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

Study identifier:D5780C00005

ClinicalTrials.gov identifier:NCT03004638

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

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

Medical condition

Atherosclerosis

Phase

Phase 2

Healthy volunteers

Study drug

MEDI6012 40 mg, Placebo, MEDI6012 120 mg, MEDI6012 300 mg, Placebo IV Push, MEDI6012 IV Push

Sex

All

Actual Enrollment

Study type

Interventional

Age

60 Years - 80 Years

Date

Study Start Date: 23 Jan 2017

Primary Completion Date: 02 Nov 2017

Study Completion Date: 02 Nov 2017

Study design

Allocation: Randomized
Endpoint Classification: Safety/Efficacy
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Nov 2018 by MedImmune, LLC

Collaborators

Inclusion and exclusion criteria

Location

Research Site

Jacksonville, FL, United States, 32216

Location

Research Site

Anniston, AL, United States, 36207

Location

Research Site

Cincinnati, OH, United States, 45246

Location

Research Site

Port Orange, FL, United States, 32127

Arms	Assigned Interventions
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. Other Name: None
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. Other Name: None
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. Other Name: None
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. Other Name: None
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. Other Name: None
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. Other Name: None

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The study was conducted at 4 sites in the USA between 23Jan2017 and 02Nov2017.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Participant Flow: Overall Study

	Placebo	MEDI6012 40 mg	MEDI6012 120 mg	MEDI6012 300 mg	Placebo IV Push	MEDI6012 IV Push
STARTED	6	6	6	6	1	7
COMPLETED	6	6	6	6	1	7
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

As-treated population included all participants who received at least one dose of study drug.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Baseline Measures

	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
Number of Participants [units: Participants]	6	6	6	6	1	7	32
Age Continuous [units: Years] Mean ± Standard Deviation	67.8 ± 4.8	66.7 ± 3.3	68.8 ± 2.8	66.2 ± 2.6	65.0 ± NA	71.4 ± 4.2	68.2 ± 3.9
Sex: Female, Male [units: Participants]
Male	4	4	5	3	1	6	23
Female	2	2	1	3	0	1	9
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	1	0	0	1	1	0	3
White	5	6	6	5	0	7	29
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0
Race/Ethnicity, Customized [units: Participants]
Hispanic or Latino	1	0	0	0	0	0	1
Not Hispanic or Latino	5	6	6	6	1	7	31

Outcome Measures

1. Primary Outcome Measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [ 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) ]

Measure Type	Primary
Measure Name	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Measure Description	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)
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
As-treated population included all participants who received at least one dose of study drug.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	6	1	7
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [units: Participants]
TEAEs	3	3	3	4	0	3
TESAEs	0	0	1	0	0	0

No statistical analysis provided for Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

2. Primary Outcome Measure: Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs [ 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) ]

Measure Type	Primary
Measure Name	Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs
Measure Description	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)
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
As-treated population included all participants who received at least one dose of study drug.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	6	1	7
Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs [units: Participants]	0	1	0	0	0	0

No statistical analysis provided for Number of Participants With Abnormal Clinical Laboratory Evaluations Reported as TEAEs

3. Primary Outcome Measure: Number of Participants With Abnormal Vital Signs Reported as TEAEs [ 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) ]

Measure Type	Primary
Measure Name	Number of Participants With Abnormal Vital Signs Reported as TEAEs
Measure Description	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)
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
As-treated population included all participants who received at least one dose of study drug.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	6	1	7
Number of Participants With Abnormal Vital Signs Reported as TEAEs [units: Participants]
Hypertension	1	1	0	0	0	0
Hypotension	0	0	1	0	0	0

No statistical analysis provided for Number of Participants With Abnormal Vital Signs Reported as TEAEs

4. Primary Outcome Measure: Number of Participants With Abnormal Electrocardiogram Reported as TEAEs [ 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) ]

Measure Type	Primary
Measure Name	Number of Participants With Abnormal Electrocardiogram Reported as TEAEs
Measure Description	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)
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
As-treated population included all participants who received at least one dose of study drug.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	6	1	7
Number of Participants With Abnormal Electrocardiogram Reported as TEAEs [units: Participants]	0	0	1	0	0	0

No statistical analysis provided for Number of Participants With Abnormal Electrocardiogram Reported as TEAEs

