Clinical Trials Register

Summary
EudraCT Number:	2016-003948-36
Sponsor's Protocol Code Number:	PROBE2TRIAL
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:	2021-09-06
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

2016-003948-36

A.3

Full title of the trial

Multicenter, national, prospective, open label, randomized, pilot, proof-of-concept study on the use of rilpivirine plus Darunavir/cobicistat as substitutive agents in virologic suppressed patients

A.3.1

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

A pilot study to evaluate the use of rilpivirine plus darunavir / cobicistat as substitute agents in virologic suppressed patients

Studio pilota per valutare l'uso di rilpivirina più darunavir / cobicistat come agenti sostitutivi nei pazienti con carica virologica soppressa

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

PROBE2TRIAL

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 PAPA GIOVANNI XXIII
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	Janseen- Cilag S.p.A
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 Papa Giovanni XXIII
B.5.2	Functional name of contact point	responsabile studio
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	24121
B.5.3.4	Country	Italy
B.5.4	Telephone number	0352678344
B.5.5	Fax number	0352674906
B.5.6	E-mail	malinf@asst-pg23.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	REZOLSTA - 800 MG/ 150 MG- COMPRESSA RIVESTITA CON FILM- 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+cobicistat
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.3.11 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	EDURANT - 25 MG - COMPRESSA RIVESTITA CON FILM - 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	rilpivirina
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.3.11 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-1 infection on an effective ARV therapy (HIV-RNA < copies/ml)

pazienti con infezione HIV-1 virologicamente soppressi

E.1.1.1

Medical condition in easily understood language

HIV-1 infection

pazienti 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	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

To evaluate efficacy and safety of rilpivirine as substitutive agent for the nucleosidic backbone within a dual therapy including darunavir/cobicistat in virologic suppressed patients

Valutare l'efficacia e la sicurezza di rilpivirina come agente sostitutivo all'interno di una duplice terapia con darunavir / cobicistat nei pazienti con attività virologica soppressa.

E.2.2

Secondary objectives of the trial

• Immunologic response after therapy switch
• Incidence and severity of adverse events (AEs) over time
• Incidence and severity of laboratory abnormalities over time
Number and type of resistance mutations in case of virologic failure
• Incidence of disease progression in terms of HIV-associated conditions, AIDS]and death
• Medication adherence over time
To quantify bone alteration by ultrasound scan (substudy)

1. • risposta immunologica dopo switch della terapia
• L'incidenza e la gravità degli eventi avversi (EA) nel corso del tempo
• L'incidenza e la gravità delle anomalie di laboratorio nel corso del tempo
• Numero e tipo di mutazioni di resistenza in caso di fallimento virologico
• L'incidenza di progressione della malattia in termini di condizioni associata ad HIV, AIDS] e la morte
• aderenza farmaci nel corso del tempo
l'alterazione delle ossa da ecografia (sottostudio)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written signed and dated informed consent to participate in the study must be given by the subject, in accordance with the International Conference of Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E627 and applicable regulations, before completing any procedure related to the study.
2. HIV-1 documented infection
3. Male and female subjects ¿ 18 years of age.
4. Males, or non-pregnant, non-lactating females of childbearing potential, as demonstrated by a negative pregnancy test, who agree to comply with any applicable contraceptive requirements of the protocol.
5. Being on a stable therapy for at least 6 months.
6. SBR must be based on any 2NRTI plus a third NNRTI, PI or INI agent. Any possible registered drug is allowed among NRTI (e.g. tenofovir, lamivudine, emtricitabine and abacavir), PI (e.g. lopinavir, atazanavir, darunavir), NNRTI (efavirenz, nevirapine, rilpivirine) or INI (raltegravir, elvitegravir, dolutegravir).
7. Having a fully suppressed HIV replication as documented by 2 prior HIV-RNA tests (at least two months apart) below the detection limit (50 copies/ml).
8. Subjects and investigator must agree that participation in this study is in the best interest of the subject.

1. Firma del consenso informato
2. HIV-1 documentata
3. Pazienti di entrambi i sessi di età maggiore o uguale ai 18 anni di età.
4. Donne non gravide, che non allattano o in età fertile, con test di gravidanza negativo
Uomini e donne in età fertile che accettano di rispettare tutti i requisiti applicabili contraccettivi del protocollo.
5. in terapia stabile per almeno 6 mesi.
6. SBR deve essere basata su qualsiasi 2NRTI più un terzo NNRTI, PI o un agente INI. L'eventuale farmaco registrato è consentito tra NRTI (ad esempio tenofovir, lamivudina, emtricitabina e abacavir), PI (ad esempio lopinavir, atazanavir, darunavir), NNRTI (efavirenz, nevirapina, rilpivirina) o INI (raltegravir, elvitegravir, Dolutegravir).
7. Avere una replicazione di HIV completamente soppressa come documentato da 2 prove precedenti di HIV-RNA (almeno due mesi di distanza) al di sotto del limite di rilevabilità (50 copie / ml).

