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| Name | Class |
|---|---|
| Bayer | INDUSTRY |
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Evaluation of safety, tolerability, PK and PD of ISIS 416858 in patients with end-stage renal disease (ESRD) receiving chronic hemodialysis.
Evaluation of Safety, PK and PD of ISIS 416858 in patients with end-stage renal disease (ESRD) receiving chronic hemodialysis.
The overall objectives are to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS 416858 in ESRD patients on hemodialysis.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PK Cohort | Experimental | A 4-week screening period followed by a 4-week treatment period followed by a 6-week post-treatment evaluation period. Treatment period includes 1 dose of 300 mg ISIS 416858 on Day 1 and again on Day 29. Both doses of Study Drug will be administered subcutaneously (SC). |
|
| Cohort A | Placebo Comparator | Patients in Cohort A will be randomized to receive either 200 mg ISIS 416858 or placebo. A 2:1 ratio will be used. For Cohort A, the study will include a 4-week screening period and a 12-week treatment period followed by a 12-week post-treatment evaluation period. Cohort A will receive Study Drug (ISIS 416858 or placebo) twice a week during the first 2 weeks, followed by once weekly for the remaining 10 weeks of the treatment period. All doses of Study Drug will be administered subcutaneously (SC) 10 minutes after completion of the hemodialysis treatment. |
|
| Cohort B | Placebo Comparator | Patients in Cohort B will be randomized to receive either 300 mg ISIS 416858 or placebo. A 2:1 ratio will be used. For Cohort B, the study will include a 4-week screening period and a 12-week treatment period followed by a 12-week post-treatment evaluation period. Cohort B will receive Study Drug (ISIS 416858 or placebo) twice a week during the first 2 weeks, followed by once weekly for the remaining 10 weeks of the treatment period. All doses of Study Drug will be administered subcutaneously (SC) 10 minutes after completion of the hemodialysis treatment. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ISIS 416858 | Drug | subcutaneous injection |
|
| Measure | Description | Time Frame |
|---|---|---|
| Safety and Tolerability - evaluated by reviewing frequency and severity of Adverse events (including bleeding events) and use of concomitant medications, changes in vital signs and laboratory evaluations for all patients | The safety and tolerability of ISIS 416858 will be evaluated by reviewing frequency and severity of Adverse events (including bleeding events) and use of concomitant medications, changes in vital signs and laboratory evaluations for all patients | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacodynamic Outcomes in FXI antigen and activity as measured by absolute change over time. | Pharmacodynamic Outcomes as measured by absolute change over time for FXI antigen and activity (units/milliliter) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetic Outcome for PK Cohort of effect of dialysis on peak concentrations | Effect of dialysis on peak concentrations post single dose drug administration. | Patients will be followed for 29 days for this outcome measure. |
| Pharmacokinetic Outcome for PK Cohort of effect of dialysis on partial area under the plasma concentration-time curve |
Inclusion Criteria:
Exclusion Criteria:
Documented thrombotic event (acute coronary syndrome, stroke or transient ischemic attack, venous thromboembolic event) in the past 3 months.
Active bleeding within the past 3 months from screening or documented bleeding diathesis (history of bleeding disorder) or Screening values of:
Abnormal liver function at Screening:
Concomitant medication restrictions: Concomitant use of anticoagulant/antiplatelet agents (e.g., dabigatran, rivaroxaban, clopidogrel) that may affect coagulation (except low dose aspirin (≤ 100 mg/day) during Treatment and Post-treatment Evaluation Periods is not allowed.
Uncontrolled hypertension as judged by the Investigator. Patients with a pre- or post-dialysis blood pressure (BP) that is > 160 mmHg on at least 3 of last 5 dialysis treatments.
Planned major surgery in the next 6 months (e.g. renal transplant surgery)
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| Name | Affiliation | Role |
|---|---|---|
| Sanjay Bhanot, MD | Ionis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ionis Investigative Site | Edmonton | Alberta | T6G 2P4 | Canada | ||
| Ionis Investigative Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38189593 | Derived | Natale P, Palmer SC, Ruospo M, Longmuir H, Dodds B, Prasad R, Batt TJ, Jose MD, Strippoli GF. Anticoagulation for people receiving long-term haemodialysis. Cochrane Database Syst Rev. 2024 Jan 8;1(1):CD011858. doi: 10.1002/14651858.CD011858.pub2. | |
| 35155859 | Derived | Walsh M, Bethune C, Smyth A, Tyrwhitt J, Jung SW, Yu RZ, Wang Y, Geary RS, Weitz J, Bhanot S; CS4 Investigators. Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXIRx in Patients With ESRD. Kidney Int Rep. 2021 Nov 24;7(2):200-209. doi: 10.1016/j.ekir.2021.11.011. eCollection 2022 Feb. |
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| Placebo | Drug | subcutaneous injection |
|
|
| Pharmacodynamic Outcomes in FXI antigen and activity as measured by percent change over time. |
Pharmacodynamic Outcomes as measured by percent change over time for FXI antigen and activity (units/milliliter) |
| For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. |
| Pharmacodynamic Outcomes in aPTT as measured by absolute change over time. | Pharmacodynamic Outcomes as measured by absolute change over time for aPTT (seconds) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. |
| Pharmacodynamic Outcomes in aPTT as measured by percent change over time. | Pharmacodynamic Outcomes as measured by percent change over time for aPTT (seconds) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. |
| Pharmacodynamic Outcomes for PT and the PT derived INR as measured by absolute change over time. | Pharmacodynamic Outcomes as measured by absolute change over time for PT (seconds) and the PT derived INR (International Normalization Ratio) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. |
| Pharmacodynamic Outcomes for PT and the PT derived INR as measured by percent change over time. | Pharmacodynamic Outcomes as measured by percent change over time for PT (seconds) and the PT derived INR (International Normalization Ratio) | For the PK Cohort: Patients will be followed for 72 days. For Cohorts A and B: Patients will be followed for 162 days. |
Effect of dialysis on partial area under the plasma concentration-time curve post single dose drug administration (AUC 0-24hr). |
| Patients will be followed for 29 days for this outcome measure. |
| Pharmacokinetic Outcome for Cohorts A and B to assess steady state concentrations | Plasma will be collected at each dosing interval to assess steady state concentrations. | Patients will be followed for 162 days for this outcome measure |
| Halifax |
| Nova Scotia |
| B3H 1V8 |
| Canada |
| Ionis Investigative Site | Hamilton | Ontario | L8N 4A6 | Canada |
| Ionis Investigative Site | London | Ontario | N6A 5W9 | Canada |
| Ionis Investigative Site | Toronto | Ontario | M5B 1W8 | Canada |
| Ionis Investigative Site | Toronto | Ontario | M9N 1N8 | Canada |
| Ionis Investigative Site | Montreal | Quebec | H2X 0A9 | Canada |
| Ionis Investigative Site | Montreal | Quebec | H4J 1C5 | Canada |
| ID | Term |
|---|---|
| D007676 | Kidney Failure, Chronic |
| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C572197 | ISIS 416858 |
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