Clinical trial NCT03773172: Study to Evaluate the Effects of MEDI6012 on Apolipoprotein B100 Metabolism
Official title: Study to Evaluate the Effects of Two Doses Over 48 Hours of MEDI6012 on Apolipoprotein B100 Metabolism in Subjects With Stable Atherosclerotic Cardiovascular Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Cardiovascular Diseases
Keywords: Lipid and Lipoprotein Metabolism
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: MedImmune LLC
name: AstraZeneca
First posted: 2018-12-12
Enrollment: 7
Sex: ALL
Minimum age (years): 35
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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).

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).

Eligibility criteria: 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.

Primary outcomes:
measure: Fractional Clearance Rate (FCR) of Lipoprotein B (Pools/Day)
timeFrame: Up to 48 hours from first dose
Secondary outcomes:
measure: Production Rate (PR) of Apolipoprotein B100 (mg/kg/Day)
timeFrame: Up to 48 hours from first dose
Other outcomes:
measure: ADA Measurement
timeFrame: Up to 60 days post administration of first dose
Locations:
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Henry Ginsberg, MD
role: PRINCIPAL_INVESTIGATOR
References: