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

Primary Purpose

End-stage Renal Disease (ESRD)

Status
Completed
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
ISIS 416858
Placebo
Sponsored by
Ionis Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for End-stage Renal Disease (ESRD)

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Ionis Investigative Site
  • Ionis Investigative Site
  • Ionis Investigative Site
  • Ionis Investigative Site
  • Ionis Investigative Site
  • Ionis Investigative Site
  • Ionis Investigative Site
  • Ionis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Placebo Comparator

Arm Label

PK Cohort

Cohort A

Cohort B

Arm Description

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).

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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)
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)
Pharmacodynamic Outcomes in aPTT as measured by absolute change over time.
Pharmacodynamic Outcomes as measured by absolute change over time for aPTT (seconds)
Pharmacodynamic Outcomes in aPTT as measured by percent change over time.
Pharmacodynamic Outcomes as measured by percent change over time for aPTT (seconds)
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)
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)

Full Information

First Posted
September 14, 2015
Last Updated
December 12, 2016
Sponsor
Ionis Pharmaceuticals, Inc.
Collaborators
Bayer
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1. Study Identification

Unique Protocol Identification Number
NCT02553889
Brief Title
A Study of Safety, PK, & PD of ISIS 416858 Administered Subcutaneously to Patients With End-Stage Renal Disease 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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2016
Overall Recruitment Status
Completed
Study Start Date
October 2015 (undefined)
Primary Completion Date
November 2016 (Actual)
Study Completion Date
November 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ionis Pharmaceuticals, Inc.
Collaborators
Bayer

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
End-stage Renal Disease (ESRD)

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
49 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PK Cohort
Arm Type
Experimental
Arm Description
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).
Arm Title
Cohort A
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Cohort B
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
ISIS 416858
Other Intervention Name(s)
ISIS-FXI Rx, BAY2306001, IONIS-FXI Rx
Intervention Description
subcutaneous injection
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
0.9% sterile saline
Intervention Description
subcutaneous injection
Primary Outcome Measure Information:
Title
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
Description
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
Time Frame
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 Measure Information:
Title
Pharmacodynamic Outcomes in FXI antigen and activity as measured by absolute change over time.
Description
Pharmacodynamic Outcomes as measured by absolute change over time for FXI antigen and activity (units/milliliter)
Time Frame
For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days.
Title
Pharmacodynamic Outcomes in FXI antigen and activity as measured by percent change over time.
Description
Pharmacodynamic Outcomes as measured by percent change over time for FXI antigen and activity (units/milliliter)
Time Frame
For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days.
Title
Pharmacodynamic Outcomes in aPTT as measured by absolute change over time.
Description
Pharmacodynamic Outcomes as measured by absolute change over time for aPTT (seconds)
Time Frame
For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days.
Title
Pharmacodynamic Outcomes in aPTT as measured by percent change over time.
Description
Pharmacodynamic Outcomes as measured by percent change over time for aPTT (seconds)
Time Frame
For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days.
Title
Pharmacodynamic Outcomes for PT and the PT derived INR as measured by absolute change over time.
Description
Pharmacodynamic Outcomes as measured by absolute change over time for PT (seconds) and the PT derived INR (International Normalization Ratio)
Time Frame
For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days.
Title
Pharmacodynamic Outcomes for PT and the PT derived INR as measured by percent change over time.
Description
Pharmacodynamic Outcomes as measured by percent change over time for PT (seconds) and the PT derived INR (International Normalization Ratio)
Time Frame
For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days.
Other Pre-specified Outcome Measures:
Title
Pharmacokinetic Outcome for PK Cohort of effect of dialysis on peak concentrations
Description
Effect of dialysis on peak concentrations post single dose drug administration.
Time Frame
Patients will be followed for 29 days for this outcome measure.
Title
Pharmacokinetic Outcome for PK Cohort of effect of dialysis on partial area under the plasma concentration-time curve
Description
Effect of dialysis on partial area under the plasma concentration-time curve post single dose drug administration (AUC 0-24hr).
Time Frame
Patients will be followed for 29 days for this outcome measure.
Title
Pharmacokinetic Outcome for Cohorts A and B to assess steady state concentrations
Description
Plasma will be collected at each dosing interval to assess steady state concentrations.
Time Frame
Patients will be followed for 162 days for this outcome measure

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sanjay Bhanot, MD
Organizational Affiliation
Ionis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Ionis Investigative Site
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2P4
Country
Canada
Facility Name
Ionis Investigative Site
City
Halifax
State/Province
Nova Scotia
ZIP/Postal Code
B3H 1V8
Country
Canada
Facility Name
Ionis Investigative Site
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 4A6
Country
Canada
Facility Name
Ionis Investigative Site
City
London
State/Province
Ontario
ZIP/Postal Code
N6A 5W9
Country
Canada
Facility Name
Ionis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5B 1W8
Country
Canada
Facility Name
Ionis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M9N 1N8
Country
Canada
Facility Name
Ionis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2X 0A9
Country
Canada
Facility Name
Ionis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H4J 1C5
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
35155859
Citation
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.
Results Reference
derived

Learn more about this trial

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

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