Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2, Randomized, Double Blind, Placebo Controlled Study of the Safety, PK, and PD of Multiple Doses of ISIS 416858 (ISIS-FXI RX), Administered Subcutaneously to Patients With End-Stage Renal Disease on Hemodialysis
Brief Summary: Evaluation of safety, tolerability, PK and PD of ISIS 416858 in patients with end-stage renal disease (ESRD) receiving chronic hemodialysis.


Options:
A: Inclusion Criteria:

* Prevalent NHHD patients who have received \>1 year dialysis with unfractionated heparin as anticoagulant
* Age \>= 18
* Informed consent available

Exclusion Criteria:

* History of intolerance to LMWHs during HD
* Receiving warfarin or other oral anticoagulant
* Pregnant patients
B: Inclusion Criteria:

* Outpatient conventional hemodialysis three times per week for at least three months.
* Arteriovenous fistula as vascular access
* Patients who have given their informed consent in writing.

Exclusion Criteria:

* Catheter as vascular access
* Allergy or intolerance to citrate
* Patients with sufficient cognitive impairment that would prevent the compression of information and informed consent.
* Inflammatory intercurrent diseases (chronic infections, autoimmune diseases or tumors) that can mask the results of the study.
C: Inclusion Criteria:

* End-stage kidney disease (ESKD) with chronic hemodialysis treatment 3 times per week (with about at least 3.5 hours per dialysis)
* Chronic (i.e. repeated) paroxysmal, persistent or permanent atrial fibrillation (AF) or atrial flutter (AFL) documented by standard or Holter ECG on at least 2 separate days before (or apart from) hemodialysis procedures
* Increased risk of stroke or systemic embolism identified by a CHA2DS2-VASc score of 2 or more as an indication for oral anticoagulation
* Patients with ischemic stroke that meet the above criteria, can be included after more than 3 months if not severely handicapped (modified Rankin scale 0 or 1 of 6, i.e. no symptoms or no significant disability and able to carry out all usual activities, despite some symptoms (Farrell, Godwin, Richards, and Warlow (1991))
* Males and females, aged 18 or older

Exclusion Criteria:

* AF or AFL due to reversible causes (e.g., thyrotoxicosis, pericarditis)
* Patients with a new onset of hemodialysis within the last 3 months
* Clinically significant (moderate or severe) aortic and mitral stenosis
* Conditions other than AF or AFL that require chronic anticoagulation (e.g., a prosthetic mechanical heart valve).
* Active infective endocarditis
* Any planned interventional or surgical AF or AFL ablation procedure
* Any active bleeding
* A serious bleeding event in the previous 6 months before screening
* Inadequately controlled (HbA1c levels \>8.5%) or untreated diabetes
* History of malignant neoplasms at high risk of current bleeding (see summary of product characteristics (SmPC) of study drugs)
* Known indication for treatment with NSAIDs (see SmPC of study drugs) - acetylsalicylic acid (ASA) up to 100 mg per day is allowed
* Known Antiphospholipid Syndrome requiring anticoagulation
* Impaired liver function e.g., caused by active infection with HIV, HBV or HCV, hepatitis or other liver damage (No limits for ALT and AST values are defined in this study protocol, although mentioned in the SmPC because they are frequently elevated in dialysis patients. In case of clinically relevant increase of ALT or AST level, patient's eligibility is to be decided by the responsible investigator)
* Any type of stroke within 3 months prior to baseline
* Other indication for anticoagulation than AF or AFL
* Valvular heart disease requiring surgery
* A high risk of bleeding (e.g., active peptic ulcer disease, a platelet count of \<100,000 per cubic millimeter or hemoglobin level of \<8 g per deciliter)
* Documented hemorrhagic tendencies or blood dyscrasias
* Current alcohol or drug abuse
* Life expectancy of less than 1 year
* Indication for dual platelet inhibition at baseline (ASA ≤ 100 mg/day is allowed, clopidrogel is excluded at any dose).
* Active infection or symptoms suggestive of COVID-19 infection.
D: Inclusion Criteria:

* End stage renal disease maintained on outpatient hemodialysis at a healthcare center for \> 3 months from screening with hemodialysis using heparin (unfractionated heparin or low-molecular weight heparin) 3 times per week for a minimum of 3 hours per dialysis session and plan to continue this throughout the study.

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:

  * Platelet count \< 150,000 cells/mm3
  * INR \> 1.4
  * aPTT \> upper limit of normal (ULN)
* Abnormal liver function at Screening:

  * ALT or AST \> 2 x ULN
  * Total bilirubin \> ULN
* 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)

Answer: D