Evolocumab or Normal Strategies to Reach LDL Objectives in Acute Myocardial Infarction Upbound to PCI (AMUNDSEN)

Acute Myocardial Infarction Upbound to PCI Immediately (STEMI) or in the Next Three Days (NSTEMI), and Randomized to Subcutaneous Evolocumab or Normal Strategies to Reach Guidelines LDL Objectives in the Real-world - The AMUNDSEN-real Study

AMUNDSEN-real is a phase IV, international (7 European countries), multicenter, controlled, open label study randomized, in 2 parallel groups of patients with a diagnosis of STEMI or NSTEMI with an indication for PCI, using the PROBE study design (Prospective Randomised Open, Blinded Endpoint).

The objective of this study is to demonstrate the superiority of evolocumab versus standard of care in reaching a LDL-C reduction of ≥ 50% from baseline and a LDL-C goal of <1.4 mmol/L (<55 mg/dL) at 12 months follow-up on the overall population.

Central randomization uses an IWRS. Stratification is by center and stratum with random block size, generated according to the procedures of the sponsor, by a statistician not involved in the study.

Study Overview

• Status: Recruiting
• Conditions: NSTEMI - Non-ST Segment Elevation MI; STEMI - ST Elevation Myocardial Infarction
• Intervention / Treatment: Drug: Evolocumab 140 MG/ML; Drug: Standard of care (SOC)

Detailed Description

Previous randomized studies and several meta-analyses have shown a positive effect of high-dose statins pretreatment on peri-procedural Myocardial Infarction (MI) incidence with favorable trends on mortality in both Acute Coronary Syndrome (ACS) and stable Coronary Artery Disease patients.

Numerous epidemiological studies, Mendelian randomization studies, and Randomized Controled Trials have consistently demonstrated a log-linear relationship between the absolute changes in plasma LDL-C and the risk of Cardio-Vascular (CV) disease. The effect of LDL-C on the risk of a new CV event appears to be determined by the absolute magnitude, the duration of exposure to LDL-C and possibly the time to reach the recommended target of low LDL in ACS patients.

There are good reasons to believe that the Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors could provide additional benefits when used early in MI patients treated with PCI revascularization.

That's why the hypothesis of AMUNDSEN study is to demonstrate the superiority of a strategy using evolocumab before PCI in STEMI or NSTEMI patients versus standard of care (SOC) as described in the 2019 European Society of Cardiology / European Atherosclerosis Society (ESC/EAS) guidelines on dyslipidemia, to reach a Low-Density Lipoprotein Cholesterol (LDL-C) reduction of ≥ 50% from baseline and a LDL-C goal of <1.4 mmol/L (<55 mg/dL) at the end of the study (LDL targets of the 2019 ESC/EAS guidelines).

• Study Type: Interventional
• Enrollment (Estimated): 1666
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Gilles MONTALESCOT, Pr; Phone Number: 00 33 01 42 16 30 07; Email: gilles.montalescot@aphp.fr

Study Locations

• France
  • Paris, France, 75013
    • Recruiting
    • ACTION Group, Institut de Cardiologie, Centre Hospitalier Universitaire Pitié Salpêtrière (APHP), UPMC
    • Contact: Gilles MONTALESCOT, Pr; Phone Number: 0033 01 42 16 30 07; Email: gilles.montalescot@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Participant meeting all of the following criteria will be considered for enrolment into the study:

1. Male or female

2. Diagnosis of STEMI or NSTEMI

   STEMI defined as:

   • symptoms of acute MI of at least 30 min AND
   • within the previous 24 hours with new persistent ST-segment elevation ≥1 mm in ≥2 continuous ECG leads AND
   • an indication for primary PCI AND
   • > 55 years

   NSTEMI defined as:

   • Age≥18
   • a history of chest discomfort or ischemic symptoms of ≥10 minutes duration at rest ≤48 hours prior to entry into the study with no evidence of persistent ST-segment elevation and with an elevated troponin (≥ the upper limit of normal according to local laboratory norms), AND
   • indication for a coronary angiogram within 72hrs AND
   • indication for PCI AND
   • at least one the following high-risk characteristics: Diabetes Peripheral Artery Disease Multivessel (≥ 2 or LM) disease on the coronary angiogram History of MI or stroke without sequels prior to randomization eGFR: 15 to 45 mL/min/1.73 m2 calculated with MDRD formula at randomization
3. Statin at maximal tolerated dose, as part of the standard of care at randomization
4. Informed consent obtained in writing at enrolment into the study

Exclusion Criteria:

Participant presenting with any of the following will not be included in the study:

