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

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

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Biological: MEDI6012; Biological: Placebo IV; Biological: Placebo SC

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Research Site
    • Port Orange, Florida, United States, 32127
      • Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Research Site
    • Raleigh, North Carolina, United States, 27612
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Research Site
  • Texas
    • San Antonio, Texas, United States, 78229
      • Research Site
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: DOUBLE

Number of Arms

8

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: MedImmune LLC

Publications and helpful links

General Publications

• George RT, Abuhatzira L, Stoughton SM, Karathanasis SK, She D, Jin C, Buss NAPS, Bakker-Arkema R, Ongstad EL, Koren M, Hirshberg B. MEDI6012: Recombinant Human Lecithin Cholesterol Acyltransferase, High-Density Lipoprotein, and Low-Density Lipoprotein Receptor-Mediated Reverse Cholesterol Transport. J Am Heart Assoc. 2021 Jul 6;10(13):e014572. doi: 10.1161/JAHA.119.014572. Epub 2021 Jun 14.

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2015
• Primary Completion (Actual): August 20, 2016
• Study Completion (Actual): November 3, 2016

Study Registration Dates

• First Submitted: November 9, 2015
• First Submitted That Met QC Criteria: November 9, 2015
• First Posted (Estimate): November 10, 2015

Study Record Updates

• Last Update Posted (Actual): March 19, 2018
• Last Update Submitted That Met QC Criteria: March 16, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Coronary Artery Disease; CAD
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
• Other Study ID Numbers: D5780C00002

Drug and device information, study documents

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