Clinical Trials Register

Summary
EudraCT Number:	2017-004656-30
Sponsor's Protocol Code Number:	ICOR-2016-05
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:	2018-09-17
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

2017-004656-30

A.3

Full title of the trial

EVOlocumab in stable Heart Failure with reduced ejection fraction of ischemic etiology: EVO-HF Pilot

Evolocumab en insuficiencia cardíaca estable con fracción de eyección reducida de etiología isquémica: EVO-HF Pilot.

A.3.1

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

Evolocumab treatment in patients with stable heart failure with reduced ejection fraction of ischemic etiology

Tratamiento con Evolocumab en pacientes con insuficiencia cardíaca estable con fracción de eyección reducida de etiología isquémica

A.3.2

Name or abbreviated title of the trial where available

EVO-HF pilot

EVO-HF

A.4.1

Sponsor's protocol code number

ICOR-2016-05

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	Instituto de Investigación en Ciencias de la Salud Germans Trias i Pujol (IGTP)
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	Instituto de Investigación en Ciencias de la Salud Germans Trias i Pujol (IGTP)
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	AMGEN
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	FLS-Reseach Support
B.5.2	Functional name of contact point	Cristina Herrero
B.5.3	Address:
B.5.3.1	Street Address	Ctra. Canyet sn
B.5.3.2	Town/ city	Badalona/Barcelona
B.5.3.3	Post code	08916
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34934978414
B.5.5	Fax number	+34934657602
B.5.6	E-mail	cherrero@fls-rs.com

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	Repatha
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
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	EVOLOCUMAB
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EVOLOCUMAB
D.3.9.3	Other descriptive name	EVOLOCUMAB
D.3.9.4	EV Substance Code	SUB128552
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	140
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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

stable coronary artery disease and stable heart failure with reduced ejection fraction

enfermedad arterial coronaria estable e insuficiencia cardíaca estable con fracción de eyección reducida

E.1.1.1

Medical condition in easily understood language

stable coronary artery disease and stable heart failure with reduced ejection fraction

enfermedad arterial coronaria estable e insuficiencia cardíaca estable con fracción de eyección reducida

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10078289
E.1.2	Term	Heart failure with reduced ejection fraction
E.1.2	System Organ Class	100000004849

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 primary objective is to assess if LDL-C lowering at 1 year with monthly subcutaneous (SC) evolocumab 420 mg for 1 year will result in a significant reduction of high-sensitivity troponin T (hs-TnT), surrogate marker of myocyte injury and atherosclerosis progression, compared with current Standard of care (SOC) in subjects with elevated LDL-C, stable coronary artery disease (CAD) and stable heart failure with reduced ejection fraction (HFrEF).

El objetivo principal es evaluar si la disminución de LDL-C a 1 año con 420 mg de evolocumab subcutáneo (SC) dará como resultado una reducción significativa de troponina T ultrasensible (hs-TnT), biomarcador de lesión del cardiomiocito y progresión de la aterosclerosis, en comparación con la atención actual estándar en sujetos con niveles elevados de LDL-C, enfermedad de arterias coronarias estable (EAC) e insuficiencia cardíaca estable con fracción de eyección reducida (HFrEF).

E.2.2

Secondary objectives of the trial

To assess change of high-sensitivity troponin T (hs-TnT) after 6 months of treatment with monthly SC evolocumab 420 mg
To assess change of NT-proBNP, ST2, and hs-CRP levels after 6 and 12 months of treatment with monthly SC evolocumab 420 mg
To assess change of LDL, LDLR, HDL, and sPCSK9 levels after 6 and 12 months of treatment with monthly SC evolocumab 420 mg
To evaluate change in exercise tolerance in patients with stable Heart Failure with reduced ejection fraction of ischemic etiology at 6 months and 1 year
To evaluate change in quality of life Using Kansas city cardiomyopathy questionnaire (KCCQ) at 6 months and 1 year
To evaluate the safety profile of evolocumab administered together with top of guideline-driven medical treatment
Biomarkers will be used to elucidate the effects of evolocumab as well as to perform exploratory correlational analysis to assess their interactions and roles within the mediation of study-drug effects on cardiac remodeling.

