Study to Evaluate the Effects of MEDI6012 on Apolipoprotein B100 Metabolism

Study to Evaluate the Effects of Two Doses Over 48 Hours of MEDI6012 on Apolipoprotein B100 Metabolism in Subjects With Stable Atherosclerotic Cardiovascular Disease

This is a Phase 2, single-center, placebo controlled, double-blind, randomized crossover study to determine the effects of MEDI6012 on the metabolism of apolipoprotein B100 (apoB100) lipoproteins in individuals with stable atherosclerotic cardiovascular disease (ASCVD).

Study Overview

• Status: Terminated
• Conditions: Cardiovascular Diseases
• Intervention / Treatment: Drug: Placebo; Drug: MEDI6012

Detailed Description

Atherosclerosis, characterized by excess fat deposit in arteries, is a progressive and life-threatening condition. Therefore, treatments that can remove fat deposits from the arteries are being developed. These treatments may prevent subsequent heart attacks or other cardiovascular events, addressing an unmet medical need. MEDI16012 is a new drug that targets a substance produced by the body to assist participants in breaking down the bodies "good" fat. The investigators are interested in understanding why MEDI6012 increases the good fat, but also why it increases other types of "bad" fat such as low-density lipoprotein-C (LDL-C).

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult male and female subjects (non-childbearing potential for females) ages 35 through 80 years at the time of screening who are capable of providing informed consent prior to screening and any protocol-related procedures.
2. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act (HIPAA) in the USA) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
3. Ability to complete and meet all eligibility requirements for randomization within 28 days of informed consent (56 days if washing out from lipid altering agent other than statins or ezetimibe).

4. A diagnosis of stable atherosclerotic cardiovascular disease (CVD) documented prior to screening:

   • Coronary artery disease defined as a history of prior myocardial infarction, coronary revascularization, history of coronary atherosclerosis based on invasive or non-invasive imaging, and/or abnormal stress testing diagnostic of coronary artery disease.
   • Carotid artery disease (extracranial internal carotid artery (ICA) stenosis) defined as evidence of carotid atherosclerosis by carotid imaging, or history of percutaneous or surgical carotid revascularization
   • Peripheral artery disease defined as ankle-brachial index < 0.90 and claudication, or prior peripheral revascularization for ischemia, or evidence of lower extremity (below the inguinal ligament) atherosclerosis on invasive or noninvasive imaging
5. Currently receiving statin as standard of care, at a stable dose for ≥ 8 weeks prior to screening and intended to remain at a stable dose throughout the study duration. Subjects may also be receiving ezetimibe, 10 mg/day for ≥ 8 weeks prior to screening.
6. Nonsterilized males who are sexually active with a female partner of childbearing potential must use condom and spermicide from Day 1 through the end of their participation in the study. Because male condom and spermicide is not a highly effective contraception method it is strongly recommended that female partners of a male study subjects also use a highly effective method of contraception throughout this period.

Exclusion Criteria:

1. Unstable cardiovascular conditions within 3 months prior to screening, including acute coronary syndrome (ACS), stroke or transient ischemia attack, critical limb ischemia, non-elective arterial revascularization, life-threatening arrhythmias, or heart failure hospitalization.
2. Elective arterial revascularization (in any vascular territory) in the past 1 month. Any planned arterial revascularization (coronary, peripheral or carotid).
3. New York Heart Association (NYHA) Class III or IV congestive heart failure or treatment with advanced therapies (cardiac transplant, ventricular assist device, cardiac resynchronization therapy,and/or chronic IV inotropic support), or severe valvular heart disease.
4. Body mass index < 18 or > 45.

5. Lipid measurements with any of the following:

   1. Triglycerides (TG) > 400 mg/dL
   2. LDL-C > 120 mg/dL
   3. High-density lipoprotein C (HDL-C) > 70 mg/dL for males or > 80 mg/dL for females.

6. Clinically significant vital sign abnormalities at screening or on Day -1:

   1. Systolic blood pressure (BP) < 90 or >160 mm Hg
   2. Diastolic BP > 100 mm Hg
7. Females currently breastfeeding or of childbearing potential. Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who are not postmenopausal; defined as 12 months with no menses without an alternative medical cause and a follicle-stimulating hormone level in the central laboratory's normal range for post-menopausal phase is required at screening.
8. Use of lipid-lowering medications, with the exception of statins and ezetimibe, and the following dietary supplements: ≥ 2 grams/day of fish oil (≥ 2 grams/day docosahexaenoic acid (DHA) and EPA combined), ≥ 30 grams/day of flaxseed oil or ground flaxseed, red yeast extract, > 100 mg/day of niacin. At the investigator's discretion, subjects may undergo a 6-week washout period of any exclusionary lipid-lowering agents with the expectation that post-washout lipid levels will be rechecked and acceptable per above criteria.

