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

Ionis Pharmaceuticals

Status and phase: Completed; Phase 2

Conditions: End-stage Renal Disease (ESRD)

Treatments: Drug: ISIS 416858; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT03358030

2017-002165-21 (EudraCT Number)

NL62709.000.17 (Other Identifier)

ISIS 416858 CS5

Details and patient eligibility

About

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.

Full 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.

Enrollment: 213 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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213 participants in 4 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

Treatment:

Drug: Placebo

Cohort A: ISIS 416858, 200 mg

Experimental group

Description:

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.

Treatment:

Drug: ISIS 416858

Cohort B: ISIS 416858, 250 mg

Experimental group

Description:

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.

Treatment:

Drug: ISIS 416858

Cohort C: ISIS 416858, 300 mg

Experimental group

Description:

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.

Treatment:

Drug: ISIS 416858