Evaluar el cambio de la troponina T ultrasensible después de 6 meses de tratamiento con evolocumab SC 420 mg mensual
Evaluar el cambio de los niveles de NT-proBNP, ST2 y hs-CRP después de 6 y 12 meses de tratamiento con evolocumab SC mensual de 420 mg
Evaluar el cambio de los niveles de LDL, LDLR, HDL y sPCSK9 después de 6 y 12 meses de tratamiento con evolocumab SC 420 mg mensual
Evaluar el cambio en la tolerancia al ejercicio en pacientes con insuficiencia cardíaca estable con fracción de eyección reducida de etiología isquémica a los 6 meses y 1 año.
Evaluar el cambio en la calidad de vida utilizando el Cuestionario de miocardiopatía de Kansas City a los 6 meses y 1 año.
Evaluar el perfil de seguridad de evolocumab administrado junto con el tratamiento médico dirigido por guías.
Los biomarcadores se usarán para dilucidar los efectos de evolocumab así como para realizar un análisis correlacional exploratorio.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signing of the informed consent
2. Patient ≥18 years and ≤80 years of age
3. LVEF <40%
4. Ischemic etiology (evidence of at least one acute coronary event and/or CAD by coronary angiography or multi slice CT)
5. New York Heart Association (NYHA) class II
6. NT-proBNP ≥600 pg/mL
7. Hs-TnT >14 pg/mL
8. LDL ≥ 100 mg/dL
9. Stable CAD (last ACS before the last 3 months)
10. GDMT according to 2016 ESC HF guidelines for at least the last 3 months.
11. Statin treatment, whichever dose the patient receives at the time of enrolment, stable for at least 1 month, without need to statin uptitration

1. Firma del consentimiento informado
2. Paciente ≥18 años y ≤80 años de edad
3. FEVI <40%
4. Etiología isquémica (evidencia de al menos un evento coronario agudo y / o EAC por angiografía coronaria o CT de múltiples cortes)
5. Clase II de la New York Heart Association (NYHA)
6. NT-proBNP ≥ 600 pg / ml
7. Hs-TnT> 14 pg / mL
8. LDL ≥ 100 mg / dL
9. EAC estable (último síndrome coronario agudo antes de los últimos 3 meses)
10. GDMT según las guías ESC HF 2016 al menos los últimos 3 meses.
11. Tratamiento con estatinas, cualquiera que sea la dosis que el paciente reciba en el momento de la inclusión, estable durante al menos 1 mes, sin necesidad de aumentar la estatina

E.4

Principal exclusion criteria

1. Extracardiac disease with estimated life expectancy less than 1 year
2. Contraindication to receiving evolocumab
3. Hypersensitivity to the active substance or to any of the excipients
4. Female subject who has not used an acceptable method of birth control for at least 1 month prior to screening and/or is not willing to inform her partner of her participation in this clinical trial and to use an acceptable method of effective birth control during treatment with evolocumab and for an additional 15 weeks after the end of treatment with evolocumab, unless the female subject is permanently sterilized or postmenopausal:
A female is considered of childbearing potential unless permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or postmenopausal with menopause defined as:
- Age ≥55 years and ≥12 months of spontaneous and continuous amenorrhea, or
- Age <55 years but no spontaneous menses for ≥2 years, or
- Age <55 years and spontaneous menses within the past 1 year, but currently amenorrheic, AND with follicle-stimulating hormone (FSH) levels >40 IU/L or estradiol levels <5 ng/dL or according to the definition of “postmenopausal range” for the laboratory involved.
5. Patient <18 or ≥81 years
6. Liver dysfunction (AST or ALT> 3 times the upper limit of normal value).
7. Severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73m²) or renal replacement therapy at screening (CKD-EPI equation).
8. Coronary revascularization in the 3 months prior to randomization or pending coronary revascularization.
9. Previous haemorrhagic stroke
10. Uncontrolled hypertension (systolic blood pressure ≥ 140 or/and diastolic blood pressure ≥ 90 mmHg) either on or off therapy at screening or at baseline
11. Uncontrolled hypothyroidism or hyperthyroidism
12. Type 1 diabetes; newly diagnosed or poorly controlled type 2 diabetes (HbA1c > 8.5%)
13. Uncontrolled cardiac arrhythmia