5. Primary Outcome Measure: 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) [ 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. ]

Measure Type	Primary
Measure Name	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)
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	5	1	7
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) [units: mg*h/dL] Mean (Standard Deviation)	-6.72 (467.59)	1355.64 (576.94)	2874.86 (1232.21)	6465.05 (2074.77)	266.68 (NA)^[1]	1803.12 (1684.32)

No statistical analysis provided for 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. Primary Outcome Measure: 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) [ 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. ]

Measure Type	Primary
Measure Name	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)
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	5	1	7
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) [units: mg*h/dL] Mean (Standard Deviation)	-23.75 (422.76)	1161.47 (506.67)	2580.51 (1076.11)	5710.09 (1622.36)	273.03 (NA)^[1]	1597.12 (1531.40)

No statistical analysis provided for 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)

7. Primary Outcome Measure: Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for 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. ]

Measure Type	Primary
Measure Name	Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Cholesterol Ester
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	5	1	7
Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Cholesterol Ester [units: mg*h/dL] Mean (Standard Deviation)	373.04 (1060.76)	2267.37 (1126.43)	4047.38 (1314.67)	9004.31 (2086.47)	371.75 (NA)^[1]	2649.56 (3039.83)

No statistical analysis provided for Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Cholesterol Ester

8. Secondary Outcome Measure: Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for 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. ]

Measure Type	Secondary
Measure Name	Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein A1
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	5	1	7
Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein A1 [units: mg*h/dL] Mean (Standard Deviation)	821.33 (1465.70)	2440.48 (1021.34)	3740.59 (1508.93)	5302.87 (1739.86)	-20.42 (NA)^[1]	2399.42 (2611.21)

No statistical analysis provided for Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein A1

9. Secondary Outcome Measure: 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). [ 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. ]

Measure Type	Secondary
Measure Name	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).
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	5	1	7
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). [units: mg*h/dL] Mean (Standard Deviation)	-55.96 (886.81)	1125.45 (872.40)	1043.39 (700.00)	3056.76 (1765.33)	-78.79 (NA)^[1]	1364.12 (2375.93)

No statistical analysis provided for 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).

10. Secondary Outcome Measure: Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for 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. ]

Measure Type	Secondary
Measure Name	Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein B
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	5	1	7
Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein B [units: mg*h/dL] Mean (Standard Deviation)	-82.95 (667.65)	-40.06 (477.21)	145.42 (283.62)	-374.38 (588.54)	-239.17 (NA)^[1]	73.01 (864.30)

No statistical analysis provided for Baseline-adjusted Area Under the Curve From Time 0 to 96 Hour (hr) (AUC [0-96 hr]) Post Dose 3 for Apolipoprotein B

11. Secondary Outcome Measure: Change From Baseline in Serum Concentration for MEDI6012 Mass [ 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. ]

Measure Type	Secondary
Measure Name	Change From Baseline in Serum Concentration for MEDI6012 Mass
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	6	1	7
Change From Baseline in Serum Concentration for MEDI6012 Mass [units: μg/mL] Mean (Standard Deviation)
Day 3					0.0000 (NA)^[1]	16.2684 (4.5094)
Day 8	0.0000 (0.0000)	0.0000 (0.0000)	0.0000 (0.0000)	3.8646 (2.0753)
Day 10					0.0000 (NA)^[1]	2.4407 (2.1437)
Day 15	0.0000 (0.0000)	0.0000 (0.0000)	0.0000 (0.0000)	5.4320 (2.6999)
Day 17					0.0000 (NA)^[1]	0.3980 (0.8900)
Day 22	0.0000 (0.0000)	0.0000 (0.0000)	0.5478 (0.8613)	7.1622 (2.7936)

No statistical analysis provided for Change From Baseline in Serum Concentration for MEDI6012 Mass

12. Secondary Outcome Measure: Change From Baseline in Serum Concentration for Total LCAT Activity [ 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. ]

