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

Phase 2

Completed

Conditions: End-Stage Renal Disease
Blood Clotting during blood dialysis
Coagulopathy during hemodialysis
10064477

Registration Number: NL-OMON46462

Lead Sponsor: Ionis Pharmaceuticals, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 30

Inclusion Criteria

1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements.
2. Males or females aged 18 to 85 years old at the time of informed consent.
a. Females: must be non-pregnant and non-lactating and either:
i. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy);
ii. post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females * 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and FSH levels in the postmenopausal range for the laboratory involved); or,
iii. if engaged in sexual relations and of child-bearing potential, agree to use 2 highly effective contraceptive methods from the time of signing the informed consent form until at least 84 days (approximately 5 half-lives of ISIS 416858) after the last dose of Study Drug (ISIS 416858 or placebo).
b Males: Surgically sterile or if engaged in sexual relations with a female of child-bearing potential, subject is utilizing an acceptable contraceptive method from the time of signing the informed consent form until at least 84 days (approximately 5 half-lives of ISIS 416858) after the last dose of Study Drug (ISIS 416858 or placebo).
3. 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

1. Subjects with a history of a major medical event (e.g., 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 (not accounted for by past medical history), except for documented atrial fibrillation.
2. Active bleeding (as judged clinically significant by the Investigator) within the past 3 months from screening or documented bleeding diathesis (excluding uremia), coagulopathy, or recent history of prolonged compression time at arteriovenous fistula.
3. Screening laboratory results as follows:
* Platelet count < 150,000 cells/mm3
* < 180,000 cells/mm3 for platelet function/activation subgroup
* INR > 1.4
* aPTT > upper limit of normal (ULN)
* FXI activity < 0,3 U/ml
* ALT or AST > 2 x ULN
* Total bilirubin > ULN
4. Subject is not willing to have weekly subcutaneous injections over the study period as assessed during screening.
5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 (first dose) or IV antibiotic use at the time of Screening.
6. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator.
7. Known history of or positive test at Screening for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B.
8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Subjects with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor Medical Monitor (or designee).
9. Treatment with another investigational drug, biological agent, or device within 1 month of screening, or 5 half-lives of investigational agent, whichever is longer.
10. Any history of previous treatment with an oligonucleotide (including siRNA). Subjects that have previously received only a single-dose of an ISIS-oligonucleotide as part of a clinical study may be included as long as a duration * 4 months has elapsed since dosing.
11. Attending nephrologist answers no to the question, Would you be surprised if this patient died in the next year?
12. 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 (1) event of hypoglycemia in which the patient required hospitalization
* Recurrent syncope and recurrent hypotension in the inter-dialytic period requiring intervention
13. Planned major surgery in the next 6 months, including subjects receiving a kidney transplant or subjects that anticipate changing dialysis modality (i.e. hemodialysis to peritoneal dialysis).
14. Recent history of, or current drug or alcohol abuse as determined by the Investigator.
15. 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 doses of heparins during dialysis are perm

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Safety and Tolerability Evaluations<br /><br>The safety and tolerability of ISIS 416858 will be assessed by determining the<br /><br>incidence and severity of adverse events (including bleeding events) and<br /><br>changes in laboratory evaluations.<br /><br>The primary safety outcome is the combination of major bleeding (MB) and<br /><br>clinically-relevant non-major bleeding (CRNMB) during the treatment period (or<br /><br>early study termination).</p><br>

Secondary Outcome Measures