1. Enfermedad extracardíaca con esperanza de vida estimada inferior a 1 año
2. Contraindicación para recibir evolocumab
3. Hipersensibilidad a la sustancia activa o a cualquiera de los excipientes
4. Mujer que no ha utilizado un método anticonceptivo aceptable durante al menos 1 mes antes del examen y / o no está dispuesta a informar a su pareja sobre su participación en este ensayo clínico y a utilizar un método anticonceptivo aceptable durante el tratamiento con evolocumab y durante 15 semanas después del final del tratamiento con evolocumab, exceptuando a mujeres posmenopáusico o con métodos de esterilización permanente:
Una mujer se considera potencialmente fértil a menos que tenga un método de esterilización permanente (histerectomía, ooforectomía bilateral o salpingectomía bilateral) o posmenopáusica con menopausia definida como:
 Edad ≥55 años y ≥12 meses de amenorrea espontánea y continua, o
 Edad <55 años pero sin menstruación espontánea durante ≥2 años, o
 Edad <55 años y menstruación espontánea en el último año, pero actualmente amenorreica, Y con niveles de hormona folículoestimulante (FSH)> 40 UI / L o niveles de estradiol <5 ng / dL o según la definición de "rango posmenopáusico" "Para el laboratorio involucrado.
5. Paciente <18 o ≥ 81 años
6. Insuficiencia hepática (AST o ALT> 3 veces el límite superior del valor normal).
7. Insuficiencia renal severa (tasa estimada de filtración glomerular [TFGe] <30 ml / min / 1.73m²) o terapia de reemplazo renal en el screening (ecuación CKD-EPI).
8. Revascularización coronaria en los 3 meses previos a la aleatorización o pendiente de revascularización coronaria.
9. Accidente cerebrovascular hemorrágico previo
10. Hipertensión no controlada (presión arterial sistólica ≥ 140 o / y presión arterial diastólica ≥ 90 mmHg) ya sea dentro o fuera de la terapia durante el screening o al inicio del estudio
11. Hipotiroidismo incontrolado o hipertiroidismo
12. Diabetes tipo 1; diabetes tipo 2 recién diagnosticada o mal controlada (HbA1c> 8,5%)
13. Arritmia cardíaca no controlada

7. Hs-TnT> 14 pg / mL
8. LDL ≥ 100 mg / dL
9. EAC estable (último síndrome coronario agudo antes de los últimos 3 meses)
10. GDMT según las guías ESC HF 2016 al menos los últimos 3 meses.
11. Tratamiento con estatinas, cualquiera que sea la dosis que el paciente reciba en el momento de la inclusión, estable durante al menos 1 mes, sin necesidad de aumentar la estatina

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this study is the change in hs-TnT levels at 1 year

Cambio en los niveles de hs-TnT a 1 año

E.5.1.1

Timepoint(s) of evaluation of this end point

at 1 year

Al año

E.5.2

Secondary end point(s)

• Change in Hs-TnT levels at 6 months
• Change in NT-proBNP, ST2, and hs-CRP levels at 6 months and 1 year
• Change in LDL, LDLR, HDL, and sPCSK9 levels at 6 months and 1 year
• Change in 6 minutes walking test at 6 months and 1 year
• Change in quality of life test (KCCQ) at 6 months and 1 year
• Number and percentage of AEs

• Cambios en los niveles de Hs-TnT a los 6 meses
• Cambios en los niveles de NT-proBNP, ST2 y hs-CRP a los 6 meses y 1 año
• Niveles de LDL, LDLR, HDL y sPCSK9 a los 6 meses y 1 año
• Cambios en la prueba de la marcha de 6 minutos a los 6 meses y 1 año
• Cambiso en el cuestionario de calidad de vida (KCCQ) a los 6 meses y 1 año
• Número y porcentaje de eventos adversos

E.5.2.1

Timepoint(s) of evaluation of this end point

at 6 months and 1 year

A los 6 meses y al año

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

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

tratamiento médico dirigido por guías

GDMT according to 2016 ESC HF guidelines

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

LVLS (last visit of the last subject )

Ultima 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

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

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)

Once the 12 month follow-up study period is finished, patients will not receive more treatment with evolocumab. Safety follow-up visit will be considered the end of study visit for each patient.

Una vez que finalice el período de 12 meses de seguimiento, los pacientes no recibirán más tratamiento con evolocumab. La visita de seguimiento de seguridad se considerará la visita de fin de estudio para cada paciente.

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

2018-10-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-05

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

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