Drug-drug Interaction Study to Evaluate the Effect of ISIS 681257 on Warfarin

Study Overview
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Brief Summary
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This is a single center, open label, single sequence, two-treatment, two-period drug-drug interaction study to evaluate the effect of multiple doses of ISIS 681257 on the pharmacokinetics of a single dose of warfarin.

Official Title
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Phase 1, Drug-Drug Interaction Study To Evaluate The Effect Of Multiple Doses Of ISIS 681257 40 mg Subcutaneous Injections On The Pharmacokinetics And Pharmacodynamics Of Warfarin In Healthy Subjects

Conditions
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Elevated Lipoprotein(a), Cardiovascular Diseases

Intervention / Treatment
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* Drug: ISIS 681257
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Motivated and available for duration of study and willing to adhere to protocol Males who are unable to procreate or agree to contraception throughout study Females who are postmenopausal or surgically sterile BMI between 18.5 and 30 kg/m2 Weighing greater than or equal to 50kg Normal lab results No known diseases or significant findings on physical exam Exclusion Criteria: Females of childbearing potential Reactions/infection at injection site Hypersensitivity to any drugs or similar drugs to those used in the study Conditions or disease that may interfere with study drug Any significant diseases Known history or familial history of bleeding disorders Drug dependency or abuse Illness within 28 days Previous exposure to other investigational drug within 28 days Blood donations within 28 days

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose of warfarin<br>Single dose of warfarin administered to obtain pharmacokinetic information. | Drug: Warfarin<br>* 25mg tablet administered orally<br>|
| Experimental: Warfarin in combination with ISIS 681257<br>ISIS 681257 administered and pharmacokinetic assessments are taken. Then ISIS 681257 is administered with warfarin and additional pharmacokinetic information is obtained. | Drug: ISIS 681257<br>* Xmg dose administered as a subcutaneous injection<br>Drug: Warfarin<br>* 25mg tablet administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The plasma concentrations of warfarin and ISIS 681257 will be measured at each individual time point. | To evaluate the effect of multiple doses of ISIS 681257 40 mg subcutaneous injections on the pharmacokinetics of a single oral dose of warfarin in healthy adult subjects. | Each day for days 1-10 and 15-45 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety of ISIS 681257 by the incidence of treatment-emergent adverse events. | To evaluate the safety and tolerability of multiple doses of ISIS 681257 40 mg subcutaneous injections when coadministered with a single oral dose of warfarin in healthy adult subjects. | 45 days | 
| Prothrombin Time will be measured by testing blood samples at each individual time point. | To evaluate the effect of multiple doses of ISIS 681257 40 mg subcutaneous injections on the pharmacodynamics (anticoagulant activity) of a single oral dose of warfarin in healthy adult subjects. | Each day for days 1-7 and 15-21 | 
| International normalized ratio will be measured at each individual time point by comparing prothrombin time to the normal mean prothrombin time. | To evaluate the effect of multiple doses of ISIS 681257 40 mg subcutaneous injections on the pharmacodynamics (anticoagulant activity) of a single oral dose of warfarin in healthy adult subjects. | Each day for days 1-7 and 15-21 | 
| Activated partial thromboplastin time will be measured by testing blood samples at each individual time point. | To evaluate the effect of multiple doses of ISIS 681257 40 mg subcutaneous injections on the pharmacodynamics (anticoagulant activity) of a single oral dose of warfarin in healthy adult subjects. | Each day for days 1-7 and 15-21 | 
| The plasma concentrations of warfarin and ISIS 681257 will be measured at each individual time point. | To evaluate the effect of a single dose of warfarin on the pharmacokinetics of a single subcutaneous 40 mg injection of ISIS 681257 in healthy adult subjects. | Each day for days 1-10 and 15-45 |