Measure Type	Secondary
Measure Name	Change From Baseline in Serum Concentration for Total LCAT Activity
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	6	1	7
Change From Baseline in Serum Concentration for Total LCAT Activity [units: μg/mL] Mean (Standard Deviation)
Day 8	0.2046 (0.3035)	0.0282 (0.9432)	0.6710 (0.8715)	0.9720 (0.7029)
Day 10					0.0000 (NA)^[1]	0.5503 (0.5960)
Day 15	-0.1467 (0.8494)	0.1700 (0.7582)	0.2418 (0.9939)	1.1188 (0.7320)
Day 22	0.4983 (0.3355)	-0.1617 (0.7031)	0.0824 (1.0816)

No statistical analysis provided for Change From Baseline in Serum Concentration for Total LCAT Activity

13. Secondary Outcome Measure: Maximum Observed Serum Concentration (Cmax) of MEDI6012 [ 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. ]

Measure Type	Secondary
Measure Name	Maximum Observed Serum Concentration (Cmax) of MEDI6012
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.

Measured Values

	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	5	5
Maximum Observed Serum Concentration (Cmax) of MEDI6012 [units: μg/mL] Mean (Standard Deviation)
Dose 1	9.17 (3.27)	27.5 (7.78)	83.7 (27.7)	75.1 (14.6)
Dose 3	9.63 (3.5)	27.1 (5.37)	94.7 (33.1)	28.5 (6.89)

No statistical analysis provided for Maximum Observed Serum Concentration (Cmax) of MEDI6012

14. Secondary Outcome Measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 [ 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. ]

Measure Type	Secondary
Measure Name	Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.

Measured Values

	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	5
Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012 [units: Hours] Mean (Standard Deviation)
Dose 1	0.0417 (0.00)	0.0417 (0.00)	0.0417 (0.00)	0.000696 (0.00)
Dose 3	14.0417 (0.00)	14.0417 (0.00)	14.0417 (0.00)	9.00070 (0.00)

No statistical analysis provided for Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI6012

15. Secondary Outcome Measure: Accumulation Ratio (Rac) of MEDI6012 [ 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. ]

Measure Type	Secondary
Measure Name	Accumulation Ratio (Rac) of MEDI6012
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.

Measured Values

	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	7
Accumulation Ratio (Rac) of MEDI6012 [units: Ratio] Mean (Standard Deviation)
ARCmax	1.09 (0.214)	1.01 (0.112)	1.02 (0.177)
ARAUC	0.897 (NA)^[1]	1.16 (0.0982)	1.21 (0.169)

No statistical analysis provided for Accumulation Ratio (Rac) of MEDI6012

16. Secondary Outcome Measure: Terminal Half-life (t1/2) 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. ]

Measure Type	Secondary
Measure Name	Terminal Half-life (t1/2) of MEDI6012
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.

Measured Values

	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	1	5	5	4
Terminal Half-life (t1/2) of MEDI6012 [units: Days] Mean (Standard Deviation)	2.7 (NA)^[1]	1.79 (0.374)	2.52 (0.702)	2.6 (0.942)

No statistical analysis provided for Terminal Half-life (t1/2) of MEDI6012

17. Secondary Outcome Measure: Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012 [ 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. ]

Measure Type	Secondary
Measure Name	Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.

Measured Values

	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	5
Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012 [units: µg*day/mL] Mean (Standard Deviation)
Dose 1	10.9 (10.1)	35.2 (17.8)	152 (50.5)
Dose 3	8.98 (5.61)	48.3 (23.6)	205 (63.7)	38.6 (21.9)

No statistical analysis provided for Area Under the Concentration Time Curve to Last Measurable Time Point (AUClast) of MEDI6012

18. Secondary Outcome Measure: Number of Participants with Positive Anti-Drug Antibodies for MEDI6012 [ 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. ]

Measure Type	Secondary
Measure Name	Number of Participants with Positive Anti-Drug Antibodies for MEDI6012
Measure Description	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.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Immunogenicity population included all participants in the as-treated population who had at least one serum sample for immunogenicity testing

Reporting Groups

	Description
Placebo	Participants received 3 doses of placebo matching with MEDI6012 intravenously (IV) on Days 1, 8, and 15.
Cohort 1: MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
Cohort 2: MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
Cohort 3: MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Measured Values

	Placebo	Cohort 1: MEDI6012 40 mg	Cohort 2: MEDI6012 120 mg	Cohort 3: MEDI6012 300 mg	Placebo IV Push	Cohort 4: MEDI6012 IV Push
Number of Participants Analyzed [units:participants]	6	6	6	6	1	7
Number of Participants with Positive Anti-Drug Antibodies for MEDI6012 [units: Participants]
ADA positive at baseline	0	0	0	0	0	0
ADA positive post-baseline	0	0	0	0	0	0

No statistical analysis provided for Number of Participants with Positive Anti-Drug Antibodies for MEDI6012

Serious Adverse Events

Time Frame	Adverse events were collected from baseline (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).
Additional Description	No text entered.

