Clinical Trials Register

Summary
EudraCT Number:	2011-001635-23
Sponsor's Protocol Code Number:	TMC114IFD3003
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-11-17
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

2011-001635-23

A.3

Full title of the trial

PROTEAse inhibitor (DRV/rtv) in mono- or triple therapy in suppressed HIV-1 infected subjects

Inibitore della PROTEAsi (DRV/rtv) in mono o triplice terapia in soggetti con infezione da HIV-1 virologicamente soppressi.

A.3.1

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

PROTEA: A clinical trial comparing the efficacy of darunavir/ritonavir 800/100 mg monotherapy versus a triple combination therapy containing darunavir/ritonavir 800/100 mg and 2 nucleoside/nucleotide reverse transcriptase inhibitors in patients with undetectable plasma HIV-1 RNA on current treatment

PROTEA:Uno studio clinico che confronta l'efficacia del darunavir/ritonavir 800/100 mg in monoterapia verso terapia con triplice combinazione contenente darunavir/ritonavir 800/100 mg e 2inibitori nucleosidici/nucleotidici della trascrittasi inversa in pazienti in trattamento con livelli plasmaticiHIV-1 RNA non rilevabili

A.3.2

Name or abbreviated title of the trial where available

PROTEA

A.4.1

Sponsor's protocol code number

TMC114IFD3003

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	JANSSEN-CILAG INTERNATIONAL N.V.
B.1.3.4	Country	Belgium
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	Janssen Medical Affairs
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Janssen Biologics
B.5.2	Functional name of contact point	Clinical Registry Group
B.5.3	Address:
B.5.3.1	Street Address	Archimedesweg 29
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333CM
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31 071 524 21 66
B.5.5	Fax number	+31 071 524 21 10
B.5.6	E-mail	ClinicaltrialsEU@its.jnj.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	Prezista
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	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	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	DARUNAVIR
D.3.9.1	CAS number	206361-99-1
D.3.9.2	Current sponsor code	Darunavir ethanolate (formerly known as TMC114 ethanolate)
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	Norvir®
D.2.1.1.2	Name of the Marketing Authorisation holder	Abbott Laboratories Limited
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	RITONAVIR
D.3.9.1	CAS number	155213-67-5
D.3.9.4	EV Substance Code	SUB10342MIG
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	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-1 infection

Infezione da HIV-1

E.1.1.1

Medical condition in easily understood language

HIV-1 infection

Infezione da 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	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10020192
E.1.2	Term	HIV-1
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

The primary objective is to demonstrate non-inferiority in terms of the percentage of subjects who have plasma HIV-1 RNA levels <50 copies/mL after 48 weeks of follow-up after switching to DRV/rtv monotherapy versus triple therapy containing DRV/rtv (FDA Snapshot method).

L’obiettivo primario è dimostrare la non-inferiorità in termini di percentuale di soggetti con livelli plasmatici di acido ribonucleico (RNA) del virus dell’immunodeficienza umana di tipo 1 (HIV-1) < 50 copie/mL dopo 48 settimane di follow-up successive al passaggio alla monoterapia con DRV/ritonavir (rtv) verso la triplice terapia contenente DRV/rtv (analisi snapshot della FDA).

E.2.2

Secondary objectives of the trial

1. the correlation of plasma HIV-1 RNA, cerebrospinal fluid (CSF) HIV-1 RNA, and neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv at week 48 2. change in neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv over 48 and 96 weeks 3. the rate of plasma HIV-1 RNA suppression after 48 and 96 weeks of follow-up to DRV/rtv monotherapy versus triple therapy containing DRV/rtv, using the time to loss of virologic response (TLOVR) method. 4. the correlation of plasma HIV-1 RNA and neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv at Weeks 48 and 96 5. the loss of treatment options as defined by treatment-emergent phenotypic drug resistance 6. the viral genotype of subjects 7. To evaluate and compare safety and tolerability

valutare la correlazione tra l’ HIV-1 RNA plasmatico, l’ HIV-1 RNA nel liquido cerebrospinale (CSF) e funzione neurocognitiva nella monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv alla Settimana 48;-valutare e confrontare la variazione della funzione neurocognitiva nella monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv in 48 e 96 settimane;-valutare e confrontare la soppressione dell’HIV-1 RNA plasmatico dopo 48 e 96 settimane di follow-up alla monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv, utilizzando il metodo del tempo alla perdita della risposta virologica (TLOVR);-valutare la correlazione tra l’ HIV-1 RNA plasmatico e funzione neurocognitiva nella monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv alle Settimane 48 e 96;...per gli altri obiettivi si prega di fare riferimento al protocollo.

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

a lumbar puncture (extraction of cerebrospinal fluid [CSF] from the spinal canal) for laboratory testing (antiviral effectiveness, pharmacokinetic analysis, biochemistry and immune markers) and an additional blood sample for pharmacokinetic analysis (to measure the drug level in blood) will be taken. The study hypothesis is that, after 48 weeks of randomised treatment, DRV/rtv monotherapy is as effective as the triple therapy containing DRV/rtv plus plus 2 nucleoside analogues

è prevista una puntura lombare(estrazione di liquido cerebrospinale (CFS)dal canale spinale)x analisi di labor e un prelievo di sangue x analisi PK, al Basale 1 e dopo 48wks randomizzazione...

E.3

Principal inclusion criteria

HIV-1 infection; receiving HAART for at least 48 weeks; Have plasma HIV-1 RNA <50 copies/mL for at least 48 weeks prior to screening; Be taking the same antiretroviral (ARV) combination for at least 8 weeks before screening; Have the preference, together with the physician, to change the current HAART regimen for reasons of simplification and/or toxicity.

-avere un’infezione da HIV-1 documentata;-ricevere trattamento corrente con HAART da almeno 48 settimane;-avere livelli plasmatici di HIV-1 RNA < 50 copie/mL da almeno 48 settimane prima dello screening;-assumere la stessa combinazione di ARV da almeno 8 settimane prima dello screening;-aver volontà, di concerto con il medico, di modificare il regime HAART corrente per motivi di semplificazione e/o tossicità.

E.4

Principal exclusion criteria

Has a history of virologic failure defined as 2 consecutive plasma HIV-1 RNA >500 copies/mL while on previous or current antiretroviral therapy; Has a history of any primary PI mutations; Has clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels (liver insufficiency); Is diagnosed with acute viral hepatitis at screening or before Baseline 1; Is coinfected with hepatitis B

-ha una storia di fallimento virologico, definito come 2 misurazioni consecutive di livelli plasmatici di HIV-1 RNA > 500 copie/mL durante la terapia antiretrovirale precedente o corrente;-ha evidenze cliniche o agli esami di laboratorio di compromissione epatica significativa o di scompenso epatico, indipendentemente dai livelli degli enzimi epatici (insufficienza epatica);-ha una diagnosi di epatite virale acuta formulata allo screening o prima del Basale 1;-ha un’infezione concomitante da epatite B.

E.5 End points

E.5.1

Primary end point(s)

the percentage of patients who have (HIV-1) ribonucleic acid (RNA) levels <50 copies/mL after 48 weeks of follow-up after switching to DRV/ritonavir (rtv) monotherapy versus triple therapy containing DRV/rtv

-la percentuale di soggetti con risposta virologica, definita come un livello plasmatico confermato di HIV-1 acido ribonucleido (RNA) < 50 copie/mL dopo 48 Settimane di follow up dopo essere passati al DRV/ritonavir(rtv) verso la triplice terapia contenente DRV/rtv.

E.5.1.1

Timepoint(s) of evaluation of this end point

48 weeks

48 settimane

E.5.2

Secondary end point(s)

-the correlation of plasma HIV-1 RNA, cerebrospinal fluid (CSF) HIV-1 RNA, and neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv at week 48;-change in neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv over 48 and 96 weeks;- the rate of plasma HIV-1 RNA suppression after 48 and 96 weeks of follow-up to DRV/rtv monotherapy versus triple therapy containing DRV/rtv, using the time to loss of virologic response (TLOVR) method;-the correlation of plasma HIV-1 RNA and neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv at Weeks 48 and 96;-the loss of treatment options of DRV/rtv monotherapy versus triple therapy containing DRV/rtv at Weeks 48 and 96, as defined by treatment-emergent phenotypic drug resistance;- the viral genotype of subjects treated with DRV/rtv monotherapy versus triple therapy containing DRV/rtv over 48 and 96 weeks;-to evaluate and compare safety and tolerability of DRV/rtv monotherapy versus triple therapy containing DRV/rtv over 48 and 96 weeks.

-valutare la correlazione tra l’ HIV-1 RNA plasmatico, l’ HIV-1 RNA nel liquido cerebrospinale (CSF) e funzione neurocognitiva nella monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv alla Settimana 48; -valutare e confrontare la variazione della funzione neurocognitiva nella monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv in 48 e 96 settimane;-valutare e confrontare la soppressione dell’HIV-1 RNA plasmatico dopo 48 e 96 settimane di follow-up alla monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv, utilizzando il metodo del tempo alla perdita della risposta virologica (TLOVR); -valutare la correlazione tra l’ HIV-1 RNA plasmatico e funzione neurocognitiva nella monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv alle Settimane 48 e 96;-confrontare la perdita di opzioni terapeutiche della monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv alle Settimane 48 e 96, come indicata dalla resistenza fenotipica al farmaco insorta durante il trattamento;-valutare l’evoluzione del genotipo virale dei soggetti in monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv in 48 e 96 settimane;-valutare e confrontare la sicurezza e la tollerabilità della monoterapia con DRV/rtv verso la triplice terapia contenente DRV/rtv in 48 e 96 settimane.

E.5.2.1

Timepoint(s) of evaluation of this end point

48 weeks and 96 weeks

48 settimane e 96 settimane

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

Tollerabilità

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

monoterapia vs combinazione di triplice terapia

monotherapy vs triple combination therapy

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

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Israel

Switzerland

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

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:

255

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

215

F.4.2.2

In the whole clinical trial

260

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)

If a subject discontinues study treatment before the end of the treatment phase, early withdrawal assessments will be obtained. Thereafter, these subjects will continue with scheduled assessment until Week 96, unless the subject withdraws consent. If subject completes the study treatment, will be switched to commercially available medication and will be asked to attend a Follow-up visit 30-35 days after Wk 96 study visit to monitor any side effects.

Se un soggetto interrompe l’assunzione del trattamento in studio prima del termine della fase di trattamento, saranno effettuate le valutazioni di ritiro anticipato.In seguito, questi soggetti continueranno con le valutazioni programmate e saranno seguiti fino alla Settimana 96, salvo in caso di ritiro del consenso. Se il soggetto completa l’assunzione del trattamento in studio, passerà al farmaco disponibile in commercio e gli sarà richiesto di presentarsi allaFU30-35 wk96

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

2012-03-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-03-18

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IMP with orphan designation in the indication
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