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

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

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.

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

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, D-14050

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:

• 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Akdim F, Tribble DL, Flaim JD, Yu R, Su J, Geary RS, Baker BF, Fuhr R, Wedel MK, Kastelein JJ. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. Eur Heart J. 2011 Nov;32(21):2650-9. doi: 10.1093/eurheartj/ehr148. Epub 2011 May 18.

Study record dates

Study Major Dates

• Study Start: August 1, 2005
• Primary Completion (Actual): March 1, 2007
• Study Completion (Actual): August 1, 2007

Study Registration Dates

• First Submitted: September 19, 2005
• First Submitted That Met QC Criteria: September 19, 2005
• First Posted (Estimate): September 22, 2005

Study Record Updates

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

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: 301012CS3; EudraCT No.: 2004-003934-32