Reporting Groups

	Description
Placebo	Description (Arm-group)
MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Serious Adverse Events

Placebo

MEDI6012 40 mg

MEDI6012 120 mg

MEDI6012 300 mg

Placebo IV Push

MEDI6012 IV Push

Total, serious adverse events

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

0/7 (0.00%)

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

0/7 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 20.0

Other Adverse Events

Time Frame	Adverse events were collected from baseline (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).
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Placebo	Description (Arm-group)
MEDI6012 40 mg	Participants received 3 doses of 40 milligram (mg) MEDI6012 IV on Days 1, 8, and 15.
MEDI6012 120 mg	Participants received 3 doses of 120 mg MEDI6012 IV on Days 1, 8, and 15.
MEDI6012 300 mg	Participants received 3 doses of 300 mg MEDI6012 IV on Days 1, 8, and 15.
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.
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.

Other Adverse Events

Placebo

MEDI6012 40 mg

MEDI6012 120 mg

MEDI6012 300 mg

Placebo IV Push

MEDI6012 IV Push

Total, other (not including serious) adverse events

# participants affected / at risk

3/6 (50.00%)

4/6 (66.67%)

0/1 (0.00%)

3/7 (42.86%)

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

2/6 (33.33%)

0/1 (0.00%)

0/7 (0.00%)

# events

General disorders and administration site conditions

Chest discomfort¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

0/7 (0.00%)

# events

General disorders and administration site conditions

Infusion site erythema¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/1 (0.00%)

0/7 (0.00%)

# events

General disorders and administration site conditions

Infusion site pain¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/1 (0.00%)

0/7 (0.00%)

# events

General disorders and administration site conditions

Infusion site induration¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/1 (0.00%)

0/7 (0.00%)

# events

General disorders and administration site conditions

Infusion site reaction¹,^†

# participants affected / at risk

0/6 (0.00%)

0/1 (0.00%)

1/7 (14.29%)

# events

General disorders and administration site conditions

Non-cardiac chest pain¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

1/7 (14.29%)

# events

Infections and infestations

Epididymitis¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

0/7 (0.00%)

# events

Infections and infestations

Viral upper respiratory tract infection¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

0/7 (0.00%)

# events

Injury, poisoning and procedural complications

Laceration¹,^†

# participants affected / at risk

0/6 (0.00%)

0/1 (0.00%)

1/7 (14.29%)

# events

Injury, poisoning and procedural complications

Upper limb fracture¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/1 (0.00%)

0/7 (0.00%)

# events

Metabolism and nutrition disorders

Hypoglycaemia¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

0/7 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Groin pain¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/1 (0.00%)

0/7 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Basal cell carcinoma¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

0/7 (0.00%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/1 (0.00%)

0/7 (0.00%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/1 (0.00%)

0/7 (0.00%)

# events

Nervous system disorders

Hypoaesthesia¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/1 (0.00%)

0/7 (0.00%)

# events

Psychiatric disorders

Anxiety¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

0/7 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/1 (0.00%)

1/7 (14.29%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

0/7 (0.00%)

# events

Vascular disorders

Hypotension¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/1 (0.00%)

0/7 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 20.0

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: MedImmune has 60 days to review results communications prior to public release and may delete information that compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Richard George
Organization:	MedImmune LLC
Phone	+1-301-398-5681
E-mail:	[email protected]

Documents available

D5780C00005-CSP-amendment-1_REDACTED_16Jul2017_PDF-A
Download
5780C00005 MEDI6012 Statistical Analysis Plan_21Jul2017_Version2_Redacted_PDF-A.pdf
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

D5780C00005-CSP-amendment-1_REDACTED_16Jul2017_PDF-A

5780C00005 MEDI6012 Statistical Analysis Plan_21Jul2017_Version2_Redacted_PDF-A.pdf

Trial Results Summaries