Clinical Trials Register

Summary
EudraCT Number:	2016-002949-32
Sponsor's Protocol Code Number:	SPHERE-HF
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:	2016-11-17
Trial results	View 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

2016-002949-32

A.3

Full title of the trial

β3 adrenergic agoniSt treatment in chronic Pulmonary HypERtEnsion secondary to heart failure: a randomized placebo-controlled phase 2 clinical trial

Tratamiento con agonistas B3 en hipertensión pulmonar crónica secundaria a insuficiencia cardiaca: ensayo clínico aleatorizado y controlado con placebo fase 2

A.3.1

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

β3 adrenergic agoniSt Treatment in Chronic Pulmonary HypERtEnsion Secondary to heart failure

Tratamiento con agonistas B3 en hipertensión pulmonar crónica secundaria a insuficiencia cardiaca

A.4.1

Sponsor's protocol code number

SPHERE-HF

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 la recerca Biomédica
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	Marató TV3
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	Fundació Clínic per la Recerca Biomédica
B.5.2	Functional name of contact point	Dra. Ana García Álvarez
B.5.3	Address:
B.5.3.1	Street Address	c/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	349322754004031
B.5.5	Fax number	34932279305000
B.5.6	E-mail	ANAGARCI@clinic.cat
B.Sponsor: 2
B.1.1	Name of Sponsor	CNIC
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	Marató TV3
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	CNIC
B.5.2	Functional name of contact point	Ana Gracía Álvarez
B.5.3	Address:
B.5.3.1	Street Address	c/ Melchor Fernández Almagro
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	028029
B.5.3.4	Country	Spain
B.5.4	Telephone number	349145312001507
B.5.5	Fax number	34914531265000
B.5.6	E-mail	ana.garcia@cnic.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	Betmiga®
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma S.A.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Mirabegron
D.3.2	Product code	YM178
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	mirabegron
D.3.9.1	CAS number	223673-61-8
D.3.9.2	Current sponsor code	SPHERE
D.3.9.3	Other descriptive name	MIRABEGRON
D.3.9.4	EV Substance Code	SUB32690
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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pulmonary Hypertension secondary to heart failure

Hipertensión pulmonar secundaria a insuficiencia cardiaca

E.1.1.1

Medical condition in easily understood language

Pulmonary hypertension affects 60-80% of patients with chronic heart failure and has an important prognostic value. Currently, there is no specific treatment for this condition.

Hipertensión pulmonar afecta a 60-80% de pacientes con insuficiencia cardiaca crónica y tiene un gran impacto pronóstico. Actualmente, no hay tratamiento específico aprobado para esta indicación.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

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

The overall objective is to evaluate the efficacy and safety of mirabegron for the treatment of patients with PH secondary to HF. The primary objective is changes in PVR after 16 weeks of treatment.

Nuestro objetivo principal es evaluar la eficacia y seguridad del mirabegron en pacientes con HP secundaria a IC. El objetivo principal es el cambio en las RVP a las 16 semanas de tratamiento.

E.2.2

Secondary objectives of the trial

- 6-minute walking distance.
- NYHA functional class.
- Quality of life evaluated with the Kansas City Cardiomyopathy Questionnaire
- Dyspnea Borg scale score.
- Mean PAP assessed by RHC.
- Transpulmonary gradient.
- Diastolic pressure difference (diastolic PAP – PAWP).
- Cardiac output as assessed by RHC and CMR
- RV ejection fraction as assessed by CMR.
- NT-proBNP.

o Distancia recorrida en 6 minutos.
o Clase funcional de la NYHA.
o Calidad de vida evaluado por el cuestionario Kansas City Cardiomyopathy Questionnaire
o Escala de disnea de Borg.
o Presión arterial pulmonar media evaluada mediante cateterismo.
o Gradiente transpulmonar.
o Gradiente de presión arterial pulmonar diastólico.
o Gasto cardiaco determinado mediante cateterismo y RMC.
o Fracción de eyección cuantificada mediante RMC.
o NT-proBNP.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Written inform consent;
• ≥18 years-old;
• HF with reduced, intermediate or preserved ejection fraction, according to the definition of the European Society of Heart Failure guidelines.
• Significant PH combined postcapillary and precapillary PH determined by RHC showing the following:
Pulmonary artery wedge pressure or enddiastolic LV pressure ≥15 mmHg;
- Mean PAP≥25 mmHg and:
.PVR≥3 UW and/or diastolic gradient≥7 mmHg or transpulmonary gradient≥12mmHg.
• NYHA functional class II-III;
• On optimized evidence-based pharmacological treatment;
• Stable clinical condition defined as no changes in therapeutic regimen or hospitalization in the 30 days preceding recruitment and no current plan for changing therapy.

