Multiple Ascending Doses of MEDI6012 in Subjects With Stable Atherosclerotic Cardiovascular Disease

A Phase 2a Randomized, Blinded, Placebo-controlled Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Ascending Doses of MEDI6012 in Subjects With Stable Atherosclerotic Cardiovascular Disease

To evaluate the safety pharmacokinetics, and pharmacodynamics of repeat weekly dosing of MEDI6012 in subjects with stable atherosclerosis.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease; Atherosclerosis
• Intervention / Treatment: Drug: MEDI6012 40 mg; Drug: Placebo; Drug: MEDI6012 120 mg; Drug: MEDI6012 300 mg; Drug: MEDI6012 IV Push; Drug: Placebo IV Push

Detailed Description

A Phase 2a Randomized, Blinded, Placebo-controlled Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of MEDI6012 in Subjects with Stable Atherosclerotic Cardiovascular Disease

• Study Type: Interventional
• Enrollment (Actual): 32
• 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
  • Ohio
    • Cincinnati, Ohio, United States, 45246
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Non-childbearing potential
• Diagnosis of stable atherosclerotic CVD
• Currently receiving a stable dose of Statin

Exclusion Criteria:

• Unstable cardiovascular condition within 3 months of screening
• Elective arterial revascularization with in the past month
• Any planned arterial revascularization
• Body mass index <18 or >45
• Clinically significant ECG that may interfere with the interpretation of serial ECG and QT interval changes at screening
• Chronic kidney disease defined by estimated glomerular filtration rate of less than 30 mL/mim/1.73m2
• Triglycerides greater than 500 mg/dL, LDL-C greater than 160 mg/dL, or HDL-C greater than 60 for males, or 65 for females
• Clinically significant vital sign abnormalities
• Genetic disorder of cholesterol metabolism
• History of overt liver disease
• Poorly controlled endocrine disorder (Diabetes or Thyroid disorder)
• Current or recent use of systemic corticosteroids
• Recent or ongoing infection or febrile illness
• History of active malignancy within 5 years
• History of alcohol or recreational substance abuse in the past 6 months
• 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: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MEDI6012 40 mg; Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.	Drug: MEDI6012 40 mg; Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Placebo Comparator: Placebo; Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.	Drug: Placebo; Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Experimental: MEDI6012 120 mg; Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.	Drug: MEDI6012 120 mg; Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Experimental: MEDI6012 300 mg; Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.	Drug: MEDI6012 300 mg; Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
Experimental: MEDI6012 IV Push; Participants received 3 doses of MEDI6012 by IV push as 300 mg loading dose on Day 1, and maintenance doses of 150 mg and 100 mg on Day 3 and Day 10, respectively.	Drug: MEDI6012 IV Push; Participants received 3 doses of MEDI6012 by IV push as 300 mg loading dose on Day 1, and maintenance doses of 150 mg and 100 mg on Day 3 and Day 10, respectively.
Placebo Comparator: Placebo IV Push; Participants received 3 doses of placebo matching with MEDI6012 by IV push. A loading dose on Day 1 and maintenance doses on Days 3 and 10.	Drug: Placebo IV Push; Participants received 3 doses of placebo matching with MEDI6012 by IV push. A loading dose on Day 1 and maintenance doses on Days 3 and 10.

