E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of thrombosis while on hemodialysis |
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E.1.1.1 | Medical condition in easily understood language |
Prevention of blood clotting while on hemodialysis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10042613 |
E.1.2 | Term | Surgical and medical procedures |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10043634 |
E.1.2 | Term | Thrombosis prophylaxis |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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.
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E.2.2 | Secondary objectives of the trial |
Exploratory Objectives: To evaluate the incidence of myocardial infarction (MI), stroke, systemic embolism, and cardiovascular (CV) mortality. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Platelet Function/Activation Subgroup: In a subgroup of approximately 12 subjects in each cohort, platelet function and/or activation will be assessed. These subjects must have platelet counts that are ≥ 180,000/mm3 at Screening and must not take any anticoagulants, antiplatelet agents, or NSAIDs.At regularly scheduled visits during Weeks 1 (pre-dose), 12, 26, and 38, additional blood samples will be collected and processed for platelet function and/or activation tests.
Pharmacokinetic Subgroup: In a subgroup of approximately 12 subjects in each cohort, additional 0 to 24-hour PK sampling will be conducted following the first (Day 1, Week 1) and last dose (Day 176, Week 26) in order to determine the plasma PK parameters of ISIS 416858 in ESRD subjects, e.g., peak maximum concentration (Cmax) and total plasma exposure (AUC0-t and AUC0-168hr), as well as clearance at steady-state (CLss/F). Subjects in this subgroup will have additional visits to the clinic to collect a 24-hour post-dose blood draw after dosing on Day 1, and a 24-hour, 2-day, and 7-day post-dose blood draw after Day 176 (Week 26) dose. In the event that dialysis is performed on these days, the blood draw should occur pre-dialysis.
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E.3 | Principal 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. |
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E.4 | Principal 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., 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 permitted. • For a subgroup of subjects (approximately 36) being evaluated for platelet function/activation, the concomitant use of aspirin, clopidogrel, and nonsteroidal anti-inflammatory drugs (NSAIDs) is not allowed. 16. Uncontrolled hypertension as judged by the Investigator. For example, patients with a pre- or post-dialysis blood pressure (BP) that is > 180 mmHg on at least 3 of the last 5 dialysis treatments. 17. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the study. |
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E.5 End points |
E.5.1 | 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). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening Visit through End of Study Visit |
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E.5.2 | 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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening Visit through End of Study Visit for both pharmacokinetic and pharmacodynamic evaluations. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Bulgaria |
Canada |
Czech Republic |
Netherlands |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |