Clinical Trials Register

Summary
EudraCT Number:	2013-003359-39
Sponsor's Protocol Code Number:	ZEST
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-01-16
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

Spain - AEMPS

A.2

EudraCT number

2013-003359-39

A.3

Full title of the trial

Bisphosphonate Therapy with Zoledronic acid or Tenofovir Switching to Improve Low Bone Mineral Density in HIV-Infected Adults

Tratamiento con ácido zoledrónico vs sustitución de tenofovir para mejorar la densidad mineral baja en pacientes adultos infectados por el VIH

A.3.1

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

Treatment with Zoledronic acid or Tenofovir Switching in HIV-Infected

Tratamiento con ácido zoledrónico vs sustitución de tenofovir en pacientes infectados por el VIH

A.4.1

Sponsor's protocol code number

ZEST

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	Fundació Clínic per a la Recerca Biomèdica
B.1.3.4	Country	Spain
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	St. Vicent's Hospital
B.4.2	Country	Australia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CTU (Clinical Trials Unit)
B.5.2	Functional name of contact point	Joan Albert Arnaiz
B.5.3	Address:
B.5.3.1	Street Address	Villarroel, 170
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08036
B.5.3.4	Country	Spain
B.5.4	Telephone number	34932279838
B.5.5	Fax number	34932279877
B.5.6	E-mail	jaarnaiz@clinic.ub.es

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	Aclasta
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ZOLEDRONIC ACID
D.3.9.1	CAS number	118072-93-8
D.3.9.4	EV Substance Code	SUB00176MIG
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	5
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

low bone mineral density - HIV

Baja densidad mineral ósea - VIH

E.1.1.1

Medical condition in easily understood language

low bone mineral density - HIV

Baja densidad mineral ósea - VIH

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10068341
E.1.2	Term	HIV-1 infection
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 compare the effects of zoledronic acid 5 mg IV yearly to switching from tenofovir to another antiretroviral drug on lumbar spine BMD (primary endpoint) over 2 years.

Comparar el efecto de ácido zolendrónico o la sustitución de tenofovir sobre la densidad mineral ósea lumbar (DMO) a los 2 años.

E.2.2

Secondary objectives of the trial

To compare the randomised groups for:

1. other bone parameters
- mean percent change in hip BMD
- incidence of osteoporosis (T-score <-2.5 at hip or spine) and of normal BMD (T-score >-1 at hip and spine)
- fracture risk estimated with the Australian version of the FRAX equation48
- serum levels of CTx and P1NP
- fractures (except of the skull, and of the small bones of the hands and feet)

2. safety (clinical adverse events [all grades]; all serious adverse events; AIDS; death; use of concomitant medications for toxicity; estimated glomerular filtration rate (eGFR, by MDRD equation; laboratory adverse events; virological failure (FDA definition: plasma HIV RNA >400 copies/mL on 2 consecutive occasions ?4 weeks apart)
3. modifications to ART (after baseline)

Comparar los efectos de ácido zolendrónico o sustitución de tenofovir sobre:

1. Otros parámetros óseos:
- Cambio en la DMO femoral
- Incidencia de osteoporosis (T-score <-2.5 en columna o fémur) y de DMO normal (T-score >-1 en columna o fémur)
- Riesgo de fractura estimado con la ecuación FRAX
- Niveles plasmáticos de telopéptido C terminal (CTx) y del propéptido amino-terminal del procolágeno tipo 1 (P1NP)
- Fracturas (excepto cráneo y huesos pequeños de manos y pies)
2. Parámetros de seguridad (acontecimientos adversos clínicos y de laboratorio, acontecimientos adversos graves, SIDA, muerte, uso de medicaciones concomitantes por toxicidad, tasa de filtrado glomerular estimado, y fracaso virológico)
3. Cambios en el tratamiento antirretroviral

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. provision of written, informed consent
2. HIV infected adult ?18 years of age
3. stable and well-tolerated ART including tenofovir for the preceding 6 months
4. plasma HIV RNA <50 copies/ml for at least the preceding 3 months
5. eGFR >60ml/min (patients at higher risk of zoledronic acid/tenofovir nephrotoxicity)
6. spine or neck of femur T score ? -1.0 measured by DXA (i.e. osteopenia)

1. Otorgar consentimiento informado por escrito
2. Pacientes adultos VIH positivos (?18 años)
3. En combinación estable y bien tolerada de tratamiento antirretroviral que incluya tenofovir durante los últimos 6 meses
4. VIH RNA <50 copias/mL en los últimos 3 meses
5. Tasa de filtrado glomerular estimada >60 mL/min
6. T-score (DEXA) de columna o cuello de fémur ?-1.0

