Clinical Trials Register

Summary
EudraCT Number:	2013-002349-12
Sponsor's Protocol Code Number:	RALBAT
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:	2013-06-21
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

2013-002349-12

A.3

Full title of the trial

“Switching HIV-positive Women With Undetectable Viremia on Tenofovir/Emtricitabine plus Boosted Atazanavir to RALtegravir (400 mg twice-daily) plus Boosted ATazanavir (300/100 mg once-daily): A Pilot Randomized Clinical Trial Investigating 48-weeks Changes in Bone Mineral Density”

“Switch in donne HIV-positive con viremia soppressa in corso di terapia con tenofovir/emtricitabina e boosted atazanavir (300/100 mg qd) a RALtegravir (400 mg bid) con boosted Atazanavir (300/100 mg qd): Studio Pilota Randomizzato sulle modificazioni della densità minerale ossea a 48 settimane”

A.3.1

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

Switch from tenofovir/emtricitabine to raltegravir in female HIV-positive patients taking atazanavir/ritonavir evaluating bone mineral density improvement after one year.

Cambio di terapia da tenofovir/emtricitabina a raltegravir in pazienti di genere femminile HIV-positive che stanno assumendo atazanavir/ritonavir per valutare il miogliramento della densità minerale ossea dopo un anno

A.3.2

Name or abbreviated title of the trial where available

RALBAT Study

Studio RALBAT

A.4.1

Sponsor's protocol code number

RALBAT

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	Unit of Infectious Diseases, Department of Medical Scieces, University of Torino c/o ASLTO2, Amedeo di Savoia Hospital
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	Merck Sharp and Dohme
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	Unit of Infectious Diseases, Department of Medical Scieces, University of Torino c/o ASLTO2, Amedeo di Savoia Hospital
B.5.2	Functional name of contact point	Clinica Universitaria di Malattie I
B.5.3	Address:
B.5.3.1	Street Address	C,so Svizzera 164
B.5.3.2	Town/ city	Torino
B.5.3.3	Post code	10149
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390114393856
B.5.5	Fax number	+390114393942
B.5.6	E-mail	andrea.calcagno@unito.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	Isentress
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohm
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.3.11 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 infection, osteopenia

infezione da HIV, osteopenia

E.1.1.1

Medical condition in easily understood language

HIV infection, reduced bone density

infezione da HIV, ridotta densità ossea

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 improvement in Bone Mineral Density and markers of bone turnover in women on TDF/FTC + ATV/r in a switch arm (RAL + ATV/r) vs. an unchanged arm (TDF/FTC + ATV/r).

Obiettivo primario è valutare se la sostituzione di tenofovir/emtricitabina (in un regime contenente atazanavir/r) con raltegravir si associ a un miglioramento nella densità minerale ossea a 48 settimane dallo switch.

E.2.2

Secondary objectives of the trial

Secondary Objectives:
• To assess the variation in glomerular filtration rate, urinary markers of tubular dysfunction (nondiabetic glucosuria, altered resorption of phosphorus, hyperaminoaciduria, b2-microglobulinuria and abnormal uric acid excretion.) and urinary retinol binding protein in the two arms at 24 and 48 weeks;
• To asses metabolic and hormonal profile changes at 48 weeks in the two arms (cholesterol, triglycerides, glucose fasting levels, insulin, PTH and 25-OH-vitamin D);

Obiettivi secondari sono la valutazione delle variazioni nella qualità ossea, nei marcatori di funzione renale tubulare e nel profilo metabolico a 48 settimane dallo switch con raltegravir.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria:
• Adult HIV-positive female patients;
• osteopenia (t-score from -1 to -2.5)
• On antiretroviral treatment with tenofovir/emtricitabine and atazanavir/ritonavir (300/100 mg) for at least six months;
• Plasma HIV RNA below 50 copies/ml since six months;
• Premenopausal women: female patients at any phase of the reproductive period with regular menstrual cycles and normal FSH (< 25 ng/mL) That would probably esclude patients with ovarian or endocrinological dysfunctions. Pre and postmenopausal should be therefore well-characterized.
• Women in menopausal period (the menopause was defined as 12 months of amenorrhoea without any pathological or physiological cause and using the endocrinological definition of ovary insufficiency (LH>25ng/mL, FSH>25ng/mL and E2<30ng/mL).
• Each premenopausal sexually active subject of child-bearing potential must agree to use a medically accepted method of contraception while receiving protocol-specified medication and for 3 months after stopping the medication.
Medically accepted methods of contraception include condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed IUD, inert or copper-containing IUD, hormone-releasing IUD, systemic hormonal contraceptive, and surgical sterilization (eg, hysterectomy or tubal ligation).
• Postmenopausal women are not required to use contraception.

