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

NCT02553889 | Completed Phase 2

• 1 other identifier: ISIS 416858 CS4
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 8

Brief Summary

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

Conditions

End-stage Renal Disease (ESRD)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Pharmacodynamic Outcomes in FXI antigen and activity as measured by absolute change over time.

  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.

  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.

  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.

  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.

  For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days.

Other Outcomes (3)

• Pharmacokinetic Outcome for PK Cohort of effect of dialysis on peak concentrations

  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

  Patients will be followed for 29 days for this outcome measure.

• Pharmacokinetic Outcome for Cohorts A and B to assess steady state concentrations

  Patients will be followed for 162 days for this outcome measure

Study Arms (3)

PK Cohort

EXPERIMENTAL

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

Cohort A

PLACEBO COMPARATOR

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; Drug: Placebo

Cohort B

PLACEBO COMPARATOR

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; Drug: Placebo

Interventions

ISIS 416858 DRUG

subcutaneous injection

Also known as: ISIS-FXI Rx, BAY2306001, IONIS-FXI Rx

Cohort A; Cohort B; PK Cohort

Placebo DRUG

subcutaneous injection

Also known as: 0.9% sterile saline

Cohort A; Cohort B

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead
• Bayer: collaborator

Study Sites (8)

Ionis Investigative Site

Edmonton, Alberta, T6G 2P4, Canada

Location

Ionis Investigative Site

Halifax, Nova Scotia, B3H 1V8, Canada

Location

Ionis Investigative Site

Hamilton, Ontario, L8N 4A6, Canada

Location

Ionis Investigative Site

London, Ontario, N6A 5W9, Canada

Location

Ionis Investigative Site

Toronto, Ontario, M5B 1W8, Canada

Location

Ionis Investigative Site

Toronto, Ontario, M9N 1N8, Canada

Location

Ionis Investigative Site

Montreal, Quebec, H2X 0A9, Canada

Location

Ionis Investigative Site

Montreal, Quebec, H4J 1C5, Canada

Location

Related Publications (2)

• Natale P, Palmer SC, Ruospo M, Longmuir H, Dodds B, Prasad R, Batt TJ, Jose MD, Strippoli GF. Anticoagulation for people receiving long-term haemodialysis. Cochrane Database Syst Rev. 2024 Jan 8;1(1):CD011858. doi: 10.1002/14651858.CD011858.pub2.

  PMID: 38189593 DERIVED

• 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.

  PMID: 35155859 DERIVED

MeSH Terms

Conditions

Kidney Failure, Chronic

Interventions

ISIS 416858

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Sanjay Bhanot, MD

  Ionis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2015
• First Posted: September 18, 2015
• Study Start: October 1, 2015
• Primary Completion: November 1, 2016
• Study Completion: November 1, 2016
• Last Updated: December 13, 2016

Record last verified: 2016-12

Locations

CA (8)