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) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is 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 56 days after last dose of study drug (Day 66 for Cohort 4 and placebo IV push arm and Day 71 for Cohorts 1 to 3 and placebo arm) that were absent before treatment or that worsened relative to pre-treatment state.	From Day 1 to Day 56 after last dose of study drug (Day 66 for Cohort 4 and Placebo IV push arm and Day 71 for Cohorts 1 to 3 and placebo arm)
Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs	An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator as medically significant was reported as an AE. Laboratory evaluations included haematology, serum chemistry, and urinalysis.	From Day 1 to Day 56 after last dose of study drug (Day 66 for Cohort 4 and Placebo IV push arm and Day 71 for Cohorts 1 to 3 and placebo arm)
Number of Participants With Abnormal Vital Signs Reported as TEAEs	Treatment-emergent adverse events observed in participants with clinically significant vital signs abnormalities are reported. Vital sign parameters included blood pressure, respiration rate, heart rate, pulse oximetry, and body temperature.	From Day 1 to Day 56 after last dose of study drug (Day 66 for Cohort 4 and Placebo IV push arm and Day 71 for Cohorts 1 to 3 and placebo arm)
Number of Participants With Abnormal Electrocardiogram Reported as TEAEs	Treatment-emergent adverse events observed in participants with clinically significant ECG abnormalities are reported.	From Day 1 to Day 56 after last dose of study drug (Day 66 for Cohort 4 and Placebo IV push arm and Day 71 for Cohorts 1 to 3 and placebo arm)
Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for High-density Lipoprotein-cholesterol (HDL-C)	The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of high-density lipoprotein-cholesterol.	Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 15 dose (third dose) for Cohorts 1 to 3 and Placebo arm; Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 10 dose (third dose) for Cohort 4 and Placebo IV push arm.
Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for High-density Lipoprotein-cholesterol Ester (HDL-CE)	The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of high-density lipoprotein-cholesterol ester.	Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 15 dose (third dose) for Cohorts 1 to 3 and Placebo arm; Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 10 dose (third dose) for Cohort 4 and Placebo IV push arm.
Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Cholesterol Ester	The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of cholesterol ester.	Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 15 dose (third dose) for Cohorts 1 to 3 and Placebo arm; Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 10 dose (third dose) for Cohort 4 and Placebo IV push arm.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein A1	The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of Apolipoprotein A1.	Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 15 dose (third dose) for Cohorts 1 to 3 and Placebo arm; Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 10 dose (third dose) for Cohort 4 and Placebo IV push arm.
Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Low-density Lipoprotein Cholesterol (LDL-C).	The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of LDL-C.	Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 15 dose (third dose) for Cohorts 1 to 3 and Placebo arm; Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 10 dose (third dose) for Cohort 4 and Placebo IV push arm.
Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein B	The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of Apolipoprotein B.	Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 15 dose (third dose) for Cohorts 1 to 3 and Placebo arm; Pre-dose, end of infusion, 12, 24, and 96 hrs post Day 10 dose (third dose) for Cohort 4 and Placebo IV push arm.
Change From Baseline in Serum Concentration for MEDI6012 Mass	The trough concentration level of MEDI6012 following each dose is reported (concentration at Days 8, 15, and 22 for Cohorts 1 to 3 and placebo; Concentration at Days 3, 10, and 17 for Cohort 4 and placebo IV push arm).	Seven days post-dose following Doses 1 to 3 in Cohorts 1 to 3 and placebo arm (Days 8, 15, 22); 2 days post-dose following Dose 1 (Day 3) and 7 days post-dose following Doses 2 and 3 (Days 10, 17) in Cohort 4 and placbo IV push.
Change From Baseline in Serum Concentration for Total LCAT Activity	Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme secreted by the liver. Serum LCAT activity was estimated to provide an alternative measure to LCAT mass in establishing the relationship between pharmacokinetics and pharmacodynamics of MEDI6012. Change in LCAT activity from baseline (pre-dose of each dose) to post doses was reported (concentration at Days 8, 15, and 22 for Cohorts 1 to 3 and placebo; Concentration at Days 3, 10, and 17 for Cohort 4 and placebo IV push arm).	Seven days post-dose following Doses 1 to 3 in Cohorts 1 to 3 and placebo arm (Days 8, 15, 22); 2 days post-dose following Dose 1 (Day 3) and 7 days post-dose following Doses 2 and 3 (Days 10, 17) in Cohort 4 and placbo IV push.
Maximum Observed Serum Concentration (Cmax) of MEDI6012	The maximum observed serum concentration following the first and third dose of MEDI6012 was reported.	Day 1 end of infusion to Day 8 predose for Cohorts 1 to 3; Day 1 end of infusion to Day 3 predose for Cohort 4; Cmax following the third dose: Day 15 end of infusion to Day 71 for Cohort 1 to 3; Day 10 end of infusion to Day 65 for Cohort 4.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012	The time to reach the maximum observed serum concentration following the first and third dose of MEDI6012 was reported.	Day 1 end of infusion to Day 8 predose for Cohorts 1 to 3; Day 1 end of infusion to Day 3 predose for Cohort 4; Tmax following the third dose: Day 15 end of infusion to Day 71 for Cohort 1 to 3; Day 10 end of infusion to Day 65 for Cohort 4.
Accumulation Ratio (Rac) of MEDI6012	The accumulation ratio (Rac) is defined as the ratio of accumulation of a study drug going from a single dose to steady state with repeated administration. Accumulation ratio was reported on the basis of maximum concentration (ARC max) and area under the concentration-time curve (ARAUC).	Day 1 end of infusion to Day 8 predose for Cohorts 1 to 3; Day 1 end of infusion to Day 3 predose for Cohort 4; The Rac following third dose: Day 15 end of infusion to Day 71 for Cohort 1 to 3; Day 10 end of infusion to Day 65 for Cohort 4.
Terminal Half-life (t1/2) of MEDI6012	The t1/2 is the time measured for the serum concentration to decrease by one half after the third dose of MEDI6012.	The t1/2 following third dose: Day 15 end of infusion to Day 71 for Cohort 1 to 3; Day 10 end of infusion to Day 65 for Cohort 4.
Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012	The area under the concentration time-curve to the last measured concentration after the third dose of MEDI6012 was reported.	Day 1 end of infusion to Day 8 predose for Cohorts 1 to 3; Day 1 end of infusion to Day 3 predose for Cohort 4; AUClast following the third dose: Day 15 end of infusion to Day 71 for Cohort 1 to 3; Day 10 end of infusion to Day 65 for Cohort 4.
Number of Participants With Positive Anti-Drug Antibodies for MEDI6012	Participants with positive serum antibodies to MEDI6012 were reported.	For Cohorts 1 to 3 and Placebo arm: Pre-dose on Days 1 and 15, and on Days 29, 43, and 71; For Cohort 4 and Placebo IV push arm: Pre-dose on Days 1 and 10, and on Days 24, 38, and 66.

Collaborators and Investigators

• Sponsor: MedImmune LLC

Publications and helpful links

Helpful Links

• D5780C00005-CSP-amendment-1_REDACTED_16Jul2017_PDF-A
• 5780C00005 MEDI6012 Statistical Analysis Plan_21Jul2017_Version2_Redacted_PDF-A.pdf

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2017
• Primary Completion (Actual): November 2, 2017
• Study Completion (Actual): November 2, 2017

Study Registration Dates

• First Submitted: December 12, 2016
• First Submitted That Met QC Criteria: December 22, 2016
• First Posted (Estimate): December 29, 2016

Study Record Updates

• Last Update Posted (Actual): December 19, 2018
• Last Update Submitted That Met QC Criteria: November 30, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: Cardiovascular Disease; Atherosclerosis; CAD; Atherosclerotic Cardiovascular Disease
• Additional Relevant MeSH Terms: Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Cardiovascular Diseases; Atherosclerosis
• Other Study ID Numbers: D5780C00005

Drug and device information, study documents

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