9. History of any of the following:

   • Documented familial hypercholesterolemia
   • Chronic kidney disease defined by estimated glomerular filtration rate < 30 mL/min/1.73 m2 by the modification of diet in renal disease equation, or end stage renal disease treated with kidney transplant or renal replacement therapy
   • History of clinically overt chronic liver disease or biochemical evidence of liver disease

   • Poorly controlled endocrine disorder including:

     • Type 1 Diabetes excluded
     • Type 2 Diabetes Mellitus with glycated hemoglobin (HbA1c) > 8.0% as assessed at screening or
   • Uncontrolled thyroid disorder defined as thyroid stimulating hormone (TSH)> upper limit of normal (ULN) and abnormal free T4; subjects with thyroid deficiency should have received a stable dose of thyroid hormone for > 6 weeks prior to screening and have a normal TSH.
   • Current or previous use of systemic corticosteroids within 28 days prior to screening. Topical, intra-articular, intranasal, inhaled, and ophthalmic steroid therapies are allowed
   • History of severe infection or ongoing febrile illness within 30 days of screening, or a medical history of a chronic viral illness including hepatitis B or C virus, or human immunodeficiency virus (HIV).
   • History of active malignancy within 5 years (subjects with non-melanotic skin cancer may be included)
   • Any other disease or condition or laboratory value that, in the opinion of the investigator or medical monitor, would place the subject at an unacceptable risk or interfere with the evaluation of the investigative product.
   • Known allergy/hypersensitivity to any component of the investigational product formulation, other biologics, IV infusion equipment, plastics, adhesive or silicone, history of infusion site reactions with IV administration of other medicines, or ongoing clinically important allergy/hypersensitivity as judged by the investigator.
10. Subjects who are legally institutionalized
11. Previous Exposure to rhLCAT
12. Concurrent enrollment in another clinical study of any investigational drug therapy or use of any biologicals within 6 months prior to screening or within 5 half-lives of an investigational agent or biologic, whichever is longer.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Control Group; Subjects will receive placebo treatment to mimic active treatment.	Drug: Placebo; The placebo will mimic the active treatment.; Other Names: Placebo compound provided by funding agency
Active Comparator: Active treatment; IV push loading dose of 300 mg MEDI6012 followed by a 150 mg maintenance dose of MEDI6012 at 48 hours.	Drug: MEDI6012; MEDI6012 is recombinant human lecithin-cholesterol acyltransferase (rhLCAT), an approximately 60 kilodalton, glycosylated, single-chain protein consisting of 416 amino acids produced via Chinese hamster ovary cell culture. It is being explored as an acute treatment to reduce the risk of recurrent cardiovascular events as an adjunct to the standard of care in patients with acute myocardial infarction (MI). MEDI6012 and ACP501 have the identical amino acid sequence and are therefore considered the same molecular entity.; Other Names: Stable Isotopes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in FCR of LDL-apoB100 (pools/day)	Fractional Clearance Rate (FCR) of lipoprotein B.	Up to 48 hours from first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PR of LDL apoB100 (mg/kg/day)	Production Rate (PR) of LDL apoB 100.	Up to 48 hours from first dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ADA Measurement	To access the immunogenicity of MEDI6012, anti-drug antibodies (ADA) will be measured.	Up to 60 days post administration of first dose

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: AstraZeneca; MedImmune LLC
• Investigators: Principal Investigator: Henry Ginsberg, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2019
• Primary Completion (Actual): May 20, 2020
• Study Completion (Actual): May 20, 2020

Study Registration Dates

• First Submitted: December 10, 2018
• First Submitted That Met QC Criteria: December 11, 2018
• First Posted (Actual): December 12, 2018

Study Record Updates

• Last Update Posted (Actual): December 11, 2020
• Last Update Submitted That Met QC Criteria: December 10, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Lipid and Lipoprotein Metabolism
• Additional Relevant MeSH Terms: Cardiovascular Diseases
• Other Study ID Numbers: AAAS0459

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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