Safety Study of AEM-28 to Treat Refractory Hypercholesterolemia

• Sponsor: LipimetiX Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02100839
• Collaborator: (none)
• Enrollment: 52
• Location: 1
• Arms: 2
• Duration (Months): 9
• Patients Per Site Per Month: 5.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hypercholesterolemia; Hyperlipoproteinemia Type II	Drug: AEM-28; Drug: Normal Saline	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Incurred at Least One Treatment Emergent Event [Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57]

   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.

2. Number of Participants Who Incurred Mild Treatment Emergent Adverse Events [Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57]

   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.

3. Number of Participants Who Incurred Moderate Treatment Emergent Events [Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57]

   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.

Secondary Outcome Measures

1. Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change [Part A (SAD): Day 1 to Day 15; Part B (MAD): Day 1 to Day 57]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Linear Clinical Research Ltd.	Nedlands	Western Australia	Australia	6009

Sponsors and Collaborators

• LipimetiX Development, LLC

Investigators

• Principal Investigator: Janakan Krishnarajah, MBBS, FRACP, Linear Clinical Research

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: LipimetiX Development, LLC
• ClinicalTrials.gov Identifier: NCT02100839
• Other Study ID Numbers: LPMX-112
• First Posted: Apr 1, 2014
• Last Update Posted: Dec 29, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by LipimetiX Development, LLC: hypercholesterolemia; apolipoprotein E; First in Human; Apolipoprotein E (ApoE); Apolipoprotein E Mimetic (AEM)
• Additional relevant MeSH terms: Hypercholesterolemia; Hyperlipoproteinemias; Hyperlipidemias

Study Results

Participant Flow

Recruitment Details	Study conducted at Linear Clinical Research Ltd, a medical clinic in Nedlands WA Australia.

Arm/Group Title	Apolipoprotein E Mimetic (AEM)-28	Normal Saline
Arm/Group Description	Single Ascending Dose (SAD): Single IV dose for each cohort; dose range 0.032 mg/mL to 3.54 mg/mL Multiple Ascending Dose (MAD): Three (3) IV doses for each cohort, one (1) dose every two (2) weeks; dose range 1 mg/kg to 3.54 mg/kg. AEM-28: Solution for injection	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. Normal Saline: 0.9% saline for injection
Period Title: Single Ascending Dose
STARTED	24	12
COMPLETED	24	12
NOT COMPLETED	0	0
Period Title: Single Ascending Dose
STARTED	13	3
COMPLETED	9	3
NOT COMPLETED	4	0

Baseline Characteristics

Arm/Group Title	AEM-28	Normal Saline	Total
Arm/Group Description	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. AEM-28: Solution for injection	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. Normal Saline: 0.9% saline for injection	Total of all reporting groups
Overall Participants	37	15	52
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	35 94.6%	15 100%	50 96.2%
>=65 years	2 5.4%	0 0%	2 3.8%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	35.7	32	34.6
Sex: Female, Male (Count of Participants)
Female	7 18.9%	5 33.3%	12 23.1%
Male	30 81.1%	10 66.7%	40 76.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 10.8%	0 0%	4 7.7%
Not Hispanic or Latino	33 89.2%	15 100%	48 92.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	3 8.1%	3 20%	6 11.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 2.7%	1 6.7%	2 3.8%
White	31 83.8%	11 73.3%	42 80.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 5.4%	0 0%	2 3.8%
Region of Enrollment (participants) [Number]
Australia	37 100%	15 100%	52 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Incurred at Least One Treatment Emergent Event
Description	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.
Time Frame	Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AEM-28	Normal Saline
Arm/Group Description	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. AEM-28: Solution for injection	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. Normal Saline: 0.9% saline for injection
Measure Participants	37	15
Number [participants]	33 89.2%	10 66.7%

2. Primary Outcome

Title	Number of Participants Who Incurred Mild Treatment Emergent Adverse Events
Description	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.
Time Frame	Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AEM-28	Normal Saline
Arm/Group Description	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. AEM-28: Solution for injection	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. Normal Saline: 0.9% saline for injection
Measure Participants	37	15
Number [Number of Participants]	33 89.2%	10 66.7%

3. Primary Outcome

Title	Number of Participants Who Incurred Moderate Treatment Emergent Events
Description	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.
Time Frame	Part A (SAD): Day -1 to Day 15; Part B (MAD): Day 1 to Day 57

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AEM-28	Normal Saline
Arm/Group Description	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. AEM-28: Solution for injection	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. Normal Saline: 0.9% saline for injection
Measure Participants	37	15
Number [Number of Participants]	7 18.9%	0 0%

4. Secondary Outcome

Title	Very Low Density Lipoprotein Cholesterol (VLDL-C) Percent Change
Description	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.
Time Frame	Part A (SAD): Day 1 to Day 15; Part B (MAD): Day 1 to Day 57

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AEM-28	Normal Saline
Arm/Group Description	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. AEM-28: Solution for injection	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. Normal Saline: 0.9% saline for injection
Measure Participants	37	15
Part A: 3.54 mg/kg	-72.1 (15.1)	-0.33 (0.17)
Part B: 3.54 mg/kg	-79.2 (13.5)	-0.58 (0.31)
Part A: 2.0 mg/kg	-76.3 (7.25)	-0.35 (0.13)
Part B: 2.0 mg/kg	-73.3 (6.36)	-0.52 (0.15)
Part A: 1.0 mg/kg	-47.9 (19.7)	-0.23 (0.15)
Part B: 1.0 mg/kg	-51.8 (24.7)	-0.38 (0.19)

Adverse Events

Time Frame	Over 8 day study period for SAD study, and over 57 day study period for MAD study
Arm/Group Title	AEM-28		Normal Saline
Arm/Group Description	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. AEM-28: Solution for injection		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. Normal Saline: 0.9% saline for injection
All Cause Mortality
	AEM-28		Normal Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	AEM-28		Normal Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	AEM-28		Normal Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/37 (89.2%)		10/15 (66.7%)
Cardiac disorders
Palpitations	1/37 (2.7%)	1	1/15 (6.7%)	1
Gastrointestinal disorders
Nausea	1/37 (2.7%)	1	1/15 (6.7%)	1
General disorders
Administration Site Reaction	29/37 (78.4%)	46	6/15 (40%)	7
Fatigue	1/37 (2.7%)	1	2/15 (13.3%)	2
Injury, poisoning and procedural complications
Confusion	2/37 (5.4%)	2	2/15 (13.3%)	2
Infusion Related Reaction	6/37 (16.2%)	13	1/15 (6.7%)	1
Nervous system disorders
Headache	9/37 (24.3%)	12	0/15 (0%)	0
Somnolence	0/37 (0%)	0	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/37 (0%)	0	1/15 (6.7%)	1
Oropharyngeal Pain	2/37 (5.4%)	2	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Dermal Cyst	0/37 (0%)	0	1/15 (6.7%)	1
Acne	0/37 (0%)	0	1/15 (6.7%)	1
Rash Erythematous	0/37 (0%)	0	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.