Clinical Trials Register

Summary
EudraCT Number:	2012-001066-14
Sponsor's Protocol Code Number:	DENERVHTA
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2012-06-12
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

2012-001066-14

A.3

Full title of the trial

Sympathetic renal denervation versus increment of pharmacological treatment in resistant arterial hypertension

Denervación simpática renal versus escalada terapéutica farmacológica en la hipertensión arterial resistente

A.3.1

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

N/A

A.4.1

Sponsor's protocol code number

DENERVHTA

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	Consorci Mar Parc de salut de Barcelona ( Parc de Salut Mar)
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	Ministerio de Sanidad Asuntos Sociales e Igualdad
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hospital del Mar
B.5.2	Functional name of contact point	Servicio de Nefrologia
B.5.3	Address:
B.5.3.1	Street Address	Passeig Marítim, 25-29
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08003
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034932483162
B.5.5	Fax number	0034932483373
B.5.6	E-mail	87052@parcdesalutmar.cat

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	Aldactone
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER.S.L
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.3.1	Product name	SPIRONOLACTONE
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	spironolactone
D.3.9.1	CAS number	52-01-7
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	25 to 50
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

subjects with resistant hypertension

pacientes con hipertensión arterial resistente

E.1.1.1

Medical condition in easily understood language

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]

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 determine the effect of a percutaneous catheter-based renal sympathetic denervation (RSD) procedure to disrupt renal afferent and efferent nerves using radiofrequency ablation, on 24h ambulatory systolic blood pressure (SBP), in subjects with resistant hypertension (RH), as compared to the addition of spironolactone, an aldosterone receptor blocker, to the baseline pharmacological treatment, from baseline (Visit 0) to Final Examination (Week 24).

Determinar la eficacia de la denervación simpática renal mediante emisión de radiofrecuencia por catéter (DSR), en la reducción de la presión arterial sistólica (PAS) ambulatoria de 24h, en comparación con la adición de espironolactona, un antagonista de los receptores de aldosterona, al tratamiento farmacológico basal, durante un período de 6 meses.

E.2.2

Secondary objectives of the trial

To determine the effect of the RSD procedure by radiofrequency ablation in subjects with resistant hypertension (RH), as compared to the addition of spironolactone, an aldosterone receptor blocker, to the baseline pharmacological treatment, from baseline (Visit 0) to Final Examination (Week 24), with respect to: Office Blood Pressure (BP),24 h-ambulatory BP, central BP, pulse pressure, and carotid-femoral pulse wave velocity, carotid intima-media thickness, and echocardiographic parameters

Determinar el efecto de la denervación simpática renal mediante emisión de radiofrecuencia por catéter (DSR), en pacientes con HTA resistente, en comparación con la adición de espironolactona, un antagonista de los receptores de aldosterona, al tratamiento farmacológico basal, durante un período de 6 meses, respecto a : la presión arterial (PA) clínica, presión ambulatoria de 24h, la velocidad de onda del pulso, el grosor intima-media carotideo, y valores ecoradiográficos

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects aged ≥ 18 years and ≤ 80 years.

2. Subjects with diagnosed resistant arterial hypertension (office blood pressure ≥ 140 and/or 90 mm Hg despite treatment with at least 3 antihypertensive drugs given at the maximum tolerated therapeutic dosage, being one of them a diuretic), with this therapeutic regimen maintained for at least the last 3 months.

3. Office systolic blood pressure ≥150 mm Hg, with confirmation of resistance to treatment by 24h ambulatory blood pressure monitoring, with 24h-systolic blood pressure ≥140 mmHg being required to be included.

4. Patients who have freely given informed consent in writing, after the nature of the study and the disclosure of their data have been explained to them.

1. Pacientes de edad comprendida entre 18 y 80 años (ambos inclusive)
2. Diagnóstico de hipertensión arterial resistente (presión arterial clínica ≥140 y/o 90 mm Hg a pesar de recibir tratamiento con 3 o más fármacos antihipertensivos a las máximas dosis efectivas toleradas, siempre que uno de ellos sea un diurético), habiendo mantenido el mismo tratamiento en los últimos 3 meses.
3. PA sistólica clínica ≥150 mm Hg, confirmando la resistencia al tratamiento mediante monitorización ambulatoria de presión arterial de 24h, requiriendo PA sistólica de 24h ≥140 mmHg para cumplir el criterio de inclusión.
4. Y que firmen el consentimiento informado.

E.4

Principal exclusion criteria

1. Secondary hypertension, renovascular disease included with appropriate tests according to investigator criteria (with the exceptions of chronic renal disease and obstructive sleep-apnea syndrome).
2. Inability to perform magnetic resonance angiography or renal CT angiography (contrast allergy).
3. Patients unlikely compliant with treatment (assessed according to Haynes-Sackett test).
4. Patients currently on treatment with an aldosterone receptor blocker (spironolactone, eplerenone) or who had previously received one of such class of drugs and had been withdrawn due to lack of efficacy and/or adverse effects.
5. Stage 3B, 4 or 5 of chronic renal disease (estimated glomerular filtration rate by MDRD equation < 45 mL/min/1.73m2).
6. Pre-randomization serum potassium (K+) level ≥ 5.5 mmol/L.
7. Significant renal vascular anomalies.
8. Pregnant women.
9. Significant valvular heart disease.
10. Major vascular event (myocardial infarction, unstable angina or cerebrovascular disease) < 6 months prior to study enrolment.

