A Study of ISIS 416858 Administered Subcutaneously to Participants With End-Stage Renal Disease (ESRD) on Hemodialysis
Condition: End-stage Renal Disease (ESRD)
MeSH terms: Kidney Diseases; Kidney Failure, Chronic
Intervention: ISIS 416858; Placebo
Intervention description: Subcutaneous injection; Subcutaneous injection
Intervention MeSH terms: Riboflavin
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 213.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No

Summary:

      Evaluation of safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ISIS
      416858 for up to 204 participants with ESRD receiving chronic hemodialysis as assessed by FXI
      activity reduction.
    

Eligibility criteria:

        Inclusion Criteria:

        • End stage renal disease maintained on outpatient hemodialysis at a healthcare center for
        > 3 months from screening with hemodialysis at least 3 times per week for a minimum of 9
        hours per week of prescribed treatment time and plan to continue this throughout the study.

        Exclusion Criteria:

          -  Participants with a history of major medical event (previous acute coronary syndrome,
             stroke or transient ischemic attack or systemic thromboembolic event) within 3 months
             of screening, major surgery within 3 months of screening, or new major physical
             examination finding except for documented atrial fibrillation

          -  Active bleeding within the past 3 months from screening or documented bleeding
             diathesis (excluding uremia), coagulopathy, or recent prolonged compression time at
             arteriovenous fistula

          -  Screening values of:

               -  Platelet count < 150,000 cells per millimeter cube (cells/mm^3)

               -  < 180,000 cells/mm^3 for platelet function/activation subgroup

               -  International normalized ratio (INR) > 1.4

               -  Activated partial thromboplastin time (aPTT) > upper limit of normal (ULN)

               -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x ULN

               -  Total bilirubin > ULN

               -  Factor XI (FXI) activity < 0.3 units per milliliter (U/mL)

          -  Malignancy within 5 years, except basal or squamous cell carcinoma of the skin or
             carcinoma in situ of the cervix that has been successfully treated. Participants with
             malignancies that have been treated with curative intent and which have no
             reoccurrence within 5 years may also be eligible if approved by Sponsor Medical
             Monitor.

          -  Within 6 months prior to screening, have any of the following:

               -  More than 3 episodes of severe hypoglycemia requiring the assistance of another
                  person to actively administer carbohydrate, glucagon or other resuscitative
                  actions

               -  One event of hypoglycemia in which the participant required hospitalization

               -  Recurrent syncope and recurrent hypotension in the inter-dialytic period
                  requiring intervention

          -  Planned major surgery in the next 6 months, including participants receiving kidney
             transplant or participants that anticipate changing dialysis modality (i.e.
             hemodialysis to peritoneal dialysis)

          -  Concomitant use of anticoagulant/antiplatelet agents (e.g., warfarin, dabigatran,
             rivaroxaban, clopidogrel) that may affect coagulation (except low dose aspirin (≤ 100
             mg/day) during Treatment and Post-treatment Evaluation Periods is not allowed. Stable
             does of heparins during dialysis are permitted

          -  Uncontrolled hypertension as judged by the Investigator. Participants with a pre- or
             post-dialysis blood pressure (BP) that is > 180 millimeters of mercury (mmHg) on at
             least 3 of last 5 dialysis treatments.