Clinical trial NCT03358030: A Study of ISIS 416858 Administered Subcutaneously to Participants With End-Stage Renal Disease (ESRD) on Hemodialysis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: End-stage Renal Disease (ESRD)
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Bayer
First posted: 2017-11-30
Enrollment: 213
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB)
timeFrame: Up to Day 260
Secondary outcomes:
Other outcomes:
measure: Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT)
timeFrame: Baseline (Day 1) up to Day 260
measure: Percent Change From Baseline in Factor XI (FXI) Activity
timeFrame: Baseline (Day 1) up to Day 260
measure: Number of Participants With Laboratory Abnormalities Related to Platelet Count
timeFrame: Up to Day 260
measure: Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST)
timeFrame: Up to Day 260
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to Day 260
measure: Percent Change From Baseline in Factor XI (FXI) Antigen Levels
timeFrame: Baseline (Day 1) up to Day 260
Locations:
city: Santiago De Compostela
country: Spain
facility: Ionis Investigative Site
state: A Coruna
city: Alcalá De Henares
country: Spain
facility: Ionis Investigative Site
state: Madrid
Study officials:
References: