A Study of Safety, PK, & PD of ISIS 416858 Administered Subcutaneously to Patients With End-Stage Renal Disease on Hemodialysis

Study Overview
=================
Brief Summary
-----------------
Evaluation of safety, tolerability, PK and PD of ISIS 416858 in patients with end-stage renal disease (ESRD) receiving chronic hemodialysis.

Detailed Description
-----------------
Evaluation of Safety, PK and PD of ISIS 416858 in patients with end-stage renal disease (ESRD) receiving chronic hemodialysis. The overall objectives are to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS 416858 in ESRD patients on hemodialysis.

Official Title
-----------------
A Phase 2, Randomized, Double Blind, Placebo Controlled Study of the Safety, PK, and PD of Multiple Doses of ISIS 416858 (ISIS-FXI RX), Administered Subcutaneously to Patients With End-Stage Renal Disease on Hemodialysis

Conditions
-----------------
End-stage Renal Disease (ESRD)

Intervention / Treatment
-----------------
* Drug: ISIS 416858
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: End stage renal disease maintained on outpatient hemodialysis at a healthcare center for > 3 months from screening with hemodialysis using heparin (unfractionated heparin or low-molecular weight heparin) 3 times per week for a minimum of 3 hours per dialysis session and plan to continue this throughout the study. Exclusion Criteria: Documented thrombotic event (acute coronary syndrome, stroke or transient ischemic attack, venous thromboembolic event) in the past 3 months. Active bleeding within the past 3 months from screening or documented bleeding diathesis (history of bleeding disorder) or Screening values of: Platelet count < 150,000 cells/mm3 INR > 1.4 aPTT > upper limit of normal (ULN) Abnormal liver function at Screening: ALT or AST > 2 x ULN Total bilirubin > ULN Concomitant medication restrictions: Concomitant use of anticoagulant/antiplatelet agents (e.g., dabigatran, rivaroxaban, clopidogrel) that may affect coagulation (except low dose aspirin (≤ 100 mg/day) during Treatment and Post-treatment Evaluation Periods is not allowed. Uncontrolled hypertension as judged by the Investigator. Patients with a pre- or post-dialysis blood pressure (BP) that is > 160 mmHg on at least 3 of last 5 dialysis treatments. Planned major surgery in the next 6 months (e.g. renal transplant surgery)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PK Cohort<br>A 4-week screening period followed by a 4-week treatment period followed by a 6-week post-treatment evaluation period. Treatment period includes 1 dose of 300 mg ISIS 416858 on Day 1 and again on Day 29. Both doses of Study Drug will be administered subcutaneously (SC). | Drug: ISIS 416858<br>* subcutaneous injection<br>* Other names: IONIS-FXI Rx;|
| Placebo Comparator: Cohort A<br>Patients in Cohort A will be randomized to receive either 200 mg ISIS 416858 or placebo. A 2:1 ratio will be used. For Cohort A, the study will include a 4-week screening period and a 12-week treatment period followed by a 12-week post-treatment evaluation period. Cohort A will receive Study Drug (ISIS 416858 or placebo) twice a week during the first 2 weeks, followed by once weekly for the remaining 10 weeks of the treatment period. All doses of Study Drug will be administered subcutaneously (SC) 10 minutes after completion of the hemodialysis treatment. | Drug: ISIS 416858<br>* subcutaneous injection<br>* Other names: IONIS-FXI Rx;Drug: Placebo<br>* subcutaneous injection<br>* Other names: 0.9% sterile saline;|
| Placebo Comparator: Cohort B<br>Patients in Cohort B will be randomized to receive either 300 mg ISIS 416858 or placebo. A 2:1 ratio will be used. For Cohort B, the study will include a 4-week screening period and a 12-week treatment period followed by a 12-week post-treatment evaluation period. Cohort B will receive Study Drug (ISIS 416858 or placebo) twice a week during the first 2 weeks, followed by once weekly for the remaining 10 weeks of the treatment period. All doses of Study Drug will be administered subcutaneously (SC) 10 minutes after completion of the hemodialysis treatment. | Drug: ISIS 416858<br>* subcutaneous injection<br>* Other names: IONIS-FXI Rx;Drug: Placebo<br>* subcutaneous injection<br>* Other names: 0.9% sterile saline;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability - evaluated by reviewing frequency and severity of Adverse events (including bleeding events) and use of concomitant medications, changes in vital signs and laboratory evaluations for all patients | The safety and tolerability of ISIS 416858 will be evaluated by reviewing frequency and severity of Adverse events (including bleeding events) and use of concomitant medications, changes in vital signs and laboratory evaluations for all patients | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic Outcomes in FXI antigen and activity as measured by absolute change over time. | Pharmacodynamic Outcomes as measured by absolute change over time for FXI antigen and activity (units/milliliter) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. | 
| Pharmacodynamic Outcomes in FXI antigen and activity as measured by percent change over time. | Pharmacodynamic Outcomes as measured by percent change over time for FXI antigen and activity (units/milliliter) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. | 
| Pharmacodynamic Outcomes in aPTT as measured by absolute change over time. | Pharmacodynamic Outcomes as measured by absolute change over time for aPTT (seconds) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. | 
| Pharmacodynamic Outcomes in aPTT as measured by percent change over time. | Pharmacodynamic Outcomes as measured by percent change over time for aPTT (seconds) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. | 
| Pharmacodynamic Outcomes for PT and the PT derived INR as measured by absolute change over time. | Pharmacodynamic Outcomes as measured by absolute change over time for PT (seconds) and the PT derived INR (International Normalization Ratio) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. | 
| Pharmacodynamic Outcomes for PT and the PT derived INR as measured by percent change over time. | Pharmacodynamic Outcomes as measured by percent change over time for PT (seconds) and the PT derived INR (International Normalization Ratio) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. |