1. Diagnóstico de HTA secundaria, incluyendo la enfermedad vásculo-renal con las exploraciones adecuadas según el criterio del investigador (exceptuando enfermedad renal crónica y síndrome de apnea obstructiva del sueño).
2. Imposibilidad de realizar angioresonancia y angioTAC renal (alergia al contraste).
3. Incumplimiento terapéutico (evaluado según test de Haynes-Sackett).
4. Pacientes en tratamiento actual con algún antagonista de los receptores de aldosterona (espironolactona, eplerenona) o que lo hubiera recibido anteriormente y se hubiera retirado por falta de eficacia y/o efectos adversos.
5. Insuficiencia renal crónica estadios 3B, 4 o 5 (filtrado glomerular estimado por MDRD < 45 mL/min/1.73m2).
6. Nivel de potasio sérico (K+) pre-aleatorización ≥ 5.5 mmol/L.
7. Anomalías vasculares renales significativas.
8. Mujeres embarazadas.
9. Enfermedad valvular cardiaca significativa.
10. Historia reciente de episodio vascular mayor (infarto de miocardio, angina inestable o accidente cerebrovascular en los 6 meses previos).

E.5 End points

E.5.1

Primary end point(s)

Change in ambulatory 24h-systolic blood pressure (SBP) from baseline (Visit 0) to Final Examination (6 months).

Variación media de la presión arterial sistólica (PAS) ambulatoria de 24h desde la evaluación basal (Visita 0) hasta la visita final (6 meses).

E.5.1.1

Timepoint(s) of evaluation of this end point

related in secction E.5.1

recogido en la sección E.5.1

E.5.2

Secondary end point(s)

• Changes in ambulatory 24h-diastolic blood pressure (DBP), pulse pressure (PP) and heart rate (HR) from baseline (Visit 0) to Final Examination (6 months).
• Changes in day-time SBP, DBP, PP and HR measurement from baseline (Week 0) to Final Examination (6 months).
• Changes in night-time SBP, DBP, PP and HR measurement from baseline (Week 0) to Final Examination (6 months).
• Changes in conventional mean sitting SBP, DBP, PP and HR measurement from baseline (Week 0) to Final Examination (6 months).
• Changes in central SBP, DBP, PP and HR measurement from baseline (Week 0) to Final Examination (6 months).
• Changes in central augmentation index and central augmentation pressure from baseline (Week 0) to Final Examination (6 months).
• Changes in carotid-femoral pulse wave velocity from baseline (Week 0) to Final Examination (6 months).
• Changes in evaluated echocardiographic parameters (left ventricular mass index [LVMI], left atrial enlargement [LAE], ejection fraction [EF], left ventricular remodeling index [LVRI], E/e’, Global function index (E/e´)/s; left atrial parameters: area 4c, area index, volume, strain register; 2D LV strain parameters: longitudinal strain and radial strain) from baseline (Week 0) to Final Examination (6 months).
• Changes in evaluated renal function parameters (urinary albumin/creatinine ratio, serum creatinine, estimated glomerular filtration rate) and evaluated metabolic parameters (glucemia, lipidic profile) from baseline (Week 0) to Final Examination (6 months).
• Changes in carotid intima-media thickness measurement from baseline (Week 0) to Final Examination (6 months).

• variación media de PAD, PP y FC de 24h desde la evaluación basal (Visita 0) hasta el examen final (6 meses)
• variación media de PAS, PAD, PP y FC nocturnas (según MAPA-24h) desde la evaluación basal (Visita 0) hasta el examen final (6 meses)
• variación media de PAS, presión arterial diastólica (PAD), presión del pulso (PP) y frecuencia cardiaca (FC) clínicas desde la evaluación basal (Visita 0) hasta el examen final (6 meses).
• variación media de PAS, PAD, PP y FC centrales desde la evaluación basal (Visita 0) hasta el examen final (6 meses)
• variación media del índice de aumento central y de la prsión de aumentación central desde la evaluación basal (Visita 0) hasta el examen final (6 meses)
• variación media la velocidad de onda del pulso carótida-femoral desde la evaluación basal (Visita 0) hasta el examen final (6 meses)
• variación media de los parámetros ecocardiográficos evaluados desde la evaluación basal (Visita 0) hasta el examen final (6 meses)
• variación media de los parámetros de función renal evaluados (cociente albúmina/creatinina en orina, creatinina plasmática, filtrado glomerular estimado) desde la evaluación basal (Visita 0) hasta el examen final (6 meses), así como de los parámetros metabólicos evaluados (glucemia, perfil lipídico)
• variación media del grosor íntima-media carotideo desde la evaluación basal (Visita 0) hasta el examen final (6 meses)

E.5.2.1

Timepoint(s) of evaluation of this end point

related in secction E.5.2

recogido en sección E.5.2

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

denervación simpática renal

renal sympatic denervation

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

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

Se establece como final del ensayo clínico la última visita protocolizada del último paciente incluido en el ensayo clínico.

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:

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.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)

It is not different from the expected normal treatment of that condition

No es diferente del tratamiento esperado

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

2012-07-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-04-24

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

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