Dose-escalating Safety Study in Subjects on Stable Statin Therapy

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

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

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
  • Leiden, Netherlands, 2311 GZ
  • Rotterdam, Netherlands, 3021 HC
  • Utrecht, Netherlands, 3584 CX
• United States
  • Maine
    • Auburn, Maine, United States, 04210

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A; Loading doses followed by weekly maintenance doses	Drug: ISIS 301012 or Placebo; 30 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 100 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 400 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85
Experimental: Cohort B; Loading doses followed by weekly maintenance doses	Drug: ISIS 301012 or Placebo; 30 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 100 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 400 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85
Experimental: Cohort C; Loading doses followed by weekly maintenance doses	Drug: ISIS 301012 or Placebo; 30 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 100 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 400 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85
Experimental: Cohort D; Loading doses followed by weekly maintenance doses	Drug: ISIS 301012 or Placebo; 30 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 100 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 400 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85
Experimental: Cohort E; Loading doses followed by weekly maintenance doses	Drug: ISIS 301012 or Placebo; 30 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 100 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 400 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85
Experimental: Cohort F; Loading doses followed by extended weekly maintenance doses	Drug: ISIS 301012 or Placebo; 30 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 100 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 400 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85
Experimental: Cohort G; Loading doses followed by extended weekly maintenance doses	Drug: ISIS 301012 or Placebo; 30 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 100 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 400 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, and 29; Drug: ISIS 301012 or Placebo; 200 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85; Drug: ISIS 301012 or Placebo; 300 mg subcutaneous injection on days 1, 8, 10, 12, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent reduction in LDL-cholesterol from baseline	From baseline measurement

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Kastle Therapeutics, LLC
• Collaborators: Ionis Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Akdim F, Stroes ES, Sijbrands EJ, Tribble DL, Trip MD, Jukema JW, Flaim JD, Su J, Yu R, Baker BF, Wedel MK, Kastelein JJ. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol. 2010 Apr 13;55(15):1611-8. doi: 10.1016/j.jacc.2009.11.069.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): June 1, 2007
• Study Completion (Actual): December 1, 2007

Study Registration Dates

• First Submitted: October 3, 2005
• First Submitted That Met QC Criteria: October 3, 2005
• First Posted (Estimate): October 4, 2005

Study Record Updates

• Last Update Posted (Estimate): August 3, 2016
• Last Update Submitted That Met QC Criteria: August 1, 2016
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: LDL-cholesterol; apoB-100; apoB-48
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Mipomersen
• Other Study ID Numbers: 301012CS4; EudraCT No.: 2005-002119-26