Factor XI LICA to Reduce Events Such as Heart Attack and Stroke in Patients Whose Kidneys Are no Longer Able to Work as They Should and Require Treatment to Filter Wastes From the Blood: Focus is on the Safety of BAY2976217 and the Way the Body Absorbs, Distributes and Removes the Study Drug

Study Overview
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Brief Summary
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Patients whose kidneys are no longer able to work as they should and require treatment to filter wastes from the blood (hemodialysis) are at high risk for blood clots that form in blood vessels (thrombosis) blocking blood flow that causes heart attacks, strokes, and other life-threatening conditions. BAY2976217 is under clinical development for prevention of thrombosis. The goal of the study is to learn more about the safety of BAY2976217, how it is tolerated and the way the body absorbs, distributes and gets rid of the study dug given as multiple doses in participants with renal impairment who require hemodialysis.

Official Title
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Factor XI LICA to Reduce Thrombotic Events in End-Stage Renal Disease Patients on Hemodialysis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of BAY 2976217

Conditions
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End Stage Renal Disease Requiring Hemodialysis

Intervention / Treatment
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* Drug: Fesomersen sodium (BAY2976217)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be at least 18 years of age at the time of signing the informed consent form (ICF) Participants with ESRD on hemodialysis (HD) for ≥3 months at the time of signing of the ICF, receiving dialysis at least 9 hours a week and stable in the view of the investigator Male or female (contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies) Capable of giving signed ICF as described in the Protocol, which includes compliance with the requirements and restrictions listed in the ICF and in the protocol Exclusion Criteria: Participants receiving antiplatelet therapy except daily acetylsalicylic acid (ASA) ≤ 150 mg/day Participants receiving anticoagulation in therapeutic doses, other than standard anticoagulation during the hemodialysis procedure Known inherited bleeding disorder e.g. von-Willebrand disease or Hemophilia A, B or C Recent (<6 months before screening) clinically significant bleeding, or at high risk of bleeding (in the judgement of the investigator) Recent (<3 months before screening) thromboembolic event, e.g. acute coronary syndrome, stroke, or Venous thromboembolism (except dialysis access thrombosis) Recent (<3 months before screening) major surgery or scheduled major surgery during participation in the study Scheduled living donor renal transplant during study participation Known Hepatitis B or C Known HIV with recent documented detectable viral load (<3 months before screening) Persistent heart failure as classified by the New York Heart Association classification of 3 or higher Life expectancy less than 6 months Sustained uncontrolled hypertension (persistent measurements of diastolic blood pressure ≥ 100 mmHg, and/or systolic blood pressure ≥ 180 mmHg) Hepatic disease associated with either: coagulopathy leading to a clinically relevant bleeding risk, or ALT > 3x ULN, or total bilirubin >2x ULN with direct bilirubin > 20% of the total Hb < 9.0 g/dL at screening Platelet count < 120,000 mm^3 at screening Known hypersensitivity to the investigational drug or to inactive constituents of the study intervention Active malignancy requiring treatment during study participation (except non-melanoma skin cancer, or cervical carcinoma in situ) Participation in a study with an investigational medicinal product within 30 days or within 5 half-lives of the previous administered drug, whichever is longer, prior to the screening/observational period (Note: Participants from previous BAY2306001/ISIS 416858 and BAY2976217/ ION 957943 studies are eligible) Any other conditions, which, in the opinion of the investigator or Sponsor would make the subject unsuitable for inclusion Confirmed pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Pooled Placebo<br>Participants received subcutaneous treatment with matching placebo. | Drug: Placebo<br>* Matching placebo to BAY2976217 will be injected subcutaneously.<br>|
| Experimental: 40 mg BAY2976217<br>Participants received subcutaneous treatment with 40 mg BAY2976217. | Drug: Fesomersen sodium (BAY2976217)<br>* Study intervention will be injected subcutaneously.<br>* Other names: Factor XI LICA;|
| Experimental: 80 mg BAY2976217<br>Participants received subcutaneous treatment with 80 mg BAY2976217. | Drug: Fesomersen sodium (BAY2976217)<br>* Study intervention will be injected subcutaneously.<br>* Other names: Factor XI LICA;|
