Dose-escalating Safety Study in Subjects on Stable Statin Therapy

Study Overview
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Brief Summary
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The aim of this study is to assess the safety of varying doses of ISIS 301012 in subjects on Stable statin therapy.

Official Title
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A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Assess the Safety and Pharmacodynamics of ISIS 301012 in Hypercholesterolemic Subjects on Stable Statin Therapy

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
* Drug: ISIS 301012 or Placebo
* Drug: ISIS 301012 or Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: On a stable dose of >/= 40 mg Simvastatin or atorvastatin daily for >/= 3 months prior to baseline and expected to remain on this dose for the remainder of the study LDL-cholesterol between 2.60 and 5.70 mmol/L (100 and 220 mg/dL), inclusive at screening Females not of childbearing potential. Exclusion Criteria: History of CHD or CHD-equivalent (such as diabetes mellitus, or another clinical form of atherosclerotic disease, e.g., peripheral arterial disease, abdominal aortic aneurysm, or symptomatic carotid artery disease) Fasting triglyceride >2.26 mmol/L (200 mg/dL) at screening Any uncontrolled medical/surgical/psychiatric condition, including conditions that may predispose to secondary hypercholesterolemia Current diagnosis or known history of complement deficiency or abnormality A positive hepatitis B surface antigen or hepatitis C antibody, or a known positive HIV status Current diagnosis or known history of liver disease, or has an ALT >ULN at screening Known history of fibromyalgia, myopathy, myositis, rhabdomyolysis, any unexplained muscle pain, or has a CPK >ULN at screening Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin that has been adequately treated The advisability of a subject taking any prescription medication (apart from simvastatin or atorvastatin) within 6 weeks prior to screening should be discussed with the Isis Medical Monitor Subject unwilling to discontinue taking alternative/herbal medication for the duration of the study History of drug abuse within 2 years of screening Subject unwilling to limit alcohol consumption for the duration of the study: male subjects to a maximum of 3 drinks (30 g) per day, and <12 drinks (120 g) per week; female subjects to a maximum of 2 drinks (20 g) per day, and <8 drinks (80 g) per week Known allergy or hypersensitivity to simvastatin Undergoing or has undergone treatment with another investigational drug, biologic agent, or device within 3 months, or 3 half lives, prior to screening, whichever is longer

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: Cohort A<br>Loading doses followed by weekly maintenance doses | Drug: ISIS 301012 or Placebo<br>* 30 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29<br>|
| Experimental: Cohort B<br>Loading doses followed by weekly maintenance doses | Drug: ISIS 301012 or Placebo<br>* 100 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29<br>|
| Experimental: Cohort C<br>Loading doses followed by weekly maintenance doses | Drug: ISIS 301012 or Placebo<br>* 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29<br>|
| Experimental: Cohort D<br>Loading doses followed by weekly maintenance doses | Drug: ISIS 301012 or Placebo<br>* 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29<br>|
| Experimental: Cohort E<br>Loading doses followed by weekly maintenance doses | Drug: ISIS 301012 or Placebo<br>* 400 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29<br>|
| Experimental: Cohort F<br>Loading doses followed by extended weekly maintenance doses | Drug: ISIS 301012 or Placebo<br>* 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85<br>|
| Experimental: Cohort G<br>Loading doses followed by extended weekly maintenance doses | Drug: ISIS 301012 or Placebo<br>* 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85<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 |  | From baseline measurement | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent reduction in apoB-100 |  | From baseline measurement | 
| Percent change in HDL-cholesterol, triglycerides, total cholesterol, non-HDL cholesterol, VLDL plus LDL-cholesterol and LDL-cholesterol particle size and concentration |  | From baseline measurement | 
| Percent change from baseline in LDL/HDL and apoB-100/apo-A1 ratios |  | From baseline measurement | 
| AEs, SAEs, physical examination data, vital signs, and laboratory analyzes |  | Duration of study | 

 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