Atherosclerosis, Cardiovascular Disease
Conditions
Keywords
Atherosclerosis, Cardiovascular Disease, CAD, Atherosclerotic Cardiovascular Disease
Brief summary
To evaluate the safety pharmacokinetics, and pharmacodynamics of repeat weekly dosing of MEDI6012 in subjects with stable atherosclerosis.
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
Interventions
DRUGMEDI6012 40 mg
Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
DRUGPlacebo
Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
DRUGMEDI6012 120 mg
Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
DRUGMEDI6012 300 mg
Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
DRUGPlacebo 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.
DRUGMEDI6012 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.
Sponsors
MedImmune LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | 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) | 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. |
| Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs | 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) | 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. |
| Number of Participants With Abnormal Vital Signs Reported as TEAEs | 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) | 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. |
| Number of Participants With Abnormal Electrocardiogram Reported as TEAEs | 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) | Treatment-emergent adverse events observed in participants with clinically significant ECG abnormalities are reported. |
| 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) | 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. | The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of high-density lipoprotein-cholesterol. |
| 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) | 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. | 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. |
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for 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. | The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of cholesterol ester. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Accumulation Ratio (Rac) of MEDI6012 | 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. | 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). |
| Terminal Half-life (t1/2) 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. | The t1/2 is the time measured for the serum concentration to decrease by one half after the third dose of MEDI6012. |
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for 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. | The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of Apolipoprotein A1. |
| Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | 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. | Participants with positive serum antibodies to MEDI6012 were reported. |
| Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012 | 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. | The area under the concentration time-curve to the last measured concentration after the third dose of MEDI6012 was reported. |
| 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). | 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. | The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of LDL-C. |
| Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for 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. | The AUC (0-96 hr) is the area under the concentration-time curve from time 0 to 96 hrs of Apolipoprotein B. |
| Change From Baseline in Serum Concentration for MEDI6012 Mass | 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. | 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). |
| Change From Baseline in Serum Concentration for Total LCAT Activity | 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. | 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). |
| Maximum Observed Serum Concentration (Cmax) of MEDI6012 | 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. | The maximum observed serum concentration following the first and third dose of MEDI6012 was reported. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 | 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. | The time to reach the maximum observed serum concentration following the first and third dose of MEDI6012 was reported. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 4 sites in the USA between 23Jan2017 and 02Nov2017.
Pre-assignment details
A total of 91 participants were screened, of which 32 participants were randomized in a 6:2 ratio to receive MEDI6012 or placebo in 4 cohorts (8 participants in each cohort). For Cohort 4, randomization happened in a 7:1 ratio to receive MEDI6012 or placebo due to an interactive voice/web response system programming issue.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15. | 6 |
| Cohort 1: MEDI6012 40 mg Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15. | 6 |
| Cohort 2: MEDI6012 120 mg Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15. | 6 |
| Cohort 3: MEDI6012 300 mg Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15. | 6 |
| 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. | 1 |
| Cohort 4: 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. | 7 |
| Total | 32 |
Baseline characteristics
| Characteristic | Placebo | Cohort 1: MEDI6012 40 mg | Cohort 2: MEDI6012 120 mg | Cohort 3: MEDI6012 300 mg | Placebo IV Push | Cohort 4: MEDI6012 IV Push | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 67.8 Years STANDARD_DEVIATION 4.8 | 66.7 Years STANDARD_DEVIATION 3.3 | 68.8 Years STANDARD_DEVIATION 2.8 | 66.2 Years STANDARD_DEVIATION 2.6 | 65.0 Years | 71.4 Years STANDARD_DEVIATION 4.2 | 68.2 Years STANDARD_DEVIATION 3.9 |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 1 Participants | 7 Participants | 31 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 6 Participants | 6 Participants | 5 Participants | 0 Participants | 7 Participants | 29 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 9 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 5 Participants | 3 Participants | 1 Participants | 6 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 1 | 0 / 7 |
| other Total, other adverse events | 3 / 6 | 3 / 6 | 3 / 6 | 4 / 6 | 0 / 1 | 3 / 7 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 1 / 6 | 0 / 6 | 0 / 1 | 0 / 7 |
Outcome results
Primary
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.
