A Phase 2 Study to Determine the Safety and Effectiveness of Multiple Doses of ISIS 416858 Injected Subcutaneously to Patients with End-Stage Renal Disease on Hemodialysis

• Register: EUCTR
• Last refreshed on: 10 December 2019
• Main ID: EUCTR2017-002165-21-ES
• Date of registration: 31/08/2017
• Prospective Registration: Yes
• Primary sponsor: Ionis Pharmaceuticals Inc.
• Public title: A Phase 2 Study to Determine the Safety and Effectiveness of Multiple Doses of ISIS 416858 Injected Subcutaneously to Patients with End-Stage Renal Disease on Hemodialysis
• Scientific 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
• Date of first enrolment: 23/11/2017
• Target sample size: 204
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002165-21
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: no; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Bulgaria, Canada, Czech Republic, Greece, Latvia, Netherlands, Spain

Contacts

• Name: Matt Buck
• Affiliation: Ionis Pharmaceuticals Inc.

• Name: Matt Buck
• Affiliation: Ionis Pharmaceuticals Inc.

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 144
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 60

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)
• 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 one 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,
• 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., war

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Prevention of thrombosis while on hemodialysis
MedDRA version: 20.0 Level: SOC Classification code 10042613 Term: Surgical and medical procedures System Organ Class: 10042613 - Surgical and medical procedures
MedDRA version: 20.0 Level: PT Classification code 10043634 Term: Thrombosis prophylaxis System Organ Class: 10042613 - Surgical and medical procedures

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: ISIS 416858
Product Code: ISIS 416858
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ISIS 416858
CAS Number: 1223657-78-0
Current Sponsor code: ISIS 416858
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Secondary Objective: Exploratory Objectives: To evaluate the incidence of myocardial infarction (MI), stroke, systemic embolism, and cardiovascular (CV) mortality.

Primary end point(s): The primary safety outcome is the combination of major bleeding (MB) and clinically-relevant non-major bleeding (CRNMB) during the treatment period (or early study termination).

Other safety parameters including (S)AEs, deaths, vital signs, ECG and laboratory parameters will also be recorded. This may include additional information regarding events of interest (i.e. bleeding events, thrombotic events).

Main Objective: Primary Objectives: To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ISIS 416858 (200, 250, and 300 mg once weekly) as compared to placebo as assessed by FXI activity reduction in ESRD patients on hemodialysis; ISIS 416858, a FXI antisense inhibitor, is being developed to determine whether this treatment could provide anticoagulation for the prevention of thrombotic events without an increased risk of bleeding.

Timepoint(s) of evaluation of this end point: Screening Visit through End of Study Visit

Secondary Outcome(s)

Secondary end point(s): Pharmacokinetic Evaluations: Plasma pharmacokinetics will be assessed following the first and last dose in the PK subgroup, whenever possible. Additionally, plasma trough and post-treatment samples will be collected during treatment and post-treatment evaluation period, respectively, for the measurement of ISIS 416858 concentrations.

Pharmacodynamic Evaluations: Coagulation parameters such as FXI activity and antigen, aPTT, PT and INR will be monitored throughout the treatment and post-treatment evaluation period visits.
The rate/frequency of clotting on the dialysis filters and circuit will be measured as an exploratory analysis.

Timepoint(s) of evaluation of this end point: Screening Visit through End of Study Visit for both pharmacokinetic and pharmacodynamic evaluations.

Secondary ID(s)

ISIS416858-CS5

Source(s) of Monetary Support

Ionis Pharmaceuticals Inc.

Ethics review

Status: Approved
Approval date:
Contact: