Clinical Trials Register

Summary
EudraCT Number:	2011-004038-33
Sponsor's Protocol Code Number:	INMI/001/11
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:	2011-12-28
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

2011-004038-33

A.3

Full title of the trial

Non-inferiority,randomized clinical trial to evaluate the efficacy and the safety of the use of fixed-dose combination efavirenz/tenofovir/emtricitabine (Atripla) administered in alternate days versus the standard of care in HIV-1 infected patients with sustained virological response during HAART

Studio clinico randomizzato di non inferiorita' sulla efficacia e sicurezza dell`™uso di efavirenz/tenofovir/emtricitabina in combinazione fissa (Atripla) somministrato a giorni alterni comparato con lo standard of care in pazienti con infezione da HIV-1 in soppressione virologica sotto HAART

A.3.1

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

Evaluation of the efficacy and the safety of the use of Atripla in alternate days versus the standard dose in HIV-1 infected patients already treated with a successful standard regimen

Valutazione dell'efficacia e della sicurezza dell'uso di Atripla a giorni alterni rispetto alla dose standard in pazienti con infezione da HIV-1 che stanno gia' effettuando un trattamento standard con successo

A.4.1

Sponsor's protocol code number

INMI/001/11

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	ISTITUTO NAZIONALE DELLE MALATTIE INFETTIVE LAZZARO SPALLANZANI
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	Ministero della Salute
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	Istituto Nazionale per le Malattie Infettive ''Lazzaro Spallanzani''
B.5.2	Functional name of contact point	UOC Malattie Infettive e Tropicali
B.5.3	Address:
B.5.3.1	Street Address	via portuense 292
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00149
B.5.3.4	Country	Italy
B.5.4	Telephone number	0655170400
B.5.5	Fax number	0655170407
B.5.6	E-mail	chiara.tommasi@inmi.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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	ATRIPLA*30CPR RIV600+200+245MG
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD SCIENCES Srl
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	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	TENOFOVIR DISOPROXIL FUMARATE
D.3.9.1	CAS number	202138-50-9
D.3.9.4	EV Substance Code	SUB12607MIG
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	245
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EMTRICITABINE
D.3.9.1	CAS number	143491-57-0
D.3.9.4	EV Substance Code	SUB01882MIG
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EFAVIRENZ
D.3.9.1	CAS number	154598-52-4
D.3.9.4	EV Substance Code	SUB06463MIG
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	600
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	ATRIPLA*30CPR RIV600+200+245MG
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD SCIENCES Srl
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	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	TENOFOVIR DISOPROXIL FUMARATE
D.3.9.1	CAS number	202138-50-9
D.3.9.4	EV Substance Code	SUB12607MIG
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	245
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EMTRICITABINE
D.3.9.1	CAS number	143491-57-0
D.3.9.4	EV Substance Code	SUB01882MIG
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EFAVIRENZ
D.3.9.1	CAS number	154598-52-4
D.3.9.4	EV Substance Code	SUB06463MIG
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	600
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 Infection

Infezione da 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	LLT
E.1.2	Classification code	10008922
E.1.2	Term	Chronic infection with HIV
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

Assessing non-inferiority of the regimen with Atripla at alternate days (arm A) versus the standard of care (arm B) at week 48 in terms of proportion of patients with HIV RNA below 40 copies/mL.

Valutare la non inferiorità dello schema di trattamento con Atripla a giorni alterni (braccio A) versus lo standard of care (braccio B) alla settimana 48 in termini di proporzione di pazienti con HIV-RNA al di sotto di 40 cp/mL.

E.2.2

Secondary objectives of the trial

# Evaluate the changes in CD4 + T lymphocyte counts in the two arms. # Evaluate the changes in safety parameters in the two arms. # Assess the proportion of new mutations EFV-associated in case of virological failure in the two arms. # Evaluate the plasma concentrations (C trough) of efavirenz in the two arms. # Evaluate the impact of both regimens on quality of life. # Evaluate the impact of both dosing regimens on adherence to ARV therapy. # To assess the prevalence of SNPs in the CYP2B6 and the correlation between SNPs and plasma concentrations of efavirenz in both arms. # Evaluate the change in lipid parameters in both arms. # Perform a cost-effective in both arms.

