Clinical trial NCT01090661: A Study to Evaluate the Effect of Mipomersen on Cardiac Repolarization Conducted in Healthy Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: antisense
ApoB (Apolipoprotein B)
LDL (low density lipoprotein)
thorough QT
Lead sponsor: Kastle Therapeutics, LLC
Sponsor class: INDUSTRY
Collaborators: name: Ionis Pharmaceuticals, Inc.
First posted: 2010-03-22
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: change from baseline in QTcF (corrected Frederica's CT interval)
timeFrame: ECG monitoring up to 24 hours post dose
Secondary outcomes:
measure: ECG intervals (QTcB (corrected Bazett's QT interval), HR (heart rate, PR, QRS, and QT)
timeFrame: ECG monitoring up to 24 hours post dose
measure: change in ECG morphological patterns
timeFrame: ECG monitoring up to 24 hours post dose
measure: Correlation between delta delta QTc interval and plasma mipomersen concentrations
timeFrame: ECG monitoring up to 24 hours post dose
measure: Incidence of treatment-emergent Adverse Events
timeFrame: Assessed at each visit
measure: mipomersen plasma pharmacokinetic (PK) parameters: Area Under the Curve (AUC 0-22.5h), Maximum Concentration (Cmax), Time to Maximum Concentration (Tmax)
timeFrame: Serial PK sampling up to 24 hours post dose
Other outcomes:
Locations:
city: Austin
country: United States
facility: PPD Development, LP
state: Texas
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References: