Clinical Trials Register

Summary
EudraCT Number:	2013-002573-22
Sponsor's Protocol Code Number:	PROBE
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:	2013-06-20
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

2013-002573-22

A.3

Full title of the trial

PROBE TRIAL (Pilot Rilpivirine Observational Evaluation) Monocenter, national, prospective, open label, pilot, proof-of-concept study on the use of rilpivirine as substitutive agent for the HAART nucleosidic backbone in virologic suppressed patients.

STUDIO PROBE (Pilot Rilpivirine Observational Evaluation) monocentrico, nazionale, prospettico, in aperto, spontane, rivolto a pazienti con infezione da HIV tratatti con una combinazioen di tre farmaci( due nucleosidici ed un inibitore della proteasi) e che presentano una risposta ottimale con mancata replicazione stabile del virus HIV

A.3.1

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

PROBE TRIAL proof-of-concept study on the use of rilpivirine as substitutive agent for the HAART nucleosidic backbone in virologic suppressed patients

STUDIO PROBE rivolto a pazienti con infezione da HIV tratatti con una combinazioen di tre farmaci( due nucleosidici ed un inibitore della proteasi) e che presentano una risposta ottimale con mancata replicazione stabile del virus HIV

A.4.1

Sponsor's protocol code number

PROBE

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.O PAPA GIOVANNI XXIII- BERGAMO
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	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	A.O PAPA GIOVANNI XXIII- BERGAMO
B.5.2	Functional name of contact point	Franco Maggiolo
B.5.3	Address:
B.5.3.1	Street Address	Piazza OMS, 1
B.5.3.2	Town/ city	Bergamo
B.5.3.3	Post code	24127
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390352673608
B.5.6	E-mail	franco31556@hotmail.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	Edurant
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	European Union
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.3.11 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	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	European Union
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.3.11 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	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	European Union
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.3.11 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

HIV1-infected adults

pazienti con infezione HIV

E.1.1.1

Medical condition in easily understood language

HIV1-infected adults of ≥ 18 years of age on an effective ARV therapy (HIV-RNA < 50 copies/ml) based on the use of two NRTIs and a boosted-PI

Adulti con infezione da HIV1 di età ≥ 18 anni con un efficace terapia ARV (HIV-RNA <50 copie / ml), basato sull'utilizzo di due NRTI e un potenziato-PI

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

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 evaluate efficacy and safety of rilpivirine as substitutive agent for the nucleosidic backbone of HAART in virologic suppressed patients. Primary analysis will be performed after 6 months. A further analysis will be performed after a prolonged observation time of 12 months. Efficacy will be defined according to snapshot analysis.

valutare l'efficacia e la sicurezza della sostituzione in pazienti in terapia cronica con tre diversi farmaci (due nucleosidici + ritonavir) con rilpivirina e darunavir ( piu’ ritonavir)

E.2.2

Secondary objectives of the trial

To evaluate immunologic response after rilpivirine introduction
To evaluate virologic efficacy using a high sensitivity HIV-RNA test with a limit of detection of 3 copies/ml
To evaluate the risk of selecting for resistance-inducing mutations during the simplification therapy by means of a new generation sequencing assay detecting minority species at a 1% prevalence
To evaluate the change of metabolic parameters over time and quantify bone alteration by ultrasound scan
To evaluate change over time of immunoactivation markers
To evaluate long-term tolerability of the simplification treatment

valutare la risposta immunologica dopo l'introduzione rilpivirina;
valutare l'efficacia virologica mediante un test ad alta sensibilità di HIV-RNA con
un limite di rilevazione di 3 copie / ml;
valutare il rischio di selezionare mutazioni di resistenza ;
valutare la variazione di parametri metabolici nel tempo e quantificare alterazione ossea mediante ecografia;
valutare il cambiamento nel tempo dei marcatori immuno;
valutare la tollerabilità a lungo termine del trattamento semplificazione.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

HIV-1 documented infection
Age ≥ 18 years
Being on a stable HAART regimen based on the association of 2 NRTIs and a boostd-PI for at least 6 months.
Being on an effective (VL < 50 copies/ml) HAART regimen. Two consecutive HIV-RNA determination below the determination threshold before enrollment are required
No known allergy to NNRTIs
Women of childbearing potential will be asked to adopt an effective birth control system throughout the study period
Informed consent signed

HIV-1 infezione documentata;
Età ≥ 18 anni;
Essere in un trattamento farmacologico con un regime HAART stabile basato sull'associazione di 2 NRTI e un boostd-PI per almeno 6 mesi;
avere un efficace (VL <50 copie / ml) HAART regime;
No allergia nota agli NNRTI;
Le donne in età fertile verrà richiesto di adottare un contraccettivo efficace
sistema di controllo durante il periodo di studio;
firma del consenso informato.