Time frame: 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.
Population: As-treated population included all participants who received at least one dose of study drug. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Cholesterol Ester | 373.04 mg*h/dL | Standard Deviation 1060.76 |
| Cohort 1: MEDI6012 40 mg | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Cholesterol Ester | 2267.37 mg*h/dL | Standard Deviation 1126.43 |
| Cohort 2: MEDI6012 120 mg | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Cholesterol Ester | 4047.38 mg*h/dL | Standard Deviation 1314.67 |
| Cohort 3: MEDI6012 300 mg | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Cholesterol Ester | 9004.31 mg*h/dL | Standard Deviation 2086.47 |
| Placebo IV Push | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Cholesterol Ester | 371.75 mg*h/dL | — |
| Cohort 4: MEDI6012 IV Push | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Cholesterol Ester | 2649.56 mg*h/dL | Standard Deviation 3039.83 |
Primary
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.
Time frame: 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.
Population: As-treated population included all participants who received at least one dose of study drug.The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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) | -23.75 mg*h/dL | Standard Deviation 422.76 |
| Cohort 1: MEDI6012 40 mg | 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) | 1161.47 mg*h/dL | Standard Deviation 506.67 |
| Cohort 2: MEDI6012 120 mg | 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) | 2580.51 mg*h/dL | Standard Deviation 1076.11 |
| Cohort 3: MEDI6012 300 mg | 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) | 5710.09 mg*h/dL | Standard Deviation 1622.36 |
| Placebo IV Push | 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) | 273.03 mg*h/dL | — |
| Cohort 4: MEDI6012 IV Push | 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) | 1597.12 mg*h/dL | Standard Deviation 1531.4 |
Primary
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.
Time frame: 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.
Population: As-treated population included all participants who received at least one dose of study drug. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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) | -6.72 mg*h/dL | Standard Deviation 467.59 |
| Cohort 1: MEDI6012 40 mg | 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) | 1355.64 mg*h/dL | Standard Deviation 576.94 |
| Cohort 2: MEDI6012 120 mg | 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) | 2874.86 mg*h/dL | Standard Deviation 1232.21 |
| Cohort 3: MEDI6012 300 mg | 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) | 6465.05 mg*h/dL | Standard Deviation 2074.77 |
| Placebo IV Push | 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) | 266.68 mg*h/dL | — |
| Cohort 4: MEDI6012 IV Push | 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) | 1803.12 mg*h/dL | Standard Deviation 1684.32 |
Primary
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.
Time frame: 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)
Population: As-treated population included all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs | 0 Participants |
| Cohort 1: MEDI6012 40 mg | Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs | 1 Participants |
| Cohort 2: MEDI6012 120 mg | Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs | 0 Participants |
| Cohort 3: MEDI6012 300 mg | Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs | 0 Participants |
| Placebo IV Push | Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs | 0 Participants |
| Cohort 4: MEDI6012 IV Push | Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs | 0 Participants |
Primary
Number of Participants With Abnormal Electrocardiogram Reported as TEAEs
Treatment-emergent adverse events observed in participants with clinically significant ECG abnormalities are reported.
Time frame: 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)
Population: As-treated population included all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Abnormal Electrocardiogram Reported as TEAEs | 0 Participants |
| Cohort 1: MEDI6012 40 mg | Number of Participants With Abnormal Electrocardiogram Reported as TEAEs | 0 Participants |
| Cohort 2: MEDI6012 120 mg | Number of Participants With Abnormal Electrocardiogram Reported as TEAEs | 1 Participants |
| Cohort 3: MEDI6012 300 mg | Number of Participants With Abnormal Electrocardiogram Reported as TEAEs | 0 Participants |
| Placebo IV Push | Number of Participants With Abnormal Electrocardiogram Reported as TEAEs | 0 Participants |
| Cohort 4: MEDI6012 IV Push | Number of Participants With Abnormal Electrocardiogram Reported as TEAEs | 0 Participants |
Primary
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.
Time frame: 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)
Population: As-treated population included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypertension | 1 Participants |
| Placebo | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypotension | 0 Participants |
| Cohort 1: MEDI6012 40 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypertension | 1 Participants |
| Cohort 1: MEDI6012 40 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypotension | 0 Participants |
| Cohort 2: MEDI6012 120 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypertension | 0 Participants |
| Cohort 2: MEDI6012 120 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypotension | 1 Participants |
| Cohort 3: MEDI6012 300 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypertension | 0 Participants |
| Cohort 3: MEDI6012 300 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypotension | 0 Participants |
| Placebo IV Push | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypertension | 0 Participants |
| Placebo IV Push | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypotension | 0 Participants |
| Cohort 4: MEDI6012 IV Push | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypertension | 0 Participants |
| Cohort 4: MEDI6012 IV Push | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Hypotension | 0 Participants |
Primary
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.
Time frame: 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)
Population: As-treated population included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 3 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
| Cohort 1: MEDI6012 40 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 3 Participants |
| Cohort 1: MEDI6012 40 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
| Cohort 2: MEDI6012 120 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 1 Participants |
| Cohort 2: MEDI6012 120 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 3 Participants |
| Cohort 3: MEDI6012 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 4 Participants |
| Cohort 3: MEDI6012 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
| Placebo IV Push | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
| Placebo IV Push | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 0 Participants |
| Cohort 4: MEDI6012 IV Push | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAEs | 3 Participants |
| Cohort 4: MEDI6012 IV Push | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TESAEs | 0 Participants |
Secondary
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).
Time frame: 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.
Population: PK population. The Rac was not calculated for Cohort 4 as the first dose regimen (300 mg loading dose follow by 2nd dose given 48 hours later, therefore NCA was not performed for Dose 1) are different from 3rd dose (100 mg). The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Accumulation Ratio (Rac) of MEDI6012 | ARCmax | 1.09 Ratio | Standard Deviation 0.214 |
| Placebo | Accumulation Ratio (Rac) of MEDI6012 | ARAUC | 0.897 Ratio | — |
| Cohort 1: MEDI6012 40 mg | Accumulation Ratio (Rac) of MEDI6012 | ARCmax | 1.01 Ratio | Standard Deviation 0.112 |
| Cohort 1: MEDI6012 40 mg | Accumulation Ratio (Rac) of MEDI6012 | ARAUC | 1.16 Ratio | Standard Deviation 0.0982 |
| Cohort 2: MEDI6012 120 mg | Accumulation Ratio (Rac) of MEDI6012 | ARCmax | 1.02 Ratio | Standard Deviation 0.177 |
| Cohort 2: MEDI6012 120 mg | Accumulation Ratio (Rac) of MEDI6012 | ARAUC | 1.21 Ratio | Standard Deviation 0.169 |
Secondary
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.
Time frame: 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.
Population: PK population. The AUClast was not reported following first dose in Cohort 4 since NCA was not performed due to dosing period was only 48 hrs. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012 | Dose 3 | 8.98 µg*day/mL | Standard Deviation 5.61 |
| Placebo | Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012 | Dose 1 | 10.9 µg*day/mL | Standard Deviation 10.1 |
| Cohort 1: MEDI6012 40 mg | Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012 | Dose 3 | 48.3 µg*day/mL | Standard Deviation 23.6 |
| Cohort 1: MEDI6012 40 mg | Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012 | Dose 1 | 35.2 µg*day/mL | Standard Deviation 17.8 |
| Cohort 2: MEDI6012 120 mg | Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012 | Dose 1 | 152 µg*day/mL | Standard Deviation 50.5 |
| Cohort 2: MEDI6012 120 mg | Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012 | Dose 3 | 205 µg*day/mL | Standard Deviation 63.7 |
| Cohort 3: MEDI6012 300 mg | Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012 | Dose 3 | 38.6 µg*day/mL | Standard Deviation 21.9 |
Secondary
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.
