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

End Stage Renal Disease Requiring Hemodialysis Clinical Trial

— RE-THINc ESRD  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04534114
• Other study ID #: 21170
• Secondary ID: 2019-003927-39
• Status: Completed
• Phase: Phase 2
• Start date: September 4, 2020
• Est. completion date: May 12, 2022

Study information

• Verified date: June 2023
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 307
• Est. completion date: May 12, 2022
• Est. primary completion date: January 24, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• End Stage Renal Disease Requiring Hemodialysis
• Kidney Diseases
• Kidney Failure, Chronic

Intervention

Drug:
• Fesomersen sodium (BAY2976217)
Study intervention will be injected subcutaneously.
• Placebo
Matching placebo to BAY2976217 will be injected subcutaneously.

Locations

Country	Name	City	State
Belgium	OL Vrouwziekenhuis - Campus Aalst	Aalst
Belgium	UZ Brussel	Bruxelles - Brussel
Belgium	UZ Antwerpen	Edegem
Belgium	Regionaal ZH Jan Yperman Campus Mariaziekenhuis	Ieper
Bulgaria	First Dialysis Services Bulgaria Ead	Montana
Bulgaria	MHAT Samokov	Samokov
Bulgaria	MHAT "Knyaginya Klementina - Sofia"EAD	Sofia
Bulgaria	MHAT National Cardiology Hospital EAD	Sofia
Canada	Etobicoke General Hospital	Etobicoke	Ontario
Canada	St. Joseph's Healthcare - Hamilton	Hamilton	Ontario
Canada	Centre de services ambulatoires de dialyse de Gaspé	Montreal	Quebec
Canada	Lakeridge Health-Oshawa	Oshawa	Ontario
Canada	CHU de Québec-Université Laval	Quebec
Canada	Unity Health Toronto: St. Michael's Hospital	Toronto	Ontario
Czechia	Nemocnice Frydek-Mistek	Frydek-Mistek
Czechia	Klatovska nemocnice	Klatovy
Czechia	Fresenius Medical Care - DS, s.r.o.	Melnik
Czechia	Oblastni nemocnice Mlada Boleslav	Mlada Boleslav
Germany	DaVita Clinical Research Deutschland GmbH	Duesseldorf	Nordrhein-Westfalen
Germany	DaVita Clinical Resarch Germany GmbH	Geilenkirchen	Nordrhein-Westfalen
Germany	Universitätsklinikum Schleswig-Holstein (UKSH)	Kiel	Schleswig-Holstein
Greece	University General Hospital of Heraklion	Heraklion
Greece	University General Hospital of Patra	Patra
Greece	PAPANIKOLAOU General Hospital Thessaloniki	Pilea Chortiatis
Hungary	Bacs-Kiskun Megyei Korhaz	Kalocsa
Hungary	SZTE ÁOK Szent Györgyi Albert Klinikai Kozpont	Szeged
Japan	Medical corporation association Shunshin-kai Inage hospital	Chiba
Japan	Shonan Fujisawa Tokushukai Hospital	Fujisawa	Kanagawa
Japan	Public Central Hospital of Matto Ishikawa	Hakusan	Ishikawa
Japan	Hanyu General Hospital	Hanyu	Saitama
Japan	Matsunami General Hospital	Hashima-gun	Gifu
Japan	Ibaraki Prefectural Central Hospital	Kasama	Ibaraki
Japan	Sapporo Tokushukai Hospital	Sapporo	Hokkaido
Korea, Republic of	The Catholic University of Korea, Incheon St.Mary's Hospital	Incheon	Incheon Gwang''yeogsi
Korea, Republic of	Yeouido St. Mary's Hospital	Seoul	Seoul Teugbyeolsi
Latvia	Daugavpils Regional Hospital	Daugavpils
Latvia	Liepaja Regional Hospital	Liepaja
Latvia	P. Stradins Clinical University Hospital	Riga
Latvia	Vidzemes Hospital	Valmiera
Russian Federation	High Technology Center Clinic 1	Moscow
Russian Federation	Limited Liability Company "Nefroline-Novosibirsk"	Novosibirsk
Russian Federation	LLC Frezenius Nefrocare	Penza
Russian Federation	LLC Dialysis center	Podolsk
Russian Federation	Nikiforov All-Russian Center of Emergency and Radiation Med	Saint-Petersburg
Russian Federation	Botkin clinical infectious diseases hospital	St. Petersburg
Russian Federation	LLC B. Brown Avitum Russland Clinics	St. Petersburg
Russian Federation	State Budgetary Healthcare Institution City Hospital #26	St. Petersburg
Spain	Hospital Principe de Asturias	Alcalá de Henares	Madrid
Spain	Hospital Clínic i Provincial de Barcelona	Barcelona
Spain	Hospital Universitari de Bellvitge | Bellvitge Biomedical Research Institute - Cardiology - AF, Stroke Prevention	Barcelona
Spain	Hospital Universitario Virgen de las Nieves|Nefrologia	Granada
Spain	Hospital Universitari i Politècnic La Fe | Nefrología	Valencia
Taiwan	Chi Mei Medical Center	Tainan
Taiwan	Taipei Medical University Hospital	Taipei
Ukraine	Medical Center Fresenius Medical Care Ukraine, LLC	Chernigiv
Ukraine	Kyiv City Center of Nephrology and Dialysis	Kyiv
Ukraine	Kyiv Regional Clinical Hospital	Kyiv
Ukraine	Regional Clinical Hospital - Odessa	Odesa
Ukraine	Ternopil Regional Clinical Hospital	Ternopil
Ukraine	Zaporizhia Municipal Clinical Hospital No.10	Zaporizhzhya
United States	Fresenius Kidney Care Clovis	Clovis	California
United States	Davita East Ft. Lauderdale Dialysis Center	Fort Lauderdale	Florida
United States	Fresenius Medical Care - Fire Mesa Dialysis Unit	Las Vegas	Nevada
United States	Fresenius Kidney Care St. Louis Regional Dialysis	Saint Ann	Missouri
United States	Chromalloy Dialysis Center	Saint Louis	Missouri
United States	Salem VA Medical Center	Salem	Virginia
United States	DaVita Northwest Medical Center Dialysis	San Antonio	Texas
United States	San Antonio Kidney Disease Center Physicians Group, PLLC	San Antonio	Texas
United States	Desert Cities Dialysis-Amethyst & Desert Cities Dialysis	Victorville	California

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  Canada,  Czechia,  Germany,  Greece,  Hungary,  Japan,  Korea, Republic of,  Latvia,  Russian Federation,  Spain,  Taiwan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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)

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