E.4

Principal exclusion criteria

Any major NNRTI or PI resistance mutation in an historical genotype
Pregnancy or breast-feeding
An active malignancy or OI requiring active treatment (prophylactic regimens are allowed)
Life expectancy < 18 months

Qualsiasi maggiore NNRTI o PI resistenza mutazione in un genotipo storico;
Gravidanza o allattamento;
Un tumore maligno attivo o che richiedono un trattamento attivo (profilattico
regimi sono consentiti);
L'aspettativa di vita <18 mesi.

E.5 End points

E.5.1

Primary end point(s)

Being the primary goal of the study the efficacy analysis of the rilpivirine-boosted PI combination, the primary end-point will be the proportion of patients that will present a HIV-RNA < 50 copies/ml. The primary end point will be evaluated according to snapshot analysis at 24 weeks according to an ITT NC = failure approach in which all randomized patients will be included and considered failures independently of the reason they did not complete the follow-up. The sample size has been calculated on this end-point the
A secondary analysis will be performed according a per protocol (PP) approach. In this case only patients fulfilling protocol-defined timeline and continuing to assume the randomized therapy will be considered.

l'end-point primario sarà la percentuale di pazienti che presenterà un HIV-RNA <50 copie / ml. L’end point primario sarà valutata secondo l'analisi istantanea a 24
settimane secondo un approccio ITT NC = fallimento in cui tutti randomizzato
pazienti saranno inclusi e considerati insuccessi indipendentemente
ragione per cui non ha completato il follow-up. La dimensione del campione è stata
calcolato su questo punto finale la Un'analisi secondaria sarà eseguita secondo un per protocollo (PP) approccio. In questo caso solo i pazienti appagante temporale protocollo definito e continuando ad assumere la terapia randomizzata sarà considerato.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 week

24 settimane

E.5.2

Secondary end point(s)

The secondary efficacy outcome measures (end-points) of this study are:
1) The proportion of patients with viral load < 50 copies/ml at 12 months according to snapshot analysis on both ITT and PP populations and according to a time-dependent analysis of virologic response based on the Kaplan-Meier approach.
2) The changes (absolute and percentage) in CD4+ and CD8+ and CD8+CD38+HLA*DR+ counts. Cell counts will be used to evaluate immunologic response after rilpivirine introduction compared to the continuous SBR
3) The proportion of patients with viral load below the detection limit by means of an ultrasensitive PCR test with a limit of detection of 3 copies/ml. The same evaluation timing as for the primary end-point will used.
4) The proportion of patients developing resistance-conferring mutations (to any drug class) will be analyzed and cumulatively described throughout the study period
5) The absolute changes as well as proportion of patients above clinically relevant thresholds will be used to evaluate the change of metabolic parameters or chemical parameters over time
6) Absolute changes as well as proportion of patients above clinically relevant thresholds will be used to evaluate change over time of bone mineral density
7) A descriptive analysis of all reported AEs and a quantitative analysis of AEs leading to treatment interruption/change will be used to evaluate long-term tolerability of the simplification treatment

La proporzione di pazienti con carica virale <50 copie / ml a 12
mesi, secondo l'analisi istantanea su entrambe le popolazioni ITT e PP
e secondo un'analisi dipendente dal tempo di risposta virologica basata
sul metodo di Kaplan-Meier.
2) Le modifiche (assoluto e percentuale) in CD4 + e CD8 + e
CD8 + CD38 + HLA * DR + conta. La conta delle cellule saranno utilizzati per valutare
risposta immunologica dopo introduzione rilpivirine rispetto al SBR continua
3) La proporzione di pazienti con carica virale al di sotto del limite di rilevabilità
per mezzo di un test di PCR ultrasensibile con limite di rilevamento di 3
copie / ml.
4) La percentuale dei pazienti che sviluppano resistenza che conferisce
mutazioni (a qualsiasi classe di farmaci) saranno analizzati e cumulativamente
descritto nel percorso di studio degli AE conseguente interruzione del trattamento / modifica verrà utilizzata per valutare
tollerabilità a lungo termine del trattamento semplificazione
5) Le variazioni assolute come proporzione di pazienti sopra la soglia clinicamente rilevanti saranno utilizzati per valutare la variazione di parametri metabolici o parametri chimici nel tempo
6) Variazioni assolute come proporzione di pazienti di cui sopra clinicamente
soglie pertinenti saranno utilizzati per valutare il cambiamento nel tempo di osso
densità minerale
7) Una analisi descrittiva di tutti segnalati eventi avversi e un'analisi quantitativa

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months

12 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

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

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

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)

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.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)

none

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

2013-07-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-06-13

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

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