Time frame: 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.
Population: As-treated population included all participants who received at least one dose of study drug. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein A1 | 821.33 mg*h/dL | Standard Deviation 1465.7 |
| Cohort 1: MEDI6012 40 mg | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein A1 | 2440.48 mg*h/dL | Standard Deviation 1021.34 |
| Cohort 2: MEDI6012 120 mg | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein A1 | 3740.59 mg*h/dL | Standard Deviation 1508.93 |
| Cohort 3: MEDI6012 300 mg | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein A1 | 5302.87 mg*h/dL | Standard Deviation 1739.86 |
| Placebo IV Push | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein A1 | -20.42 mg*h/dL | — |
| Cohort 4: MEDI6012 IV Push | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein A1 | 2399.42 mg*h/dL | Standard Deviation 2611.21 |
Secondary
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.
Time frame: 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.
Population: As-treated population included all participants who received at least one dose of study drug. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein B | -82.95 mg*h/dL | Standard Deviation 667.65 |
| Cohort 1: MEDI6012 40 mg | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein B | -40.06 mg*h/dL | Standard Deviation 477.21 |
| Cohort 2: MEDI6012 120 mg | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein B | 145.42 mg*h/dL | Standard Deviation 283.62 |
| Cohort 3: MEDI6012 300 mg | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein B | -374.38 mg*h/dL | Standard Deviation 588.54 |
| Placebo IV Push | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein B | -239.17 mg*h/dL | — |
| Cohort 4: MEDI6012 IV Push | Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein B | 73.01 mg*h/dL | Standard Deviation 864.3 |
Secondary
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.
Time frame: 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.
Population: As-treated population included all participants who received at least one dose of study drug. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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). | -55.96 mg*h/dL | Standard Deviation 886.81 |
| Cohort 1: MEDI6012 40 mg | 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). | 1125.45 mg*h/dL | Standard Deviation 872.4 |
| Cohort 2: MEDI6012 120 mg | 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). | 1043.39 mg*h/dL | Standard Deviation 700 |
| Cohort 3: MEDI6012 300 mg | 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). | 3056.76 mg*h/dL | Standard Deviation 1765.33 |
| Placebo IV Push | 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). | -78.79 mg*h/dL | — |
| Cohort 4: MEDI6012 IV Push | 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). | 1364.12 mg*h/dL | Standard Deviation 2375.93 |
Secondary
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).
Time frame: 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.
Population: Pharmacokinetic (PK) population included all participants in the as-treated population who had at least one detectable lecithin-cholesterol acyltransferase (LCAT) serum concentration measurement. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 15 | 0.0000 μg/mL | Standard Deviation 0 |
| Placebo | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 22 | 0.0000 μg/mL | Standard Deviation 0 |
| Placebo | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 8 | 0.0000 μg/mL | Standard Deviation 0 |
| Cohort 1: MEDI6012 40 mg | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 15 | 0.0000 μg/mL | Standard Deviation 0 |
| Cohort 1: MEDI6012 40 mg | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 8 | 0.0000 μg/mL | Standard Deviation 0 |
| Cohort 1: MEDI6012 40 mg | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 22 | 0.0000 μg/mL | Standard Deviation 0 |
| Cohort 2: MEDI6012 120 mg | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 22 | 0.5478 μg/mL | Standard Deviation 0.8613 |
| Cohort 2: MEDI6012 120 mg | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 8 | 0.0000 μg/mL | Standard Deviation 0 |
| Cohort 2: MEDI6012 120 mg | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 15 | 0.0000 μg/mL | Standard Deviation 0 |
| Cohort 3: MEDI6012 300 mg | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 15 | 5.4320 μg/mL | Standard Deviation 2.6999 |
| Cohort 3: MEDI6012 300 mg | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 8 | 3.8646 μg/mL | Standard Deviation 2.0753 |
| Cohort 3: MEDI6012 300 mg | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 22 | 7.1622 μg/mL | Standard Deviation 2.7936 |
| Placebo IV Push | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 10 | 0.0000 μg/mL | — |
| Placebo IV Push | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 17 | 0.0000 μg/mL | — |
| Placebo IV Push | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 3 | 0.0000 μg/mL | — |
| Cohort 4: MEDI6012 IV Push | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 3 | 16.2684 μg/mL | Standard Deviation 4.5094 |
| Cohort 4: MEDI6012 IV Push | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 10 | 2.4407 μg/mL | Standard Deviation 2.1437 |
| Cohort 4: MEDI6012 IV Push | Change From Baseline in Serum Concentration for MEDI6012 Mass | Day 17 | 0.3980 μg/mL | Standard Deviation 0.89 |
Secondary
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).