| Experimental: 120 mg BAY2976217<br>Participants received subcutaneous treatment with 120 mg BAY2976217. | Drug: Fesomersen sodium (BAY2976217)<br>* Study intervention will be injected subcutaneously.<br>* Other names: Factor XI LICA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Composite of Major Bleeding (MB) and Clinically-relevant Non-major Bleeding (CRNMB) During the Main Treatment Period and Within the On-treatment Time Window, as Assessed by Blinded Central Independent Adjudication Committee (CIAC) | MB is defined as symptomatic bleeding and: 1) Fatal bleeding, and/or; 2) Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or; 3) Bleeding causing a fall in hemoglobin level of 20 g/L (2.0 g/dL) (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells. CRNMB is defined as any sign or symptom of hemorrhage that does not fit the criteria for the ISTH definition of major bleeding but does meet at least one of the following criteria: 1) Requiring medical intervention by a healthcare professional; 2) Leading to hospitalization or increased level of care; 3) Prompting a face-to-face evaluation. n/100 person-years: number of subjects with incident events divided by the cumulative at-risk time in the reference population, where a subject is no longer at risk once an incident event occurred. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Composite of MB and CRNMB During the Main and Extended Treatment Periods and Within the On-treatment Time Window, as Assessed by Blinded CIAC | MB is defined as symptomatic bleeding and: 1) Fatal bleeding, and/or; 2) Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or; 3) Bleeding causing a fall in hemoglobin level of 20 g/L (2.0 g/dL) (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells. CRNMB is defined as any sign or symptom of hemorrhage that does not fit the criteria for the ISTH definition of major bleeding but does meet at least one of the following criteria: 1) Requiring medical intervention by a healthcare professional; 2) Leading to hospitalization or increased level of care; 3) Prompting a face-to-face evaluation. n/100 person-years: number of subjects with incident events divided by the cumulative at-risk time in the reference population, where a subject is no longer at risk once an incident event occurred. | Up to 48 weeks | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Main Treatment Period and Within the On-treatment Time Window and Their Severity | TEAEs were analyzed during the on-treatment time window within the main treatment period in the safety analysis set (SAF). Data observed from the randomization date until the end of the main treatment period. TEAEs were defined as events occurring after first study intervention administration and up to 20 weeks after last study intervention administration. | Up to 24 weeks | 
| Number of Participants With TEAEs During the Main and Extended Treatment Periods and Within the On-treatment Time Window and Their Severity | TEAEs were analyzed during during main and extended treatment periods in the safety analysis set (SAF). Data observed from the randomization date until the end of the extension treatment period. TEAEs were defined as events occurring after first study intervention administration and up to 20 weeks after last study intervention administration. | Up to 48 weeks | 
| Number of Participants With TEAEs During the Main and Extended Treatment Periods and Until 20 Weeks After the Last Study Intervention Dose and Their Severity | TEAEs occurring from first study intervention intake until 20 weeks after last study intervention intake. | Up to 48 weeks | 
| Trough Concentrations (Ctrough) of Three Dose Levels of Fesomersen | Trough (pre-dose) fesomersen-equivalent plasma concentrations (Ctrough) for 3 dose levels of fesomersen were summarized descriptively by dose level and visit: Visit 12, Visit 14, Visit 16, Visit 18 (main treatment period). Ctrough was not measured for the placebo group. | At visits V12 (Day 57), V14 (Day 85), V16 (Day 113), V18 (Day 141) | 
| Maximum Change in FXI (Coagulation Factor XI) Antigen Levels During the Main Treatment Period | The secondary endpoint of change in FXI antigen levels during the main treatment period was an optional secondary endpoint only as mentioned in the integrated clinical protocol amendment version 3.0 and was not analyzed in this study as the FXI activity assay is sufficient to describe the effect on FXI level in plasma. | Up to 24 weeks | 
| Maximum Change in FXI Activity Levels During the Main Treatment Period | The FXIa activity was measured by a fluorogenic activated FXIa activity (AXIA) assay. Absolute change from baseline at each visit until Visit 22 (Day 169) are reported. | Baseline, Days 1 (Pre-Dose and 5 hours post-dose), 2, 8, 15, 22, 29 (Pre-dose and 5 hours post-dose), 43, 57 (Pre-dose), 71, 85 (Pre-dose), 113 (Pre-dose), 141 (Pre-dose),148, 155, 162, and 169 (Pre-dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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End stage renal disease (ESRD), Hemodialysis (HD), Thrombotic Events