• Pazienti adulte di genere femminile;
• Infezione da HIV confermata;
• In terapia con tenofovir, emtricitabina, atazanavir/ritonavir (300/100 mg) da almeno sei mesi;
• HIV RNA plasmatico inferiore a 50 copie/mL da almeno sei mesi;
• osteopenia (definitia come t-score alle densitometria ossea compreso tra -2.5 e -1);
• In donne nel periodo pre-menopausale (definite come cicli mestruali regolari e FSH al di sotto di 25 ng/mL) sessualmente attive: consenso a utilizzare un metodo contraccetivo per la durata del protocollo e nei tre mesi successivi al termine dello stesso. I metodi considerati validi includono l’utilizzo del preservativo (maschile e femminile), diaframma o cappuccio cervicale con spermicida, dispositivi intrauterini, contraccezione ormonale sistemia e la sterilizzazione chirurgica (isterectomia o legatura delle tube). In donne nel periodo post-menopausale [definito come 12 mesi di amenorrea senza condizioni patologiche che si associno a tale fenomeno e con esami di laboratorio compatibili con insufficienza ovarica (LH>25ng/mL, FSH>25ng/mL e E2<30ng/mL)]: non è necessario l’utilizzo di un metodo di contraccezione.

E.4

Principal exclusion criteria

Exclusion criteria:

• History or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might confound the results of the study, or interfere with the patient’s participation for the full duration of the study, such that it is not in the best interest of the patient to participate.
• Documented resistance to Raltegravir or/and Atazanavir.
• Patient with significant hypersensitivity or other contraindication to any of the components of the study drugs.
• Patient has a current (active) diagnosis of acute hepatitis due to any cause
• Patient with coinfection HIV/HBV
• Liver cirrhosis
• Osteoporosis (t-score less than 2.5).
• Secondary endocrinological cause of low BMD
• Chronic steroid intake;
• Chronic kidney disease (estimated glomerular filtration rate below 60 ml/min*24h);
• Concomitant use of bisphosphonate.

• Anamnesi remota o recente positiva per condizioni, terapia, anomalie di laboratorio o altre circostanze che potrebbero confondere i risultati dello studio, o interferire con la partecipazione del paziente all’intera durata dello studio, tale che non sia nel migliore interesse per il paziente di partecipare allo studio;
• Resistenza documentata a raltegravir e/o ad atazanavir;
• Significativa ipersensibilità, intolleranza o qualunque controindicazione ai componenti dei farmaci in studio;
• Diagnosi di epatite acuta dovuta a qualunque causa;
• Coinfezione con HBV;
• Cirrosi epatica;
• Osteoporosi (t-score alla DEXA inferiore a 2.5).
• Cause endocrinologiche secondarie di bassa densità minerale ossea;
• Terapia steroidea cronica;
• Insufficienza renale cronica (celarance stimata della creatinina inferiore a 60 ml/min);
• Utilizzo di difosfonati

E.5 End points

E.5.1

Primary end point(s)

• To assess variations from baseline in DEXA bone mineral density (spine and femur) at 48 weeks in the two arms;
• To assess variations from baseline in CTX (C-terminal telopeptide of type I collagen) and OC (Osteocalcin) at 24 and 48 weeks in the two arms.

Endpoint primario è il confronto tra la differenza di densità minerale ossea (vertebre lombari e femore) alla settimana 48 rispetto al basale nei due bracci.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline, week 48

basale, settimana 48

E.5.2

Secondary end point(s)

• il confronto tra la differenza di CTX (telopeptide C-terminale del collagene di tipo I), di OC (Osteocalcina) e di fosfatasi alcalina ossea (bALP) alla settimana 48 rispetto al basale, nei due bracci.
• il confronto tra la differenza di clearance della creatinina stimata, markers urinari di disfunzione tubulare (glicosuria non diabetica, alterato riassorbimento del fosforo, iperaminoaciduria, Beta2microglobinuria, alterata escrezione urinaria di urati, proteina legante il retinolo), calcemia e calciuria alla settimana 48 rispetto al basale, nei due bracci.
• il confronto tra la differenza nel profilo metabolico (colesterolo totale, colesterolo HDL, colesterolo LDL, trigliceridi, glicemia, insulina) e ormonale (paratormone, vitamina D) alla settimana 48 rispetto al basale, nei due bracci.

E.5.2.1

Timepoint(s) of evaluation of this end point

baseline, week 24 and week 48

basale, settimana 24 e 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

Yes

E.6.5

Efficacy

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

tenofovir/emtricitabina

tenofovir/emtricitabine

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

The trial ends at 48 weeks of treatment for each subject

Lo studio termina a 48 settimane per ciascun soggetto

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

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)

As clinical practice: at the end of the trial patietns will be offered to keep on with the treatment they are receiving or to go back to the previous one.

Come da pratica clinica: alla fine dello studio alle pazienti sarà proposto di ncontinuare con la terpai in atto o di ritornare alla precedente.

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

2013-08-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-08-17

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

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