Safety Study of AEM-28 to Treat Refractory Hypercholesterolemia

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Doses of AEM-28 in Healthy Subjects and Patients With Refractory Hypercholesterolemia

The purpose of the first part of this study is to determine the safety and tolerability of a single dose of AEM-28, an apolipoprotein E mimetic, in subjects with high total cholesterol who are otherwise healthy subjects. The pharmacokinetics and pharmacodynamics of AEM-28 will also be evaluated.

The second part of this study will be a multiple ascending dose evaluation of AEM-28 in patients with refractory hypercholesterolemia.

AEM-28 has demonstrated significant lipid lowering activity and positive effects on the artery wall. AEM-28 is being developed for the treatment of homozygous familial hypercholesterolemia.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia; Hyperlipoproteinemia Type II
• Intervention / Treatment: Drug: AEM-28; Drug: Normal Saline

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Linear Clinical Research ltd.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Single Ascending Dose (SAD) Study:

• Male or female non-smoker, ≥18 and ≤55 years of age, with BMI >18.5 and < 32.0 kg/m²
• Total cholesterol greater or equal to 5.0 mmol/L (≥194 mg/dL) at screening

Multiple Ascending Dose (MAD) Study:

• Male or female non-smoker, ≥18 and ≤75 years of age, with BMI >18.5 and < 35.0 kg/m²
• Diagnosis of refractory hypercholesterolemia with LDL cholesterol levels > 2.5 mmol/L (97 mg/mL) at screening.
• On stable lipid lowering therapy for ≥ 8 weeks
• On stable diet for ≥ 12 weeks.

Exclusion Criteria:

SAD Study:

• Any clinically significant abnormality or abnormal laboratory test results found during medical screening or positive test for hepatitis B, hepatitis C, or HIV found during medical screening.
• History of allergic reactions to diphenhydramine, ranitidine, methylprednisone or other related drugs, or history of significant allergic or hypersensitivity reaction (e.g. angioedema) to any substance.

MAD Study:

• Significant health problems within 6 months prior to screening, which in the opinion of the Medical Sub-Investigator would prevent the subject from participating in the study, including but not limited to: unstable coronary heart disease; transient ischemic attack; stroke; revascularization procedure; uncontrolled hyperthyroidism; coagulation disorder; peptic ulcers or GI bleeding; significant disease of the central nervous system; liver or renal disease.
• History of allergic reactions to diphenhydramine, ranitidine, methylprednisone or other related drugs, or history of significant allergic or hypersensitivity reaction (e.g. angioedema) to any substance.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AEM-28; Single Ascending Dose: Single IV dose for each cohort; dose range 0.032 mg/mL to 3.54 mg/mL Multiple Ascending Dose: Three (3) IV doses for each cohort, one (1) dose every two (2) weeks; dose range 1 mg/kg to 3.54 mg/kg.	Drug: AEM-28; Solution for injection; Other Names: apolipoprotein E mimetic
Placebo Comparator: Normal Saline; Single Ascending Dose: Single IV dose for each cohort. Multiple Ascending Dose: Three (3) IV doses for each cohort, one (1) dose every two (2) weeks.	Drug: Normal Saline; 0.9% saline for injection; Other Names: 0.9% NaCl; Sterile Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Incurred at Least One Treatment Emergent Event	Safety and tolerability to AEM-28 were evaluated through the assessment of adverse events (i.e., seriousness, severity, relationship to the study medication, outcome, duration, and management), vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight (Part B only). Treatment-emergent adverse events were tabulated by treatment. Changes from baseline values in vital signs, ECG, clinical laboratory parameters, physical examination, and body weight (Part B only) were evaluated. Safety and tolerability data were reported using descriptive statistics.	Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57
Number of Participants Who Incurred Mild Treatment Emergent Adverse Events	Safety and tolerability to AEM-28 were evaluated through the assessment of adverse events (i.e., seriousness, severity, relationship to the study medication, outcome, duration, and management), vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight (Part B only). Treatment-emergent adverse events were tabulated by treatment. Changes from baseline values in vital signs, ECG, clinical laboratory parameters, physical examination, and body weight (Part B only) were evaluated. Safety and tolerability data were reported using descriptive statistics.	Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57
Number of Participants Who Incurred Moderate Treatment Emergent Events	Safety and tolerability to AEM-28 were evaluated through the assessment of adverse events (i.e., seriousness, severity, relationship to the study medication, outcome, duration, and management), vital signs, 12-lead ECG, telemetry, clinical laboratory parameters, physical examination, and local response to each injection, and body weight (Part B only). Treatment-emergent adverse events were tabulated by treatment. Changes from baseline values in vital signs, ECG, clinical laboratory parameters, physical examination, and body weight (Part B only) were evaluated. Safety and tolerability data were reported using descriptive statistics.	Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change	Maximum observed percentage change in VLDL-C level relative to baseline for all time points measured in Parts A or Part B with highest dose, i.e. 3.54 mg/kg.	Part A (SAD): Day 1 to Day 15; Part B (MAD): Day 1 to Day 57

Collaborators and Investigators

• Sponsor: LipimetiX Development, LLC
• Investigators: Principal Investigator: Janakan Krishnarajah, MBBS, FRACP, Linear Clinical Research

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: March 27, 2014
• First Submitted That Met QC Criteria: March 27, 2014
• First Posted (Estimate): April 1, 2014

Study Record Updates

• Last Update Posted (Estimate): December 29, 2015
• Last Update Submitted That Met QC Criteria: November 23, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: First in Human; hypercholesterolemia; apolipoprotein E; Apolipoprotein E (ApoE); Apolipoprotein E Mimetic (AEM)
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Hypercholesterolemia; Hyperlipidemias; Hyperlipoproteinemias
• Other Study ID Numbers: LPMX-112

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No