A Study to Evaluate the Effect of Mipomersen on Cardiac Repolarization Conducted in Healthy Subjects

A Randomized Double-Blinded Crossover Trial to Define the ECG Effects of Mipomersen (ISIS 301012) Using a Therapeutic and Supratherapeutic Dose Compared to Placebo and Moxifloxacin (a Positive Control) in Healthy Men and Women: A Thorough ECG Trial

To assess the electrocardiogram (ECG) effects of mipomersen administered as a 200-mg subcutaneous (SC) therapeutic and a 200-mg intravenous (IV; [2-hour infusion]) supra-therapeutic dose relative to placebo in healthy adult male and female subjects; and to evaluate the safety and pharmacokinetics (PK) of mipomersen when administered as a single therapeutic (200 mg) SC and a single, supra-therapeutic (200 mg) IV dose.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: mipomersen sodium; Drug: mipomersen sodium; Drug: placebo; Drug: placebo; Drug: moxifloxacin hydrochloride (Avelox®)

Detailed Description

This will be a randomized, double-blind, single-site, crossover study in healthy male and female subjects to determine if mipomersen administered as a single therapeutic (200 mg) SC and a single supra-therapeutic (200 mg) IV dose delays cardiac repolarization as determined by the measurement of QT/corrected QT (QTc) interval. A total of 60 healthy male and female subjects will be enrolled in this 4-way crossover study, randomly assigned to 1 of 8 treatment sequences, and cross over into 4 treatment periods where each subject will receive both a single SC injection and a single IV infusion during each period.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States
      • PPD Development, LP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent provided before any study-related procedures are performed.
• Body mass index (BMI) of 19 to 32 kg/m2 inclusive.
• Subjects can not have consumed nicotine or nicotine-containing products for at least 6 months before Screening.
• Subjects are nonpregnant and nonlactating, surgically sterile, postmenopausal, abstinent, or subject or partner is willing to use a reliable method of contraception during the study and 5 months after the last dose of investigational product.

Exclusion Criteria:

• History of risk factors for Torsades de Pointes, known Long QT Syndrome, heart failure, myocardial infarction, angina, or clinically significant abnormal laboratory assessments or family history of Long QT or Brugada Syndrome.
• Abnormal screening ECG that is interpreted by the Investigator to be clinically significant.
• Use of concomitant medications (prescribed or over-the-counter), without the approval of the Investigator and Sponsor, within 7 days before the first dose of investigational product.
• Clinically significant abnormal findings on the physical examination, ECG, blood pressure, heart rate, medical history, or clinical laboratory results at Screening or before dosing.
• History of clinically significant allergies or hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or neurological disease.
• Positive test for HIV antibody, hepatitis C antibody, or hepatitis B surface antigen.
• Positive test for drugs of abuse, alcohol, or cotinine at Screening or before dosing or history of drug or alcohol abuse or dependence within 1 year before Screening.
• History of cancer, with the exception of basal cell carcinoma.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: mipomersen IV (supra-therapeutic dose); 200 mg of mipomersen IV / placebo SC	Drug: mipomersen sodium; 200 mg of mipomersen intravenous (IV) (single dose); Other Names: ISIS 301012; Drug: mipomersen sodium; 200 mg of mipomersen subcutaneous (SC) (single dose); Other Names: ISIS 301012; Drug: placebo; placebo intravenous (IV) single dose; Drug: placebo; placebo subcutaneous (SC) single dose
Experimental: mipomersen SC (therapeutic dose); 200 mg of mipomersen SC / placebo IV	Drug: mipomersen sodium; 200 mg of mipomersen intravenous (IV) (single dose); Other Names: ISIS 301012; Drug: mipomersen sodium; 200 mg of mipomersen subcutaneous (SC) (single dose); Other Names: ISIS 301012; Drug: placebo; placebo intravenous (IV) single dose; Drug: placebo; placebo subcutaneous (SC) single dose
Active Comparator: moxifloxacin IV; 400 mg of moxifloxacin IV / placebo SC	Drug: placebo; placebo intravenous (IV) single dose; Drug: placebo; placebo subcutaneous (SC) single dose; Drug: moxifloxacin hydrochloride (Avelox®); 400 mg of moxifloxacin intravenous (IV) single dose
Placebo Comparator: placebo; Placebo IV / placebo SC	Drug: placebo; placebo intravenous (IV) single dose; Drug: placebo; placebo subcutaneous (SC) single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
change from baseline in QTcF (corrected Frederica's CT interval)	ECG monitoring up to 24 hours post dose

Secondary Outcome Measures

Outcome Measure	Time Frame
ECG intervals (QTcB (corrected Bazett's QT interval), HR (heart rate, PR, QRS, and QT)	ECG monitoring up to 24 hours post dose
change in ECG morphological patterns	ECG monitoring up to 24 hours post dose
Correlation between delta delta QTc interval and plasma mipomersen concentrations	ECG monitoring up to 24 hours post dose
Incidence of treatment-emergent Adverse Events	Assessed at each visit
mipomersen plasma pharmacokinetic (PK) parameters: Area Under the Curve (AUC 0-22.5h), Maximum Concentration (Cmax), Time to Maximum Concentration (Tmax)	Serial PK sampling up to 24 hours post dose

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: March 18, 2010
• First Submitted That Met QC Criteria: March 19, 2010
• First Posted (Estimate): March 22, 2010

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: antisense; ApoB (Apolipoprotein B); LDL (low density lipoprotein); thorough QT
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptive Agents, Female; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination; Mipomersen
• Other Study ID Numbers: MIPO2800209