A Study of ISIS 416858 Administered Subcutaneously to Participants With End-Stage Renal Disease (ESRD) on Hemodialysis (EMERALD)

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of ISIS 416858 (IONIS-FXIRX, an Antisense Inhibitor of Factor XI), Administered Subcutaneously to Patients With End-Stage Renal Disease on Hemodialysis

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.

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 (Dose # 1, Dose #2 and Dose #3 once weekly) as compared to placebo as assessed by FXI activity reduction.

• Study Type: Interventional
• Enrollment (Actual): 213
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • A Coruna
    • Santiago De Compostela, A Coruna, Spain, 15706
      • Ionis Investigative Site
  • Madrid
    • Alcalá De Henares, Madrid, Spain, 28805
      • Ionis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 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 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Drug: Placebo; Subcutaneous injection; Other Names: Riboflavin; 0.9% sterile saline
Experimental: Cohort A: ISIS 416858, 200 mg; Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Drug: ISIS 416858; Subcutaneous injection; Other Names: IONIS-FXIRx
Experimental: Cohort B: ISIS 416858, 250 mg; Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Drug: ISIS 416858; Subcutaneous injection; Other Names: IONIS-FXIRx
Experimental: Cohort C: ISIS 416858, 300 mg; Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Drug: ISIS 416858; Subcutaneous injection; Other Names: IONIS-FXIRx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB)	MB was defined as one of the following: Fatal bleeding; symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular if in a major joint, or pericardial, or intramuscular with compartment syndrome, clinically overt bleeding leading to transfusion of greater than or equal to (>=) 2 units of packed red blood cells or whole blood or a fall in hemoglobin of 20 grams per liter (g/L) (1.24 millimoles per liter [mmol/L]) or more within 24 hours. CRNMB was defined as overt bleeding not meeting the criteria for MB but that resulted, in either medical examination, intervention, or had clinical consequences for a participant.	Up to Day 260

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT)		Baseline (Day 1) up to Day 260
Percent Change From Baseline in Factor XI (FXI) Activity		Baseline (Day 1) up to Day 260
Number of Participants With Laboratory Abnormalities Related to Platelet Count	Participants were assessed based on pre-defined criteria in the protocol for platelet count abnormality: 100 - less than (<)140, 75 - <100, 50 - <75, 25 - <50 and < 25 thousands per cubic millimeter (K/mm^3) based on investigator's discretion.	Up to Day 260
Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST)	Participants were assessed based on pre-defined criteria in protocol for abnormality in ALT and AST values: Confirmed ALT (serum glutamic pyruvic transaminase [SGPT]); greater than (>) 3*Upper limit of normal range (ULN), >5*ULN and confirmed AST (serum glutamic-oxaloacetic transaminase [SGOT]); >3*ULN and >5*ULN. A confirmed value was based on a consecutive lab value within 7 days of the initial value. If that value was in the same or worse category the initial value was confirmed. If the consecutive value was in a better category then the initial value was confirmed using the consecutive value category. If there were multiple results on the same day, no matter from the same lab vendor or different lab vendors, then the worst value was used in the analysis. Abnormality in laboratory parameter was based on investigator's discretion.	Up to Day 260
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)		Up to Day 260
Percent Change From Baseline in Factor XI (FXI) Antigen Levels		Baseline (Day 1) up to Day 260

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 26, 2017
• Primary Completion (Actual): July 10, 2019
• Study Completion (Actual): July 10, 2019

Study Registration Dates

• First Submitted: November 13, 2017
• First Submitted That Met QC Criteria: November 24, 2017
• First Posted (Actual): November 30, 2017

Study Record Updates

• Last Update Posted (Actual): January 20, 2023
• Last Update Submitted That Met QC Criteria: December 22, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Kidney Failure, Chronic; Physiological Effects of Drugs; Photosensitizing Agents; Dermatologic Agents; Micronutrients; Vitamins; Vitamin B Complex; Riboflavin
• Other Study ID Numbers: ISIS 416858 CS5; 2017-002165-21 (EudraCT Number); NL62709.000.17 (Other Identifier: Central Committee on Research Involving Human Subjects (CCMO))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes