To Evaluate Safety, Pharmacokinetics and Pharmacodynamics of MEDI6012 in Subjects With Stable Coronary Artery Disease

Study Overview
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Brief Summary
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This is a Phase 2a randomized, double-blind (subject/investigator blinded, MedImmune unblinded), placebo-controlled, dose-escalation study to evaluate the safety, PK/PD, and immunogenicity of single IV and SC MEDI6012 doses in adult subjects with stable CAD.

Official Title
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A Phase 2a Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Single- Ascending Doses of MEDI6012 in Subjects With Stable Coronary Artery Disease

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Biological: MEDI6012
* Biological: Placebo SC
* Biological: Placebo IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women 40 - 75 years old History of Stable CAD Currently receiving statin as standard of care Exclusion Criteria: Severe angina pectoris symptoms High-risk coronary or carotid artery disease that will likely require surgical or percutaneous intervention during the study period Hospitalization for heart failure within 12 months prior to screening Uncontrolled Hypertension Within 6 months prior to screening, a history of ACS or hospitalization for heart failure Clinically significant abnormalities in rhythm, conduction or morphology of ECG Subjects with transplanted heart, left ventricular assist device, implanted pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization therapy Untreated life-threatening ventricular arrhythmias History, within 12 months prior to screening, of myocarditis or restrictive pericarditis, or hemodynamically significant valvular hear disease or aortic disease Undergone major surgery with in 3 months prior to screening or has planned major surgery during the study period

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI6012 24 mg IV<br>Participants received a single IV dose of 24 mg MEDI6012 on Day 1. | Biological: MEDI6012<br>* Participants received a single IV (24, 80, 240, and 800 mg) and SC (80 and 600 mg) MEDI6012 doses on Day 1.<br>|
| Experimental: MEDI6012 80 mg IV<br>Participants received a single IV dose of 80 mg MEDI6012 on Day 1. | Biological: MEDI6012<br>* Participants received a single IV (24, 80, 240, and 800 mg) and SC (80 and 600 mg) MEDI6012 doses on Day 1.<br>|
| Experimental: MEDI6012 240 mg IV<br>Participants received a single IV dose of 240 mg MEDI6012 on Day 1. | Biological: MEDI6012<br>* Participants received a single IV (24, 80, 240, and 800 mg) and SC (80 and 600 mg) MEDI6012 doses on Day 1.<br>|
| Experimental: MEDI6012 800 mg IV<br>Participants received a single IV dose of 800 mg MEDI6012 on Day 1. | Biological: MEDI6012<br>* Participants received a single IV (24, 80, 240, and 800 mg) and SC (80 and 600 mg) MEDI6012 doses on Day 1.<br>|
| Experimental: MEDI6012 80 mg SC<br>Participants received a single SC dose of 80 mg MEDI6012 on Day 1. | Biological: MEDI6012<br>* Participants received a single IV (24, 80, 240, and 800 mg) and SC (80 and 600 mg) MEDI6012 doses on Day 1.<br>|
| Placebo Comparator: Placebo Intravenous (IV)<br>Participants received a single IV dose of placebo matched to MEDI6012 on Day 1 of the study. | Biological: Placebo IV<br>* Participants received a single IV dose of placebo matched to MEDI6012 on Day 1 of the study.<br>|
| Experimental: MEDI6012 600 mg SC<br>Participants received a single SC dose of 600 mg MEDI6012 on Day 1. | Biological: MEDI6012<br>* Participants received a single IV (24, 80, 240, and 800 mg) and SC (80 and 600 mg) MEDI6012 doses on Day 1.<br>|
| Placebo Comparator: Placebo Subcutaneous (SC)<br>Participants received a single SC dose of placebo matched to MEDI6012 on Day 1 of the study. | Biological: Placebo SC<br>* Participants received a single SC dose of placebo matched to MEDI6012 on Day 1 of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are the events between first dose of study drug and up to 57 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. | Baseline (Day 1) up to Day 57 | 
| Number of Participants With TEAEs Related to Electrocardiogram (ECG) Evaluations | TEAEs observed in participants with clinically significant ECG abnormalities were assessed. TEAEs are the events between first dose of study drug and up to 57 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. | Baseline (Day 1) up to Day 57 | 
| Number of Participants With TEAEs Related to Vital Sign Parameters | TEAEs observed in participants with clinically significant vital signs abnormalities were assessed. Vital signs parameters included blood pressure, respiration rate, pulse, pulse oximetry, and body temperature. | Baseline (Day 1) up to Day 57 | 
| Number of Participants With TEAEs Related to Clinical Laboratory Evaluations | An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation were reported as an adverse event. Laboratory evaluations (haematology, serum chemistry and urinalysis) of blood and urine samples were performed. | Baseline (Day 1) up to Day 57 | 
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hours (Hrs) (AUC [0-96 Hrs]) for High-Density Lipoprotein-Cholesterol (HDL-C) | The AUC (0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of HDL-C. | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion, 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hrs (AUC [0-96 Hrs]) for Total Cholesterol | The AUC (0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of total cholesterol. | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion and 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hrs (AUC [0-96 Hrs]) for Free Cholesterol | The AUC (0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of free cholesterol. | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion and 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hrs (AUC [0-96 Hrs]) for Cholesteryl Ester | The AUC(0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of cholesteryl ester. | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion and 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hrs (AUC [0-96 Hrs]) for High-Density Lipoprotein Cholesteryl Ester | The AUC (0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of high density lipoprotein cholesteryl ester. | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion and 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hrs (AUC [0-96 Hrs]) for Non-High Density Lipoprotein Cholesterol | The AUC(0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of non-high density lipoprotein cholesterol. | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion and 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hrs (AUC [0-96 Hrs]) for High-Density Lipoprotein Unesterified Cholesterol | The AUC (0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of high density lipoprotein unesterified cholesterol. | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion and 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hrs (AUC [0-96 Hrs]) for Non-High Density Lipoprotein Cholesteryl Ester | The AUC (0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of non-high density lipoprotein cholesteryl ester. | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion and 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hrs (AUC [0-96 Hrs]) for Non-High Density Lipoprotein Unesterified Cholesterol | The AUC (0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of non-high density lipoprotein unesterified cholesterol. | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion and 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hrs (AUC [0-96 Hrs]) for Low Density Lipoprotein-Cholesterol (Direct) | The AUC (0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of low density lipoprotein cholesterol (direct). | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion and 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hrs (AUC [0-96 Hrs]) Post Dose for Apolipoprotein B | The AUC (0-96 hrs) is the area under the concentration-time curve from time 0 to 96 hrs of apolipoprotein B. | Pre-dose, 12, 24, 48, 72 and 96 hrs post-dose Day 1 for IV and SC dose; additional within 5 minutes after completion of infusion and 4 and 8 hrs post-dose Day 1 (IV cohorts only) | 
| Change From Baseline in Serum Concentration of Pre Beta 1-High Density Lipoprotein at Day 29 | The change from baseline in serum concentration of pre beta 1-high density lipoprotein was estimated. | Baseline (Day 1) and Day 29 | 
| Change From Baseline in Serum Concentration of Lecithin-Cholesterol Acyltransferase (LCAT) at Day 57 | The change from baseline in serum concentration of lecithin-cholesterol acyltransferase was estimated. | Baseline (Day 1) and Day 57 | 
| Maximum Observed Serum Concentration (Cmax) of MEDI6012 | The first occurrence of the maximum observed plasma concentration of MEDI6012 determined directly from the raw concentration time data. | Pre-dose and within 5 minutes; 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 168 hrs post-dose Day 1 for IV and SC dose, Day 15 and Day 29; additional 30 min after start of 1-hour infusion (IV cohorts only) | 
| Time to Reach Concentration Maximum (Tmax) of MEDI6012 | The time at which Cmax of MEDI6012 was observed determined directly from raw concentration time data. | Pre-dose and within 5 minutes; 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 168 hrs post-dose Day 1 for IV and SC dose, Day 15 and Day 29; additional 30 min after start of 1-hour infusion (IV cohorts only) | 
| Area Under the Concentration Time Curve From 0 to 168 Hrs (AUC [0-168]) of MEDI6012 | The area under the concentration-time curve from 0 to 168 hrs of MEDI6012. | Pre-dose and within 5 minutes; 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 168 hrs post-dose Day 1 for IV and SC dose, Day 15 and Day 29; additional 30 min after start of 1-hour infusion (IV cohorts only) | 
| Area Under the Concentration Time Curve From Time Zero to Last Quantifiable Concentration (AUC [0-last]) of MEDI6012 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUC [0-last]) of MEDI6012. | Pre-dose and within 5 minutes; 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 168 hrs post-dose Day 1 for IV and SC dose, Day 15 and Day 29; additional 30 min after start of 1-hour infusion (IV cohorts only) | 
| Area Under the Concentration Time Curve to Infinite Time (AUC [0-inf]) of MEDI6012 | The area under the concentration-time curve to infinite time of MEDI6012. | Pre-dose and within 5 minutes; 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 168 hrs post-dose Day 1 for IV and SC dose, Day 15 and Day 29; additional 30 min after start of 1-hour infusion (IV cohorts only) | 
| Elimination Half Life (t1/2) of MEDI6012 | The t1/2 is the time measured for the plasma concentration to decrease by one half. | Pre-dose and within 5 minutes; 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120 and 168 hrs post-dose Day 1 for IV and SC dose, Day 15 and Day 29; additional 30 min after start of 1-hour infusion (IV cohorts only) | 
| Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | Participants were tested for immunogenicity to MEDI6012. The neutralization assay measures the capacity of participant's plasma (antibodies) to inhibit the binding of MEDI6012 to its target. | Day 1 (pre-dose), 15, 29 and 57 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary Artery Disease, CAD