Time frame: 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.
Population: PK population included all participants in the as-treated population who had at least one detectable LCAT serum concentration measurement. LCAT activity at Day 3 and Day 17 were not collected for Cohort 4. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 8 | 0.2046 μg/mL | Standard Deviation 0.3035 |
| Placebo | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 15 | -0.1467 μg/mL | Standard Deviation 0.8494 |
| Placebo | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 22 | 0.4983 μg/mL | Standard Deviation 0.3355 |
| Cohort 1: MEDI6012 40 mg | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 22 | -0.1617 μg/mL | Standard Deviation 0.7031 |
| Cohort 1: MEDI6012 40 mg | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 8 | 0.0282 μg/mL | Standard Deviation 0.9432 |
| Cohort 1: MEDI6012 40 mg | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 15 | 0.1700 μg/mL | Standard Deviation 0.7582 |
| Cohort 2: MEDI6012 120 mg | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 8 | 0.6710 μg/mL | Standard Deviation 0.8715 |
| Cohort 2: MEDI6012 120 mg | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 15 | 0.2418 μg/mL | Standard Deviation 0.9939 |
| Cohort 2: MEDI6012 120 mg | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 22 | 0.0824 μg/mL | Standard Deviation 1.0816 |
| Cohort 3: MEDI6012 300 mg | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 15 | 1.1188 μg/mL | Standard Deviation 0.732 |
| Cohort 3: MEDI6012 300 mg | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 8 | 0.9720 μg/mL | Standard Deviation 0.7029 |
| Placebo IV Push | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 10 | 0.0000 μg/mL | — |
| Cohort 4: MEDI6012 IV Push | Change From Baseline in Serum Concentration for Total LCAT Activity | Day 10 | 0.5503 μg/mL | Standard Deviation 0.596 |
Secondary
Maximum Observed Serum Concentration (Cmax) of MEDI6012
The maximum observed serum concentration following the first and third dose of MEDI6012 was reported.
Time frame: 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.
