthcare provider

Quando un/una paziente ha terminato la partecipazione allo studio, il farmaco sperimentale non sarà più reso disponibile al/alla paziente, e qualsiasi altra cura futura sarà fornita al/alla paziente dal suo medico personale/operatore sanitario.

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

2014-05-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-03-18

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-07-10

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