Safety and Tolerability of Varying Load and Dose of ISIS 301012 in People With Elevated LDL-cholesterol Levels

Study Overview
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Brief Summary
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The aim of this study is to assess the safety and tolerability of varying dose and load regimens of ISIS 301012 in people who have elevated LDL-cholesterol levels.

Official Title
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A Phase 2, Randomized, Double Blind, Placebo-Controlled, Parallel Group Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Varying Loading and Maintenance Dosing Regimens of ISIS 301012 Administered to Hypercholesterolemic Subjects

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: ISIS 301012 or Placebo
* Drug: ISIS 301012 or Placebo
* Drug: ISIS 301012 or Placebo
* Drug: ISIS 301012 or Placebo
* Drug: ISIS 301012 or Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI >/= 25 to </= 32 kg/m^2 fasting stable LDL-cholesterol >/= 130 mg/dL (3.36 mmol/L) and triglycerides < 400 mg/dL (4.55 mmol/L) Females not of childbearing potential Exclusion Criteria: No endocrine, hematologic, renal, hepatic, metabolic, psychiatric, neurology, pulmonary or cardiovascular disease Subjects who test positive for hepatitis B, C or HIV Current diagnosis or known history of liver disease, such as acute or chronic hepatitis, liver cirrhosis, liver steatosis, or liver function abnormalities such as AST, ALT, GGT, or total bilirubin >/= 1.5 x ULN at Screening A systolic blood pressure >/= 160 mmHg or a diastolic blood pressure >/= 95 mmHg on 2 occasions during Screening Concomitant medications within 14 days of dosing, except hormone replacement therapy for post-menopausal women and acetylsalicylic acid or paracetamol dosed for fewer than five consecutive days Subject has taken any lipid-lowering drug within 30 days or five half-lives (of the lipid-lowering drug) whichever is longer, prior to Screening Alcohol or drug abuse within 2 years of Screening Donated blood (450 mL) within the 3 months prior to Screening or suffered significant blood loss equal to a blood donor portion Subject smokes > 10 cigarettes, or more than one pipe or one cigar per day

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Slow load with every other week maintenance | Drug: ISIS 301012 or Placebo<br>* 200 mg subcutaneous injection - 4 loading doses within the first 11 days followed by: 200 mg subcutaneous injection - every other week for 11 weeks<br>|
| Experimental: B<br>Slow load with every other week maintenance | Drug: ISIS 301012 or Placebo<br>* 200 mg subcutaneous injection - 4 loading doses within the first 11 days followed by: 100 mg subcutaneous injection - every other week for 11 weeks<br>|
| Experimental: C<br>No load; once weekly maintenance | Drug: ISIS 301012 or Placebo<br>* 200 mg subcutaneous injection - every week for 13 weeks<br>|
| Experimental: D<br>No load; once weekly maintenance | Drug: ISIS 301012 or Placebo<br>* 300 mg subcutaneous injection - every week for 13 weeks<br>|
| Experimental: E<br>No load; once weekly maintenance | Drug: ISIS 301012 or Placebo<br>* 400 mg subcutaneous injection - every week for 13 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent reduction in LDL-cholesterol from baseline |  | 14 days post dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent reduction in apoB-100 from baseline |  | 14 days post dosing | 
| Percent change from baseline in HDL-cholesterol, triglycerides, total cholesterol, non-HDL cholesterol, VLDL and LP(a) |  | 14 days post dosing | 
| Percent change from baseline in LDL/HDL and apoB-100/apo-A1 ratios |  | 14 days post dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LDL-cholesterol, apoB-100, apoB-48