1. Fibrinolysis treatment
2. Planned CABG

3. Ongoing hemodynamic instability defined as any of the following:

   • Killip Class III or IV
   • Sustained and/or symptomatic hypotension (systolic blood pressure < 80 mm Hg)
   • Known left ventricular ejection fraction < 30%
4. Evidence of severe hepatobiliary disease: current active hepatic dysfunction or active biliary obstruction, decompensated cirrhosis or infectious/inflammatory hepatitis
5. Active malignancy
6. A comorbid condition with an estimated life expectancy of ≤ 12 months
7. Previously received or receiving evolocumab or any other therapy to inhibit PCSK9
8. Known sensitivity to any of the products or components to be administered during study
9. Female subject is pregnant, had a positive pregnancy test at inclusion, breastfeeding, or planning to become pregnant or breastfeed during treatment and for an additional 17 weeks after the last dose of IMP
10. Currently receiving treatment in any other investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies).
11. Participant likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the participant and investigator's knowledge.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Evolocumab + SOC; Investigational Product is open label Evolocumab (Repatha®) 140 mg every two weeks: first subcutaneous injection at the time of randomization, before PCI, followings during 12 months.	Drug: Evolocumab 140 MG/ML; Evolocumab (Repatha®) 140 mg every two weeks: first subcutaneous injection at the time of randomization, before PCI, followings during 12 months.; Other Names: Repatha
Active Comparator: Standard of care (SOC); management as recommended in ESC/EAS 2019 guidelines, within reimbursement criteria	Drug: Standard of care (SOC); management as recommended in ESC/EAS 2019 guidelines, within reimbursement criteria

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LDL-C reduction of ≥ 50% from baseline and a final LDL-C of <1.4 mmol/L (<55 mg/dL) at 12 months follow-up.	Monitoring of changes in LDL-C levels	From baseline and at 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LDL-C reduction of ≥ 50% from baseline and a final LDL-C of <1.4 mmol/L (<55 mg/dL) at 12 months follow-up, country by country.	The same rules as above for the primary endpoint, will apply.	From baseline and at 12 months
LDL-C reduction of ≥ 50% and an LDL-C goal of <1.4 mmol/L (<55 mg/dL)	Monitoring of changes in LDL-C levels	From baseline to 6 weeks and 22 weeks
Percent change in levels of LDL-C	Monitoring of changes in LDL-C levels	From baseline to 6 weeks, 22 weeks and 12 months
Time to achieve LDL-C target	Monitoring of changes in LDL-C levels	Up to 12 months
Time averaged LDL-C change	Monitoring of changes in LDL-C levels	Up to 12 months
Change on total cholesterol	Monitoring of changes in cholesterol levels	At baseline, 6 weeks, 22 weeks and 12 months
Change on HDL-C	Monitoring of changes in HDL-C levels	At baseline, 6 weeks, 22 weeks and 12 months
Change on triglycerides	Monitoring of changes in triglycerides levels	At baseline, 6 weeks, 22 weeks and 12 months
Change on non-HDL-C	Monitoring of changes in non-HDL-C levels	At baseline, 6 weeks, 22 weeks and 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of death or any hospitalization for a Cardiovascular (CV) reason	Data obtained from reported adverse events occurred during participation to the study	Up to 12 months
Composite of death, MI, stroke, unplanned revascularization	Data obtained from reported adverse events occurred during participation to the study	Up to 12 months
Individual endpoints of the composite endpoint above (death, MI, Stroke, unplanned revascularization)	Data obtained from reported adverse events occurred during participation to the study	Up to 12 months
Pooled analysis of relationship between time to achieve LDL-C goal and death or any hospitalization for a CV reason	Data obtained from reported adverse events occurred during participation to the study and LDL-C levels	Up to 12 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Amgen; Action Research Group
• Investigators: Principal Investigator: Gilles MONTALESCOT, Pr, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2021
• Primary Completion (Estimated): September 29, 2024
• Study Completion (Estimated): September 29, 2024

Study Registration Dates

• First Submitted: May 27, 2021
• First Submitted That Met QC Criteria: June 26, 2021
• First Posted (Actual): July 7, 2021

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: PCI; STEMI; LDL-C; NSTEMI; STATIN; EVOLOCUMAB; Anti-PCSK9
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; ST Elevation Myocardial Infarction; Non-ST Elevated Myocardial Infarction; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Protease Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Serine Proteinase Inhibitors; PCSK9 Inhibitors; Evolocumab
• Other Study ID Numbers: 201075; 2021-000573-80 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No