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EVOlocumab in Stable Heart Failure With Reduced Ejection Fraction of Ischemic Etiology: EVO-HF Pilot (EVO-HF)

Primary Purpose

Heart Failure With Reduced Ejection Fraction

Status

Completed

Phase

Phase 2

Locations

Spain

Study Type

Interventional

Intervention

Evolocumab

About this trial

This is an interventional treatment trial for Heart Failure With Reduced Ejection Fraction

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Signing of the informed consent
Patient ≥18 years and ≤80 years of age
LVEF <40%
Ischemic etiology (evidence of at least one acute coronary event and/or CAD by coronary angiography or multi slice CT)
New York Heart Association (NYHA) class II
NT-proBNP ≥ 400 pg/mL
Hs-TnT >10 pg/mL
LDL ≥ 70 mg/dL
Stable CAD (last ACS before the last 3 months)
GDMT according to 2016 ESC HF guidelines for at least the last 3 months.
Statin treatment, whichever dose the patient receives at the time of enrolment, stable for at least 1 month, without need to statin uptitration.

Exclusion Criteria:

Extracardiac disease with estimated life expectancy less than 1 year
Contraindication to receiving evolocumab
Hypersensitivity to the active substance or to any of the excipients
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.
Patient <18 or ≥ 81 years
Liver dysfunction (AST or ALT> 3 times the upper limit of normal value).
Severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73m²) or renal replacement therapy at screening (CKD-EPI equation).
Coronary revascularization in the 3 months prior to randomization or pending coronary revascularization.
Previous haemorrhagic stroke
Uncontrolled hypertension (systolic blood pressure ≥ 140 or/and diastolic blood pressure ≥ 90 mmHg) either on or off therapy at screening or at baseline
Uncontrolled hypothyroidism or hyperthyroidism
Type 1 diabetes; newly diagnosed or poorly controlled type 2 diabetes (HbA1c > 8.5%)
Uncontrolled cardiac arrhythmia

Sites / Locations

Hospital Universitari Germans Trias i Pujol
Hospital Universitario Virgen del Rocío
Hospital Clínico de Valencia

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Experimental group

Control group

Arm Description

The patient will receive evolocumab 420 mg/month on top of guideline-driven medical treatment

The patient will continue guideline-driven medical treatment

Outcomes

Primary Outcome Measures

Change in hs-TnT levels at 1 year

Change of high-sensitivity troponin T (hs-TnT) levels from baseline to 1 year.

Secondary Outcome Measures

Full Information

NCT ID

NCT03791593

First Posted

December 30, 2018

Last Updated

February 14, 2023

Sponsor

Fundació Institut Germans Trias i Pujol

1. Study Identification

Unique Protocol Identification Number

NCT03791593

Brief Title

EVOlocumab in Stable Heart Failure With Reduced Ejection Fraction of Ischemic Etiology: EVO-HF Pilot

Acronym

EVO-HF

Official Title

EVOlocumab in Stable Heart Failure With Reduced Ejection Fraction of Ischemic Etiology: EVO-HF Pilot

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Completed

Study Start Date

December 3, 2018 (Actual)

Primary Completion Date

June 30, 2021 (Actual)

Study Completion Date

July 20, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Fundació Institut Germans Trias i Pujol

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Evolocumab has been able to reduce the incidence of cardiovascular events in patients that had at least one cardiovascular risk factor [28]. In patients with chronic HFrEF, as we mentioned before, treatment with statins is not recommended as it has not shown benefits in improving its prognosis. However, CAD control stands as an approach that could improve the course of the disease by preventing microlesions that further weaken the heart. A recent multicenter study, the BIOSTAT-CHF [3436], was performed to determine whether the PCSK9-LDLR axis could predict risk in patients with HF. A multivariate analysis, which included BIOSTAT risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality and the composite endpoint (death or HF-related hospitalization). A similar analysis for LDLR revealed a negative association with mortality and the composite endpoint. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF. There is an unmet clinical need: blockade of the neurohormonal activation has provided advances in patients with HFrEF, yet mortality and morbidity remain unacceptably high. Approaching a strict control of lipid levels and CAD with evolocumab in stable HFrEF of ischemic ethology may represent a complementary pathophysiological pathway to reduce mortality and morbidity. The burden of CAD provides a solid rationale for testing the value of evolocumab in HF patients. Therefore, a pilot trial is proposed to evaluate the beneficial effect of evolocumab by surrogate biological markers before considering an event analysis study. Evolocumab reduces the risk of cardiovascular events in patients with established atherosclerotic disease, so this drug could play a role in HFrEF of ischemic etiology, by limiting macro- and micro-vascular coronary disease progression. In HFrEF patients due to ischemic etiology, there is a continuous troponin release due to persistent myocyte injury, which has been associated with adverse outcomes. Our hypothesis is that evolocumab may have the potential to reduce circulating hs-TnT levels, as a surrogate of myocyte injury due to atheroma progression in HFrEF. A positive result in this EVO-HF Pilot study may lead to the set-up of a large-scale multicenter prospective and randomized events study analyzing the role of lipid-lowering treatment by means of evolocumab in HFrEF of ischemic etiology

