Stroke prophylaxis with Apixaban in Chronic Kidney Disease stage 5 patients with Atrial fibrillation (SACK)

The primary objective of this study is to assess the **efficacy** and safety of **apixaban** as a prophylactic treatment for stroke in patients with **Chronic Kidney Disease (CKD) stage 5** and **Atrial Fibrillation (AF)**, with or without dialysis. The study aims to determine if apixaban, when used alongside standard care, reduces the incidence of ischemic stroke and systemic embolism compared to standard care without anticoagulation, without causing an unacceptable increase in fatal or intracranial bleeding. This is clinically relevant as it addresses the balance between reducing thromboembolic events and minimizing bleeding risks in a high-risk population.

Secondary objectives include evaluating the following in patients with CKD stage 5 and AF (with or without dialysis) treated with apixaban compared to standard care without anticoagulation:

• The risk of fatal bleeding and intracranial bleeding, including hemorrhagic stroke.
• The risk of cardiovascular events.
• The risk of all-cause mortality.
• The risk of all-cause stroke.
• The risk of major bleedings.
• The risk of thrombosis.

The clinical trial involves participants diagnosed with **atrial fibrillation** and **chronic kidney disease** stage 5. The study population includes both male and female subjects aged 18 years and older. Participants are selected based on their ongoing treatment with any chronic dialysis or an estimated glomerular filtration rate (eGFR) of less than 20 ml/min/1.73 m², with at least one occasion being less than 15 ml/min/1.73 m² due to chronic kidney disease within the last year. The trial includes individuals with a CHA2DS2-VASc score of 2 or more for men and 3 or more for women, indicating the need for oral anticoagulation. Women of childbearing potential are required to have a negative pregnancy test at screening and must adhere to contraception guidelines during the study. The sponsor has not provided the total number of participants. The trial population is selected to include a vulnerable population, ensuring a comprehensive evaluation of the efficacy and safety of apixaban as stroke prophylaxis in this specific group.

The clinical trial is designed to evaluate the **efficacy** and safety of **apixaban** as a prophylactic treatment for stroke in patients with **Chronic Kidney Disease** (CKD) stage 5 and **Atrial Fibrillation** (AF), with or without dialysis. This is a Phase III, randomized, double-blind, controlled trial. The trial aims to compare the outcomes of patients receiving apixaban in addition to standard care against those receiving standard care without anticoagulation. The primary endpoint is the reduction in the incidence of ischemic stroke and systemic embolism. Secondary endpoints include the occurrence of intracranial bleeding, hospitalization for myocardial infarction, cardiovascular death, and all-cause mortality.

The trial is expected to last until December 31, 2028, with recruitment having commenced on December 1, 2022. Participants will be involved in the study for a maximum treatment period of 72 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor health status and treatment effects, and an end-of-study visit to assess final outcomes. Inclusion criteria require participants to be 18 years or older, with a diagnosis of paroxysmal, persistent, or permanent AF or atrial flutter, and a CHA2DS2-VASc score indicating the need for oral anticoagulation. Women of childbearing potential must have a negative pregnancy test and agree to use contraception during the study.

Participants may be withdrawn from the study early if they experience adverse effects that outweigh the benefits of continued participation, if they withdraw consent, or if they fail to comply with study protocols. The study will utilize film-coated tablets of apixaban, administered orally, with a maximum daily dose of 5 mg. The trial is not categorized as low intervention, and it is not an orphan drug study. The trial's design ensures rigorous assessment of the safety and efficacy of apixaban in this specific patient population.

The clinical trial involves the administration of three **experimental medications** containing the active substance **apixaban**, each provided by different manufacturers. The first medication is "Apixaban Teva GmbH 2.5 mg film-coated tablets," produced by TEVA GMBH. This pharmaceutical form is a film-coated tablet, with each tablet containing 2.5 mg of apixaban. The medication is administered orally, with a maximum daily dose of 5 mg, divided into two doses of 2.5 mg each. The treatment period is set for a maximum of 72 weeks. Compliance with the dosing schedule is monitored through regular assessments.

The second medication is "Apixaban Accord 2.5 mg film-coated tablets," manufactured by ACCORD HEALTHCARE S.L.U. Similar to the first, this medication is also a film-coated tablet containing 2.5 mg of apixaban per tablet. The administration route is oral, with a maximum daily dose of 5 mg, divided into two doses. The treatment duration is up to 72 weeks, and participant adherence to the dosing regimen is closely monitored.

The third medication is "Eliquis 2.5 mg film-coated tablets," provided by BRISTOL-MYERS SQUIBB/PFIZER EEIG. This medication is also in the form of a film-coated tablet, with each tablet containing 2.5 mg of apixaban. The administration is oral, with a maximum daily dose of 5 mg, divided into two doses. The treatment period is up to 72 weeks, with compliance monitored throughout the study.

In addition to the experimental medications, the study includes a **standard-of-care therapy** as a non-experimental treatment. This involves the usual care provided to patients with chronic kidney disease stage 5 and atrial fibrillation, with or without dialysis, but without anticoagulation. The primary objective is to compare the efficacy and safety of apixaban in reducing the incidence of ischemic stroke and systemic embolism against the standard-of-care therapy without anticoagulation. The study ensures rigorous monitoring of participant compliance and safety throughout the trial duration.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary efficacy endpoint is the composite of **ischemic stroke** and systemic embolism. This will determine if treatment with apixaban, in conjunction with standard care, reduces the risk of these events compared to standard care without anticoagulation in patients with Chronic Kidney Disease (CKD) stage 5 and Atrial Fibrillation (AF), with or without dialysis.

Secondary endpoints include a composite event of intracranial bleeding (including hemorrhagic stroke) and fatal bleeding, hospitalization for myocardial infarction, cardiovascular intervention, or cardiovascular death, all-cause death, all-cause stroke or systemic embolism, and major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) consensus. These endpoints will provide a comprehensive assessment of the safety and efficacy of apixaban in the specified patient population.