Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open-label, Randomized, Active Comparator-Controlled, Adaptive Parallel-group Phase 2 Study to Assess the Safety and Efficacy of Multiple Doses of ISIS 416858 Administered Subcutaneously to Patients Undergoing Total Knee Arthroplasty
Brief Summary: The purpose of this study is:

* To assess the safety and efficacy profile of ISIS-FXIRx, including incidence of bleeding and VTE, in patients undergoing total knee arthroplasty.
* To compare the efficacy and safety profile of ISIS-FXIRx in patients who achieve less than or equal to 0.2 U/mL FXI activity levels to that of enoxaparin.


Options:
A: Inclusion Criteria:

* Give written informed consent
* Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. Males must be surgically sterile, abstinent, or if engaged in sexual relations of child-bearing potential, must use contraception
* Undergoing elective, primary unilateral total knee arthroplasty

Exclusion Criteria:

* Body weight \<50 kg
* Patients at increased risk of bleeding. History of intracranial or intraocular bleeding. History of gastrointestinal and/or endoscopically verified ulcer disease within the past year.
* History of excessive intra- or direct post operative bleeding or a traumatic spinal or epidural anesthesia
* Brain, spinal, or ophthalmologic surgery within the past 3 months
* History of clinically significant liver disease in the past year
* Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values

  * aPTT or PT or INR \>ULN
  * Factor IX activity \<LLN
  * Factor VIII activity, vWF antigen or Ristocetin cofactor activity \<0.5 U/mL
  * FXI activity \<0.3 U/mL
  * Urine protein or blood persistently positive by dipstick. In the event of positive test results, eligibility may be confirmed with urine microscopy or 24 hour urine protein measurement as applicable
  * ALT or AST \>1.5 x ULN
  * Total bilirubin \>ULN
  * Platelet count \<150,000 (or history of thrombocytopenia)
* Hypersensitivity to enoxaparin
* Anticipated concomitant use of anticoagulants/antiplatelet agents or the NSAID nimesulide that may affect study outcome or any other drug influencing coagulation (except low dose aspirin and short acting NSAIDs with a half-life \<20 hours) at least 7 days before surgery or during treatment with ISIS Rx.
* Anticipated use of indwelling intrathecal or epidural catheters
* Anemia at Screening
* Have any other conditions which could interfere with the patient participating in or completing the study
B: 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.
C: Inclusion Criteria:

* 18 years or older
* experienced stable dialysis sessions during the last 4 weeks
* double needle/lumen well-functioning vascular access

Exclusion Criteria:

* known coagulation disorder
* active inflammation
* malignancy
D: Inclusion Criteria:

* Males and females, age at least 18 years, or the local age of consent, whichever is greater.
* Patients with AF defined as AF on ECG at enrollment or two or more reports of AF from separate monitoring events at least 2 weeks apart (report of ECG, Holter monitor, event monitor or implantable loop recorder).
* CHA2DS2-VASc score of ≥ 2.
* End-stage renal disease treated with hemodialysis for ≥ 3 months.
* Considered by the treating physician(s) to be candidate for oral anticoagulation.
* If of childbearing potential, be willing to avoid pregnancy during the study.

Exclusion Criteria:

* Not considered by the treating physician(s) to be candidates for oral anticoagulation (for example, hemoglobin \< 8.5g/dL, history of intracranial hemorrhage, active bleeding, recent gastrointestinal bleed or retroperitoneal bleed, severe hepatic impairment, or anaphylactic reaction to apixaban)
* Moderate or severe mitral stenosis
* Conditions other than AF that require anticoagulation such as mechanical prosthetic valve, deep venous thrombosis, or pulmonary embolism
* Need for aspirin at a dose \> 81 mg a day or need for P2Y12 antagonist therapy (for example clopidogrel, prasugrel, or ticagrelor)
* Life expectancy \< 3 months
* Anticipated kidney transplant within the next 3 months
* Prisoners or others who are involuntarily incarcerated or detained
* Pregnant, breastfeeding, or considering pregnancy.
* Participation in a clinical trial of an experimental treatment within the past 30 days

Answer: A