A Study to Determine the Effects of Multiple Doses of Mipomersen (200 mg SC) on the Pharmacodynamics and Pharmacokinetics of Single-dose Warfarin

• ClinicalTrials.gov Identifier: NCT01133366
• Recruitment Status: Completed
• First Posted: May 28, 2010
• Last Update Posted: August 3, 2016
• Sponsor: Kastle Therapeutics, LLC
• Collaborator: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Kastle Therapeutics, LLC

Tracking Information

• First Submitted Date: May 27, 2010
• First Posted Date: May 28, 2010
• Last Update Posted Date: August 3, 2016
• Study Start Date: May 2010
• Actual Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 28, 2010)

• Area under the effect curve (AUC), for INR (international normalized ratio), PT (prothrombin time), and aPTT (activated partial thromboplastin time) [ Time Frame: Serial sampling up to 144 hours post dose ]
• Maximal Value (MAX) for INR, PT and aPTT [ Time Frame: Serial sampling up to 144 hours post dose ]
• Time of maximal effect (Tmax) for INR, PT, and aPTT [ Time Frame: Serial sampling up to 144 hours post dose ]

Original Primary Outcome Measures (submitted: May 27, 2010)

• Area under the effect curve (AUC), for INR (international normalized ratio), PT (prothrombin time), and aPTT (activated partical thromboplastin time) [ Time Frame: Serial sampling up to 144 hours post dose ]
• Maximal Value (MAX) for INR, PT and aPTT [ Time Frame: Serial sampling up to 144 hours post dose ]
• Time of maximal effect (Tmax) for INR, PT, and aPTT [ Time Frame: Serial sampling up to 144 hours post dose ]

• Change History: Complete list of historical versions of study NCT01133366 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: July 16, 2010)

• Warfarin Plasma Pharmacokinetic parameters (AUC 0-t, AUC 0-inf, Maximum Concentration (Cmax)) [ Time Frame: Serial PK sampling up to 144 hours post dose ]
• Mipomersen Plasma Pharmacokinetic parameters (AUC0-t, AUC0-inf, Cmax) [ Time Frame: Serial PK sampling up to 24 hours post dose ]
• Incidence of treatment-emergent Adverse Events [ Time Frame: Through Day 78 ]

Original Secondary Outcome Measures (submitted: May 27, 2010)

• Warfarin Plasma Pharmacokinetic parameters (AUC 0-t, AUC 0-inf, Cmax) [ Time Frame: Serial PK sampling up to 144 hours post dose ]
• Mipomersen Plasma Pharmacokinetic parameters (AUC0-t, AUC0-inf, Cmax) [ Time Frame: Serial PK sampling up to 24 hours post dose ]
• Incidence of treatment-emergent Adverse Events [ Time Frame: Through Day 78 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Determine the Effects of Multiple Doses of Mipomersen (200 mg SC) on the Pharmacodynamics and Pharmacokinetics of Single-dose Warfarin
• Official Title: A Drug-Drug Interaction Study to Assess the Effects of Multiple Doses of Mipomersen (200 mg SC) on Single-Dose Warfarin (25 mg) Pharmacodynamics and Pharmacokinetics in Healthy Adult Subjects
• Brief Summary: The purpose of this study is to assess how blood clotting and thinning time is effected when a single dose of warfarin is given alone and when a single dose of warfarin is given with mipomersen; to assess the blood levels of a single dose of warfarin, a single dose of mipomersen, and a single dose of warfarin when given with mipomersen; and to assess the safety of mipomersen when given with or without warfarin.
• Detailed Description: This will be a Phase 1, open-label, single-sequence, 2-period, crossover study to determine the effect of multiple doses of mipomersen (200 mg SC given every other day for a total of 4 doses) on the PD and PK of warfarin and to evaluate the PK of mipomersen when administered alone and in combination with warfarin. Subjects will be admitted to the clinic on Day -1 until discharge from the clinic on Day 18 and return for outpatient visits on Days 19, 20, and 78. All subjects will receive a single 25-mg oral dose of warfarin given alone on Day 1 (designated the reference treatment). All subjects will then receive 200-mg SC doses of mipomersen given every other day on Days 8, 10, 12, and 14 (total of 800 mg mipomersen) with a single 25-mg oral dose of warfarin also given on Day 14 (combination designated the test treatment).
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Healthy

Intervention

• Drug: warfarin sodium
  25 mg of warfarin oral (single dose)
  Other Name: Coumadin®
• Drug: mipomersen sodium; warfarin sodium
  200 mg of mipomersen subcutaneous (SC) (4 doses) plus a single 25 mg of warfarin oral administered with the final mipomersen SC dose
  Other Name: Coumadin®

Study Arms

• Active Comparator: warfarin alone
  Intervention: Drug: warfarin sodium
• Experimental: warfarin with mipomersen
  Intervention: Drug: mipomersen sodium; warfarin sodium

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 27, 2010): 18
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: July 2010
• Actual Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Written informed consent before any study-related procedure is performed.
• Body mass index (BMI) between 18 and 32 kg/m2, inclusive.
• No clinically significant abnormalities based on medical history, laboratory assessments, vital sign, 12-lead electrocardiogram (ECG) results, and physical examination.
• Subjects willing and able to follow a prescribed diet.
• Subjects have not consumed nicotine or nicotine-containing products for at least 6 months before Screening.
• Subjects are nonpregnant and nonlactating, surgically sterile, postmenopausal, abstinent, or the subject or partner is willing to use a reliable method of contraception during the study and for 5 months after mipomersen dosing.

Exclusion Criteria:

• Poor metabolizer of warfarin as determined by CYP2C9 genotype testing.
• Clinically significant PT, aPTT, INR, protein C, protein S, or platelet count results or hematuria.
• Abnormal prolongation of skin bleeding time or a personal or family history of coagulation or bleeding disorders, vascular malformations including aneurysms, or venous thromboembolism.
• Active or recurring clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic, neurologic, psychiatric, immunologic, hematologic, gastrointestinal, or metabolic disease.
• Active malignancy of any type other than nonmelanomatous skin malignancies.
• Use of any prescribed or over-the-counter concomitant medications within 14 days before the first dose of investigational product without approval of the Investigator and Sponsor.
• Positive test result for drugs of abuse, alcohol, or cotinine or history of alcohol abuse or drug addiction.
• Positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or HIV.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01133366
• Other Study ID Numbers: MIPO2900509
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Kastle Therapeutics, LLC
• Study Sponsor: Kastle Therapeutics, LLC
• Collaborators: Ionis Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor; Genzyme, a Sanofi Company

• PRS Account: Kastle Therapeutics, LLC
• Verification Date: August 2016