Efficacy and Safety of MEDI6570 in Patients With a History of Myocardial Infarction

Phase 2

Completed

Conditions: Coronary Heart Disease (CHD)

Interventions: Biological: Placebo
Biological: MEDI6570

Registration Number: NCT04610892

Lead Sponsor: AstraZeneca

Brief Summary: A Phase IIB Parallel group Study to Evaluate the Efficacy and Safety of MEDI6570 in Participants with a Prior Myocardial Infarction.

Detailed Description: This Phase IIB, proof-of-concept, dose-range finding clinical study is being conducted to evaluate the anti-inflammatory potential of MEDI6570 and its effect on surrogates for atherosclerotic and heart failure (HF) events in patients with a history of myocardial infarction (MI). The results of the Phase IIB study will inform future clinical development options and precision medicine strategy for future clinical studies.

Participants will be randomized in a 2:2:1:1 ratio after protocol Amend 2, 360 evaluable participants (111 evaluable participants in each of the 2 MEDI6570 groups, plus 27 evaluable participants in the legacy low dose MEDI6570 group, plus 111 participants in pooled placebo) will complete the study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 423

Inclusion Criteria

Participant must provide informed consent before any study specific activities are performed, must be able and willing to meet all requirements for randomization within 42 days after signing the full ICF, and must adhere to the schedules of activities.
Women must be ≥ 40 years of age at the time of signing the ICF. Men must be ≥ 21 years of age at the time of signing the ICF.
Participant must:
1. be 30 to 365 days after presumed type-1 (ie, due to plaque rupture or erosion) MI (either STEMI or NSTEMI) at the time of enrollment.
2. have persistent inflammation, defined as hs CRP ≥ 1 mg/L, as measured centrally at screening Visit 1.
Participant must have body mass index within the range 18 to 40 kg/m2 inclusive.
For female participants, the participant must not be pregnant or lactating and must be of non-childbearing potential, confirmed at screening Visit 1 by one of the following:
1. Postmenopausal, defined as amenorrhea for ≥ 12 months following cessation of all exogenous hormonal treatments, and with luteinizing hormone and follicle stimulating hormone levels in the postmenopausal range.
2. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy. Tubal ligation is not considered as irreversible surgical sterilization.
Participant must have an evaluable, pre-randomization CTA with quantifiable, non calcified plaque.

Exclusion Criteria

History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study.
Percutaneous coronary intervention or diagnostic angiogram planned after screening. Eligible participants who have a diagnostic angiogram performed in the absence of undergoing a new PCI may continue screening after the diagnostic angiogram has been performed or may be rescreened.
History of or planned coronary artery bypass grafting.
Documented episode of post-MI pericarditis in the 3 months before enrollment.
Ongoing New York Heart Association Class IV HF.
Increased risk of bleeding
1. Patients with history or presence of any bleeding disorder.
2. Signs of ongoing bleeding at screening (eg, identified macroscopic bleeding, low hemoglobin presumed to be caused by bleeding) or high risk for major bleeding in accordance with the Investigator's assessment.
3. Need for chronic therapeutic anticoagulation therapy anticipated to be required throughout the course of the study (short-term treatment with prophylactic doses of heparin/low molecular weight heparin are allowed).
4. Known severe liver disease.
History or presence of any of the following:
1. Ongoing infection or febrile illness that in the opinion of the investigator may be the cause of elevated hs-CRP on screening.
2. Ongoing atrial fibrillation or flutter.
3. Cancer within 5 years before randomization, with the exception of non melanoma skin cancer.
4. Alcohol or substance abuse within 6 months before randomization, as judged by the investigator.
5. Known history of hypersensitivity reactions to other biologics, to human IgG preparations, or to any component of MEDI6570, or ongoing severe allergy as judged by the investigator.
6. Patients with active positive results on screening for serum hepatitis B surface antigen, hepatitis C antibody, or HIV.
Any clinically important abnormalities in clinical chemistry, hematology, coagulation parameters, as judged by the investigator.
BP values at screening:
1. Systolic BP < 90 mmHg or > 180 mmHg.
2. Diastolic BP > 100 mmHg.
3. Participants who are excluded based on elevated BP may be rescreened following adequate treatment.
Participants with any of the following contraindications to CTA:
1. eGFR < 50 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration equation, or end stage renal disease treated with kidney transplant or renal replacement therapy.
2. Allergy to iodinated contrast.
3. History of contrast-induced nephropathy.
4. Contraindication to nitroglycerin.
5. Rapid heart rate that is uncontrolled by medical therapy.
6. Inability to hold breath for at least 6 seconds.
Receipt of any investigational device or therapy within 6 months or 5 half lives before screening (whichever is longer).

This criterion does NOT apply for inactive, non replicating COVID-19 vaccines approved by Health Authorities or under emergency use authorization.
Planned participation in an additional investigational study of an intervention or biologic before the end of the follow-up period. Participation in observational studies or studies without investigational drugs or devices is allowed.
Participants who are legally institutionalized.
An employee or close relative of an employee of the sponsor, the CRO, or the study site, regardless of the employee or close relative's role.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Low dose	Placebo	Monthly Subcutaneous administration.
Placebo Medium dose	Placebo	Monthly Subcutaneous administration
MEDI6570 Low dose	MEDI6570	Monthly Subcutaneous administration.
MEDI6570 Medium dose	MEDI6570	Monthly Subcutaneous administration.
MEDI6570 High dose	MEDI6570	Monthly Subcutaneous administration.
Placebo High dose	Placebo	Monthly Subcutaneous administration

Primary Outcome Measures

Name	Time	Method
Change From Baseline to Day 253 in Non-calcified Plaque Volume in the Most Diseased Coronary Segment (NCPVMD), as Measured by Computed Tomography Angiography (CTA) Imaging	From baseline to Day 253	To evaluate the effect of MEDI6570 on non-calcified coronary atherosclerotic plaques compared with placebo. The primary endpoint of change in NCPVMD from baseline to Day 253 was assessed based on the CTA Analysis Populations.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline to Day 253 in N Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP)	From baseline to Day 253	To evaluate the effect of MEDI6570 on a surrogate biomarker of Heart Failure (HF) compared with placebo
Change From Baseline to Day 253 in Left Ventricular Ejection Fraction (LVEF)	From baseline to Day 253	To evaluate the effect of MEDI6570 on left ventricular systolic function compared with placebo
Left Ventricular Ejection Fraction (LVEF) Change From Baseline to Day 253 Among Subjects With Reduced Ejection Fraction (< 50%)	From baseline to Day 253	To evaluate the effect of MEDI6570 on left ventricular systolic function among participants with reduced ejection fraction (defined as \<50%) compared with placebo
Change From Baseline to Day 253 in Global Longitudinal Strain (GLS)	From baseline to Day 253	To evaluate the effect of MEDI6570 on left ventricular systolic function compared with placebo
Global Longitudinal Strain (GLS) Change From Baseline to Day 253 Among Subjects With Reduced Ejection Fraction (< 50%)	From baseline to Day 253	To evaluate the effect of MEDI6570 on left ventricular systolic function among participants with reduced ejection fraction (defined as \<50%) compared with placebo
Change From Baseline to Day 253 in Global Non-calcified Plaque Volume (NCPV)	From baseline to Day 253	To evaluate the effect of MEDI6570 on other measures of non-calcified coronary atherosclerotic plaque compared with placebo
Change From Baseline to Day 253 in Low Attenuation Plaque Volume (LAPV)	From baseline to Day 253	To evaluate the effect of MEDI6570 on other measures of non-calcified coronary atherosclerotic plaque compared with placebo
Summary of ADA (Anti-drug Antibody) Responses During the Study	From baseline to Day 325/405. Day 325/405: for participants who completed the study under clinical study protocol (CSP) Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively.	To evaluate the immunogenicity of MEDI6570
Anti-drug Antibody Titre Summary by Visit	From Baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively.	To evaluate the immunogenicity of MEDI6570
Summary of Serum Concentrations (ug/mL) of MEDI6570	From baseline to Day 325/Day 405	MEDI6570 concentrations as measured in serum during the intervention and follow-up periods
Number of Participants With Adverse Events in Any Category	During study follow-up (from day 1 to day 325)	To assess the safety and tolerability of MEDI6570 compared with placebo
Number of Participants With Most Common Adverse Events (Frequency > 5%)	During study follow-up (from day 1 to day 325)	To assess the safety and tolerability of MEDI6570 compared with placebo
Vital Signs (Change in Systolic and Diastolic Blood Pressure From Baseline) Over Time	From baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively.	To assess the safety and tolerability of MEDI6570 compared with placebo
Vital Signs (Change in Heart Rate From Baseline) Variables Over Time	From baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively.	To assess the safety and tolerability of MEDI6570 compared with placebo
Vital Signs (Change of Weight From Baseline to Day 325/405 )	From baseline to Day 325/405. Day 325/405: for participants who completed the study under CSP Amendment 1 & 2, the end of study visits were Day 405 and Day 325 respectively	To assess the safety and tolerability of MEDI6570 compared with placebo