E.4

Principal exclusion criteria

1. Patients co-infected with HBV
2. Pregnancy or breast feeding.
3. Positive anamnesis for allergy to NNRTI
4. A positive historical genotypic test showing resistance-inducing mutation either toward NNRTIs or PIs
5. History or other evidence of severe illness (malignancy or OI) requiring active treatment and/or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study.
6. Subjects with current or prior (previous year) history of alcohol or other substance abuse.
7. Patients who have previously been screened for or enrolled into this study and subsequently withdrawn.
8. Patients having been given investigational drugs within 12 weeks prior to screening.
9. Inability or unwillingness to provide informed consent.
10. Life expectancy < 18 months
11. Anticipated need for Hepatitis C virus (HCV) therapy during the study period
12. Treatment with any of the following agents within 28 days of Screening: radiation therapy; cytotoxic chemotherapeutic agents; any immunomodulators that alter immune responses
13. All conditions and medicinal products listed in contraindications of DRV/c and rilpivirine

1. I pazienti co-infetti con HBV
2. Donne gravide o in allattamento.
3. anamnesi positiva per allergia al NNRTI
4. Un test genotipico storico positivo che mostra mutazione di resistenza che induce sia verso NNRTI o PI
5. Storia o altro titolo di malattia grave (tumore maligno o OI) che richiedono un trattamento attivo e / o altre condizioni che renderebbero il paziente, a giudizio dello sperimentatore, inadatto per lo studio.
6. I soggetti con (anno precedente) storia attuale o prima di alcol o altre sostanze.
7. I pazienti che sono stati precedentemente sottoposto ad altri studi
8. I pazienti che hanno assunto farmaci sperimentali entro 12 settimane prima dello screening.
9. Incapacità o mancanza di volontà a fornire il consenso informato.
10. Aspettativa di vita <18 mesi

11) Terapia durante il periodo di studio
12. Trattamento con uno qualsiasi dei seguenti agenti entro 28 giorni di screening: radioterapia; agenti chemioterapici citotossici; eventuali immunomodulatori che alterano le risposte immunitarie
13. Tutte le condizioni ei medicinali elencati controindicazioni di DRV / C e rilpivirina

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

Proporzione di pazienti che presenterà un HIV-RNA <50 copie / ml.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 week

24 settimane

E.5.2

Secondary end point(s)

1) The proportion of patients with viral load < 50 copies/ml at 48 weeks according to snapshot analysis on ITT population. A cumulative uncontrolled analysis will be performed on all patients having the 24 week response as goal. A further 48 week analysis will be performed on patients in the former experimental group.
2) The changes (absolute and percentage) in CD4+ and CD8+. Cell counts will be used to evaluate immunologic response after rilpivirine introduction compared to the continuous SBR
3) The proportion of patients developing resistance-conferring mutations (to any drug class) will be analyzed and cumulatively described throughout the study period
4) 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
5) 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
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

) La percentuale di pazienti con carica virale <50 copie / ml a 48 settimane in base alle analisi istantanea su popolazione ITT
2) I cambiamenti (assoluti e percentuali) in CD4 + e CD8 +. dopo l'introduzione rilpivirina rispetto al continuo SBR
3) La percentuale di pazienti che sviluppano mutazioni di resistenza
4) il cambiamento dei parametri metabolici o parametri chimici nel corso del tempo
5) Un'analisi descrittiva di tutti gli eventi avversi segnalati e un'analisi quantitativa di AE che portano all’ interruzione del trattamento / modifica
6) cambiamento nel tempo della densità minerale ossea

E.5.2.1

Timepoint(s) of evaluation of this end point

24 and 48 week

24 e 48 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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

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

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

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

terapia convenzionale

conventional 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

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

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:

140

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

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

160

F.4.2

For a multinational trial

F.4.2.1

In the EEA

160

F.4.2.2

In the whole clinical trial

160

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)

CONTINUATION THERAPY IN PROGRESS DURING STUDY

PROSEGUIMENTO TERAPIA IN CORSO DURANTE STUDIO

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

2017-02-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-19

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

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