# Valutare le modifiche nella conta dei linfociti T CD4+ nei due bracci. # Valutare le modifiche dei parametri di sicurezza nei due bracci. # Valutare la proporzione di nuove mutazioni EFV-associate in caso di fallimento virologico nei due bracci. # Valutare le concentrazioni plasmatiche (Ctrough) di efavirenz nei due bracci. # Valutare l'impatto di entrambi i regimi posologici sulla qualità di vita. # Valutare l'impatto di entrambi i regimi posologici sull’aderenza alla terapia ARV. # Valutare la prevalenza di SNPs sul CYP2B6 e la correlazione fra SNPs e concentrazioni plasmatiche di efavirenz in entrambi i bracci. # Valutare la variazione dei parametri lipidici in entrambi i bracci. # Eseguire un'analisi costo-efficacia in entrambi i bracci.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age> 18 years; - Treatment with a stable regimen containing efavirenz and tenofovir / emtricitabine for at least 24 weeks before screening; - Nadir CD4 +> 200 cells / mmc and CD4 +> 300 cells / mmc at screening; - Viral load <40cp/ml for at least 6 months at screening (at least 2 determinations should have been detected); - Efavirenz C trough above 1000 ng / mL at screening; -Signature of appropriate informed consent; -Pregnancy test negative on blood screening; -Willingness to use appropriate means of contraception for the duration of the study; -owning the phone

- Età > 18 anni; - Trattamento stabile con un regime contenente efavirenz e tenofovir/emtricitabina per almeno 24 settimane prima dello screening; - Nadir CD4+ >200 cellule/mmc e conta CD4+ >300 cellule/mmc allo screening; - Carica virale <40cp/ml per almeno 6 mesi al momento dello screening (almeno 2 determinazioni devono essere state rilevate); - Efavirenz Ctrough superiori a 1000 ng/mL allo screening; -Sottoscrizione di apposito consenso informato; -Test di gravidanza su sangue negativo allo screening; -Disponibilità a utilizzare idonei mezzi di contraccezione per tutta la durata dello studio; possesso del telefono cellulare

E.4

Principal exclusion criteria

- Patients aged <18 years or> 65 years; - HIV RNA> 40 copies / mL in the 6 months prior to screening; - Previous virological failure or evidence of intermediate / high-level resistance to efavirenz, tenofovir or cytidine analogs; - Co-infection with HBV; - Creatinine clearance <50 mL / min at screening or evidence of renal involute years; - Pregnancy or desire for parenthood; - Opportunistic infections or AIDS defining illnesses in place; - History of any solid or haematological malignancy; - Use of psychoactive substances that may in any way interfere with the patient's adherence to the prescribed treatment regimen; - Persons who, in the opinion of the investigator, does not ensure adequate adherence to the study; - Patients who are receiving or have received antineoplastic or immunomodulatory (IL-2, GMCSF ...) in the last 12 months; - Patients with liver cirrhosis; - Participation in other clinical trials or pharmacological treatment with experimental drugs in the 30 days prior to entry in the protocol; - Allergy to any drugs in the regimen; - Inability to sign informed consent.

- Pazienti di età <18 anni o > 65 anni; - HIV-RNA >40 cp/mL nei 6 mesi antecedenti allo screening; - Precedenti fallimenti virologici o evidenza di intermedio/alto livello di resistenza ad efavirenz, tenofovir o analoghi citidinici; - Co-infezione da HBV; - Clearance della creatinina <50 mL/min allo screening o evidenza di anno renale evolvente; - Gravidanza o desiderio di genitorialità; - Infezioni o patologie opportunistiche AIDS definenti in atto; - Storia di qualunque neoplasia solida o ematologica; - Uso di sostanze psicoattive che possano in qualsivoglia maniera interferire con l’aderenza del paziente al regime terapeutico prescritto; - Soggetti che, secondo il parere dello sperimentatore, non garantiscano adeguata aderenza allo studio; - Pazienti che siano in trattamento o che abbiano ricevuto farmaci antineoplastici o immunomodulanti (IL-2, GMCSF…) negli ultimi 12 mesi; - Pazienti con cirrosi epatica; - Partecipazione ad altri trial clinici o trattamento farmacologico con farmaci sperimentali nei 30 giorni precedenti l’ingresso nel protocollo; - Allergia ai principi attivi e agli eccipienti; - Incapacità a sottoscrivere il consenso informato.

E.5 End points

E.5.1

Primary end point(s)

Assessing the proportion of patients with virological failure in the Atripla at alternate days arm (A) versus the standard of care (arm B) at week 48

Valutare la percentuale di pazienti che con fallimento virologico a 48 settimane nel barccio con Atripla a giorni alterni (braccio A) versus lo standard of care (braccio B)

E.5.1.1

Timepoint(s) of evaluation of this end point

48 weeks

48 settimane

E.5.2

Secondary end point(s)

# Evaluate the changes in CD4 + T lymphocyte counts in the two arms. # Assess the proportion of new mutations EFV-associated in case of virological failure in the two arms.

# Valutare le modifiche nella conta dei linfociti T CD4+ nei due bracci. # Valutare la proporzione di nuove mutazioni EFV-associate in caso di fallimento virologico nei due bracci.

E.5.2.1

Timepoint(s) of evaluation of this end point

48 weeks.

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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

- Stesso farmaco ad altro dosaggio

- same IMP used at different dosage

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.8.4.1

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

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 01/Oct/2014

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:

200

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

200

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)

All patients will be re-integrated into a standard HAART without any charges for themselves

Tutti i pazienti verranno reinseriti in un trattamento HAART standard di provata efficacia senza nessun onere di spesa a loro carico

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

2011-11-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-10-12

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

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