Detailed Description

Evolocumab has been able to reduce the incidence of cardiovascular events in patients that had at least one cardiovascular risk factor [28]. In patients with chronic HFrEF, as we mentioned before, treatment with statins is not recommended as it has not shown benefits in improving its prognosis. However, CAD control stands as an approach that could improve the course of the disease by preventing microlesions that further weaken the heart. A recent multicenter study, the BIOSTAT-CHF [3436], was performed to determine whether the PCSK9-LDLR axis could predict risk in patients with HF. A multivariate analysis, which included BIOSTAT risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality and the composite endpoint (death or HF-related hospitalization). A similar analysis for LDLR revealed a negative association with mortality and the composite endpoint. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF. There is an unmet clinical need: blockade of the neurohormonal activation has provided advances in patients with HFrEF, yet mortality and morbidity remain unacceptably high. Approaching a strict control of lipid levels and CAD with evolocumab in stable HFrEF of ischemic ethology may represent a complementary pathophysiological pathway to reduce mortality and morbidity. The burden of CAD provides a solid rationale for testing the value of evolocumab in HF patients. Evolocumab reduces the risk of cardiovascular events in patients with established atherosclerotic disease, so this drug could play a role in HFrEF of ischemic etiology, by limiting macro- and micro-vascular coronary disease progression. In HFrEF patients due to ischemic etiology, there is a continuous troponin release due to persistent myocyte injury, which has been associated with adverse outcomes. Our hypothesis is that evolocumab may have the potential to reduce circulating hs-TnT levels, as a surrogate of myocyte injury due to atheroma progression in HFrEF. A positive result in this EVO-HF Pilot study may lead to the set-up of a large-scale multicenter prospective and randomized events study analyzing the role of lipid-lowering treatment by means of evolocumab in HFrEF of ischemic etiology. Therefore, a pilot trial is proposed to evaluate the beneficial effect of evolocumab by surrogate biological markers before considering an event analysis study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure With Reduced Ejection Fraction

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Masking Description

Investigators will be blinded for the biomarkers results.

Allocation

Randomized

Enrollment

46 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Experimental group

Arm Type

Experimental

Arm Description

The patient will receive evolocumab 420 mg/month on top of guideline-driven medical treatment

Arm Title

Control group

Arm Type

No Intervention

Arm Description

The patient will continue guideline-driven medical treatment

Intervention Type

Drug

Intervention Name(s)

Evolocumab

Other Intervention Name(s)

Repatha

Intervention Description

Evolocumab is a human IgG2 monoclonal antibody, it will add to patient treatment during 12 months.

Primary Outcome Measure Information:

Title

Change in hs-TnT levels at 1 year

Description

Change of high-sensitivity troponin T (hs-TnT) levels from baseline to 1 year.

Time Frame

at 12 months of follow-up

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Signing of the informed consent Patient ≥18 years and ≤80 years of age LVEF <40% Ischemic etiology (evidence of at least one acute coronary event and/or CAD by coronary angiography or multi slice CT) New York Heart Association (NYHA) class II NT-proBNP ≥ 400 pg/mL Hs-TnT >10 pg/mL LDL ≥ 70 mg/dL Stable CAD (last ACS before the last 3 months) GDMT according to 2016 ESC HF guidelines for at least the last 3 months. Statin treatment, whichever dose the patient receives at the time of enrolment, stable for at least 1 month, without need to statin uptitration. Exclusion Criteria: Extracardiac disease with estimated life expectancy less than 1 year Contraindication to receiving evolocumab Hypersensitivity to the active substance or to any of the excipients 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. Patient <18 or ≥ 81 years Liver dysfunction (AST or ALT> 3 times the upper limit of normal value). Severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73m²) or renal replacement therapy at screening (CKD-EPI equation). Coronary revascularization in the 3 months prior to randomization or pending coronary revascularization. Previous haemorrhagic stroke Uncontrolled hypertension (systolic blood pressure ≥ 140 or/and diastolic blood pressure ≥ 90 mmHg) either on or off therapy at screening or at baseline Uncontrolled hypothyroidism or hyperthyroidism Type 1 diabetes; newly diagnosed or poorly controlled type 2 diabetes (HbA1c > 8.5%) Uncontrolled cardiac arrhythmia

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Antoni Bayes-Genís, MD,PhD,FESC

Organizational Affiliation

HUGTIP

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hospital Universitari Germans Trias i Pujol

City

Badalona

State/Province

Barcelona

ZIP/Postal Code

08916

Country

Spain

Facility Name

Hospital Universitario Virgen del Rocío

City

Sevilla

ZIP/Postal Code

41013

Country

Spain

Facility Name

Hospital Clínico de Valencia

City

Valencia

ZIP/Postal Code

46010

Country

Spain

12. IPD Sharing Statement

Learn more about this trial

EVOlocumab in Stable Heart Failure With Reduced Ejection Fraction of Ischemic Etiology: EVO-HF Pilot

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