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

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

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

Study Overview

• Status: Completed
• Conditions: End-stage Renal Disease (ESRD)
• Intervention / Treatment: Drug: Placebo; Drug: ISIS 416858

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2P4
      • Ionis Investigative Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V8
      • Ionis Investigative Site
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • Ionis Investigative Site
    • London, Ontario, Canada, N6A 5W9
      • Ionis Investigative Site
    • Toronto, Ontario, Canada, M5B 1W8
      • Ionis Investigative Site
    • Toronto, Ontario, Canada, M9N 1N8
      • Ionis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H2X 0A9
      • Ionis Investigative Site
    • Montreal, Quebec, Canada, H4J 1C5
      • Ionis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PK Cohort; 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; subcutaneous injection; Other Names: ISIS-FXI Rx; BAY2306001; IONIS-FXI Rx
Placebo Comparator: Cohort A; 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: Placebo; subcutaneous injection; Other Names: 0.9% sterile saline; Drug: ISIS 416858; subcutaneous injection; Other Names: ISIS-FXI Rx; BAY2306001; IONIS-FXI Rx
Placebo Comparator: Cohort B; 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: Placebo; subcutaneous injection; Other Names: 0.9% sterile saline; Drug: ISIS 416858; subcutaneous injection; Other Names: ISIS-FXI Rx; BAY2306001; IONIS-FXI Rx

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Outcome for PK Cohort of effect of dialysis on peak concentrations	Effect of dialysis on peak concentrations post single dose drug administration.	Patients will be followed for 29 days for this outcome measure.
Pharmacokinetic Outcome for PK Cohort of effect of dialysis on partial area under the plasma concentration-time curve	Effect of dialysis on partial area under the plasma concentration-time curve post single dose drug administration (AUC 0-24hr).	Patients will be followed for 29 days for this outcome measure.
Pharmacokinetic Outcome for Cohorts A and B to assess steady state concentrations	Plasma will be collected at each dosing interval to assess steady state concentrations.	Patients will be followed for 162 days for this outcome measure

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.
• Collaborators: Bayer
• Investigators: Study Director: Sanjay Bhanot, MD, Ionis Pharmaceuticals

Publications and helpful links

General Publications

• Walsh M, Bethune C, Smyth A, Tyrwhitt J, Jung SW, Yu RZ, Wang Y, Geary RS, Weitz J, Bhanot S; CS4 Investigators. Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXIRx in Patients With ESRD. Kidney Int Rep. 2021 Nov 24;7(2):200-209. doi: 10.1016/j.ekir.2021.11.011. eCollection 2022 Feb.

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: September 14, 2015
• First Submitted That Met QC Criteria: September 16, 2015
• First Posted (Estimate): September 18, 2015

Study Record Updates

• Last Update Posted (Estimate): December 13, 2016
• Last Update Submitted That Met QC Criteria: December 12, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Kidney Failure, Chronic
• Other Study ID Numbers: ISIS 416858 CS4