Population: PK population included all participants in the as-treated population who had at least one detectable LCAT serum concentration measurement. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Observed Serum Concentration (Cmax) of MEDI6012 | Dose 1 | 9.17 μg/mL | Standard Deviation 3.27 |
| Placebo | Maximum Observed Serum Concentration (Cmax) of MEDI6012 | Dose 3 | 9.63 μg/mL | Standard Deviation 3.5 |
| Cohort 1: MEDI6012 40 mg | Maximum Observed Serum Concentration (Cmax) of MEDI6012 | Dose 3 | 27.1 μg/mL | Standard Deviation 5.37 |
| Cohort 1: MEDI6012 40 mg | Maximum Observed Serum Concentration (Cmax) of MEDI6012 | Dose 1 | 27.5 μg/mL | Standard Deviation 7.78 |
| Cohort 2: MEDI6012 120 mg | Maximum Observed Serum Concentration (Cmax) of MEDI6012 | Dose 3 | 94.7 μg/mL | Standard Deviation 33.1 |
| Cohort 2: MEDI6012 120 mg | Maximum Observed Serum Concentration (Cmax) of MEDI6012 | Dose 1 | 83.7 μg/mL | Standard Deviation 27.7 |
| Cohort 3: MEDI6012 300 mg | Maximum Observed Serum Concentration (Cmax) of MEDI6012 | Dose 1 | 75.1 μg/mL | Standard Deviation 14.6 |
| Cohort 3: MEDI6012 300 mg | Maximum Observed Serum Concentration (Cmax) of MEDI6012 | Dose 3 | 28.5 μg/mL | Standard Deviation 6.89 |
Secondary
Number of Participants With Positive Anti-Drug Antibodies for MEDI6012
Participants with positive serum antibodies to MEDI6012 were reported.
Time frame: 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.
Population: Immunogenicity population included all participants in the as-treated population who had at least one serum sample for immunogenicity testing
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive at baseline | 0 Participants |
| Placebo | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive post-baseline | 0 Participants |
| Cohort 1: MEDI6012 40 mg | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive at baseline | 0 Participants |
| Cohort 1: MEDI6012 40 mg | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive post-baseline | 0 Participants |
| Cohort 2: MEDI6012 120 mg | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive at baseline | 0 Participants |
| Cohort 2: MEDI6012 120 mg | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive post-baseline | 0 Participants |
| Cohort 3: MEDI6012 300 mg | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive at baseline | 0 Participants |
| Cohort 3: MEDI6012 300 mg | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive post-baseline | 0 Participants |
| Placebo IV Push | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive at baseline | 0 Participants |
| Placebo IV Push | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive post-baseline | 0 Participants |
| Cohort 4: MEDI6012 IV Push | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive at baseline | 0 Participants |
| Cohort 4: MEDI6012 IV Push | Number of Participants With Positive Anti-Drug Antibodies for MEDI6012 | ADA positive post-baseline | 0 Participants |
Secondary
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.
Time frame: 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.
Population: PK population included all participants in the as-treated population who had at least one detectable LCAT serum concentration measurement. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Terminal Half-life (t1/2) of MEDI6012 | 2.7 Days | — |
| Cohort 1: MEDI6012 40 mg | Terminal Half-life (t1/2) of MEDI6012 | 1.79 Days | Standard Deviation 0.374 |
| Cohort 2: MEDI6012 120 mg | Terminal Half-life (t1/2) of MEDI6012 | 2.52 Days | Standard Deviation 0.702 |
| Cohort 3: MEDI6012 300 mg | Terminal Half-life (t1/2) of MEDI6012 | 2.6 Days | Standard Deviation 0.942 |
Secondary
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.
Time frame: 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.
Population: PK population included all participants in the as-treated population who had at least one detectable LCAT serum concentration measurement. The overall number of participants analyzed denotes the number of participants evaluated specific for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 | Dose 1 | 0.0417 Hours | Standard Deviation 0 |
| Placebo | Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 | Dose 3 | 14.0417 Hours | Standard Deviation 0 |
| Cohort 1: MEDI6012 40 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 | Dose 3 | 14.0417 Hours | Standard Deviation 0 |
| Cohort 1: MEDI6012 40 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 | Dose 1 | 0.0417 Hours | Standard Deviation 0 |
| Cohort 2: MEDI6012 120 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 | Dose 1 | 0.0417 Hours | Standard Deviation 0 |
| Cohort 2: MEDI6012 120 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 | Dose 3 | 14.0417 Hours | Standard Deviation 0 |
| Cohort 3: MEDI6012 300 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 | Dose 1 | 0.000696 Hours | Standard Deviation 0 |
| Cohort 3: MEDI6012 300 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 | Dose 3 | 9.00070 Hours | Standard Deviation 0 |