E.4

Principal exclusion criteria

1. prior bisphosphonate therapy
2. use of tenofovir for previously active chronic hepatitis B co-infection
3. requiring therapy for low BMD (e.g. prior fragility fracture; other metabolic bone disease)
4. other secondary causes of osteoporosis: hypogonadism (total testosterone/oestrogen <lower limit of normal and luteinizing hormone >25% above upper normal limit); hypothyroidism (low T4 and elevated TSH); hyperparathyroidism (elevated parathyroid hormone); inhaled fluticasone in a patient receiving ritonavir; prednisolone ?7.5mg/d or equivalent
5. contra-indications to zoledronic acid (known hypersensitivity to bisphosphonates, hypocalcaemia, prior or current uveitis, eGFR<35 mL/min)
6. recent (within the last 2 months) or planned dental surgery (at investigators discretion)
7. previous virological failure (defined above), genotypic resistance, intolerance or contraindication to proposed switch antiretroviral drug
8. HLA-B*5701 positive (abacavir contra-indicated) or prior ischaemic cardiovascular disease if planning to switch from tenofovir to abacavir
9. concurrent use of any nephrotoxic drug
10. breast-feeding or pregnancy

1. Tratamiento previo con bifosfonatos
2. Uso de tenofovir para co-infección por hepatitis B crónica
3. Necesidad de tratamiento por DMO baja (por ejemplo, fractura por fragilidad previa o enfermedad metabólica ósea)
4. Otras causas de osteoporosis secundaria:
- Hipogonadismo (testosterona o estrógenos totales bajos y hormona luteinizante >25% por encima del límite normal)
- Hipotiroidismo (T4 baja y TSH elevada)
- Hiperparatiroidismo (PTH elevada)
- Fluticasona inhalada en un paciente que reciba ritonavir
- Prednisolona ?7.5mg/d o equivalente
5. Contraindicación para el uso de ácido zolendrónico:
- Hipersensibilidad conocida a bifosfonatos
- Hipocalcemia
- Uveítis previa o actual
- Tasa de filtrado glomerular estimado <35 mL/min
6. Cirugía dental reciente (previos 2 meses) o planeada
7. Fracaso virológico previo, resistencia genotípica, intolerancia o contraindicación para el cambio antirretroviral
8. Abacavir estará específicamente contraindicado como sustituto de tenofovir en caso de HLA-B*5701 positivo o presentar historia previa de evento cardiovascular isquémico
9. Uso concomitante de cualquier fármaco nefrotóxico
10. Lactancia o embarazo

E.5 End points

E.5.1

Primary end point(s)

mean percent change at the lumbar spine at 2 yeras

cambio porcentual medio en densidad mineral ósea lumbar (DMO) a los 2 años

E.5.1.1

Timepoint(s) of evaluation of this end point

2 years

2 años

E.5.2

Secondary end point(s)

- mean percent change in hip BMD
- incidence of osteoporosis (T-score <-2.5 at hip or spine) and of normal BMD (T-score >-1 at hip and spine)
- fracture risk estimated with the Australian version of the FRAX equation48
- serum levels of CTx and P1NP
- fractures (except of the skull, and of the small bones of the hands and feet)

2. safety (clinical adverse events [all grades]; all serious adverse events; AIDS; death; use of concomitant medications for toxicity; estimated glomerular filtration rate (eGFR, by MDRD equation; laboratory adverse events; virological failure (FDA definition: plasma HIV RNA >400 copies/mL on 2 consecutive occasions ?4 weeks apart)
3. modifications to ART (after baseline)

1.
- Cambio porcentual medio en la DMO femoral
- Incidencia de osteoporosis (T-score <-2.5 en columna o fémur) y de DMO normal (T-score >-1 en columna o fémur)
- Riesgo de fractura estimado con la ecuación FRAX
- Niveles plasmáticos de telopéptido C terminal (CTx) y del propéptido amino-terminal del procolágeno tipo 1 (P1NP)
- Fracturas (excepto cráneo y huesos pequeños de manos y pies)
2. Parámetros de seguridad (acontecimientos adversos clínicos y de laboratorio, acontecimientos adversos graves, SIDA, muerte, uso de medicaciones concomitantes por toxicidad, tasa de filtrado glomerular estimado, y fracaso virológico)
3. Cambios en el tratamiento antirretroviral

E.5.2.1

Timepoint(s) of evaluation of this end point

2 years

2 años

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)

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

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

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

Australia

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

last visit of the last subject

última visita del último paciente

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

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)

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

normal treatment for that condition

práctica habitual para la condición en estudio

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

2014-01-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-31

P. End of Trial
P.	End of Trial Status	Completed

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