o Firma del consentimiento informado.
o ≥18 años de edad.
o Insuficiencia cardiaca con fracción de eyección reducida, intermedia o preservada, según la definición de las Guías Europeas de insuficiencia cardiaca
o HP significativa (pre y post-capilar) determinada por cateterismo cardiaco:
-Presión arterial pulmonar enclavada o presión telediastólica del ventrículo izquierdo ≥ 15 mmHg;
-Presión arterial pulmonar media ≥25 mmHg; y:
• RVP≥3 UW y/o gradiente diastólico ≥7 mmHg, o
• Gradiente transpulmonar ≥12 mmHg.
o CF NYHA II o III.
o Bajo tratamiento farmacológico óptimo
o Condición estable (no ingresos ni cambios en la medicación para la IC en los últimos 30 días).

E.4

Principal exclusion criteria

• Non-coronary cardiac surgery within the 12 months preceding recruitment performed or scheduled;
• Myocardial infarction or coronary revascularization in the last 3 months.
• Resynchronization therapy implanted in the last 6 months.
• Sinusal tachycardia or uncontrolled atrial fibrillation (HR>100 bpm);
• Uncontrolled systemic hypertension or symptomatic hypotension.
• Infiltrative cardiomyopathy.
• Premenopausal women with childbearing potential.
• Expected survival <1 year due to a disease other than HF;
• Severe renal failure (GFR <30 mL/min/1.73 m2 or hemodialysis);
• Severe hepatic impairment (transaminases >3 upper limit of normality);
• cQT interval on the ECG >430 ms in male or >450 ms in female;
• Concomitant use of specific pulmonary vasodilators (sildenafil, bosentan, macitentan, riociguat and other endothelin receptor antagonists, fosfodiestarase-5 inhibitors or guanilate cyclase agonists.
• Under treatment with digoxin, flecainide, propafenone, dabigatran, tricyclic antidepressants, and other CYP2D6 inhibitors (other than betablockers).
• Severe COPD.
• Severe restrictive pulmonary disease.
• Participation in another clinical trial.
• Allergy to mirabegron or excipients.

o Cirugía cardiaca no coronaria o procedimiento terapéutico percutáneo no coronario en los últimos 12 meses o programada.
o Infarto de miocardio o revascularización coronaria en los últimos 3 meses.
o Implante de marcapasos tricameral en los últimos 6 meses.
o Taquicardia sinusal o fibrilación auricular con FC no controlada (FC>100 lpm).
o Hipertensión arterial no controlada (PAs>180 o PAd>110 mmHg) o hipotensión (PAs<90 mmHg) sintomática.
o Diagnóstico de miocardiopatía infiltrativa.
o Mujeres pre-menopáusicas no histerectomizadas.
o Supervivencia esperada <1 año como consecuencia de otra enfermedad diferente a la IC.
o Insuficiencia renal grave (aclaramiento de creatinina <30 ml/min/1.73 m2) o hemodiálisis
o Insuficiencia hepática significativa (elevación de transaminasas >3 el límite superior de normalidad de cada centro).
o Intervalo QT corregido en el ECG>430 seg en varones o >450 seg en mujeres.
o Uso concomitante con vasodilatadores pulmonares específicos (sildenafilo, bosentan, macitentan, riociguat u otros bloqueantes del receptor de la endotelina, inhibidores de la fosfodiesterasa 5 o estimuladores de la guanilato ciclasa).
o Tratamiento con digoxina, flecainida, propafenona, dabigatran, antidepresivos tricíclicos, u otros inhibidores del CYP2D6 (exceptuando betabloqueantes).
o EPOC grave: FEV1/CVF <0.7 asociado a FEV1<50% del valor predicho.
o Neumopatía restrictiva grave (CPT<50%).
o Participación en otro ensayo clínico.
o Alergia al mirabegron o alguno de los excipientes

E.5 End points

E.5.1

Primary end point(s)

Primary outcome will be the change from baseline to week 16 in PVR by RHC. PVR will be calculated in Wood units as:
(mean PAP [in mmHg] – PAWP [in mmHg])/cardiac output (L/min).

Cambio en la RVP a las 16 semanas con respecto a la medición basal cuantificada mediante cateterismo cardiaco derecho (unidades Wood).

E.5.1.1

Timepoint(s) of evaluation of this end point

After 16 weeks of treatment

Después de 16 semanas de tratamiento

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

After 16 weeks of treatment

Después de 16 semanas de tratamiento

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

doble ciego

double blind

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

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

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

última visita 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

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.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)

NONE

NINGUNO

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-03-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-20

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

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