Study of an Investigational Drug for the Prevention of Thrombosis-related Events Following Hip Replacement Surgery (ADVANCE-3)

Rates of Adjudicated All-cause Death, VTE-related Death, Pulmonary Embolism (PE), Nonfatal PE, Deep Vein Thrombosis (DVT) (Symptomatic and Asymptomatic), Symptomatic and Asymptomatic Proximal and Distal DVT During the Intended Treatment Period

VTE=venous thromboembolic event; VTE-related death=combination of fatal or nonfatal PE and symptomatic or asymptomatic DVT. Event rate=Number of events divided by the number of patients evaluated.

Time frame: Day 1 (first dose of study drug) to later of 2 days after last dose or 38 days after first dose

Rate of Major Bleeding, Clinically Relevant Nonmajor Bleeding (CRNM), Major or CRNM, and Any Bleeding During the Treatment Period

Event rate=Number of events divided by the number of patients evaluated. Major bleeding event defined as a bleeding event that was 1) Acute clinically overt bleeding accompanied by at least 1 of the following: decrease in hemoglobin of ≥ 2 g/dL over a 24-hour period, transfusion of ≥2 units of packed red blood cells; bleeding that occurred in at least 1 of the following sites: intracranial, intra-spinal, intraocular, pericardial, an operated joint and requires reoperation or intervention, intramuscular with compartment syndrome, or retroperitoneal; 2) Fatal. CRNM was defined as acute clinically overt bleeding that did not satisfy the criteria for a major bleeding event and met at least 1 of the following: epistaxis, gastrointestinal bleed, hematuria, bruising/ecchymosis, or hemoptysis. Minor bleeding was defined as an acute clinically overt bleeding event that did not meet the criteria for major bleeding or a CRNM. Fatal bleeding event was defined as bleeding that was the primary

Time frame: First dose of study drug (presurgery) through 2 days after the last dose of study drug

Number of Participants With Serious Adverse Events (SAEs), Bleeding Adverse Events (AEs), and Death as Outcome

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. All suspected bleeding events were to be reported by the investigator as either an AE or SAE and adjudicated by the Independent Central Adjudication Committee (ICAC). Definitions of bleeding outcomes: Acute clinically overt bleeding =new onset, visible bleeding, or signs or symptoms suggestive of bleeding with confirmatory imaging techniques that could detect the presence of blood.

Time frame: First dose of study drug (presurgery) through 30 days after the last dose of study drug

Number of Participants With a Bleeding-related Adverse Event During the Treatment Period

All suspected bleeding events were to be reported by the investigator as either an adverse event or serious adverse event or and adjudicated by the Independent Central Adjudication Committee (ICAC). Definitions of bleeding outcomes: Acute clinically overt bleeding =new onset, visible bleeding, or signs or symptoms suggestive of bleeding with confirmatory imaging techniques that could detect the presence of blood. All acute clinically overt bleeding events were adjudicated by the ICAC as a major bleeding event or a clinically relevant nonmajor bleeding event; suspected minor bleeding events were not sent for adjudication.

Time frame: First dose of study drug (presurgery) through 2 days after the last dose of study drug

Number of Participants With a Bleeding-related Adverse Events During the Treatment Period (Continued)

All suspected bleeding events were to be reported by the investigator as either an adverse event or serious adverse event or and adjudicated by the Independent Central Adjudication Committee (ICAC). Definitions of bleeding outcomes: Acute clinically overt bleeding =new onset, visible bleeding, or signs or symptoms suggestive of bleeding with confirmatory imaging techniques that could detect the presence of blood. All acute clinically overt bleeding events were adjudicated by the ICAC as a major bleeding event or a clinically relevant nonmajor bleeding event; suspected minor bleeding events were not sent for adjudication.

Time frame: First dose of study drug (presurgery) through 2 days after the last dose of study drug

Number of Participants With a Bleeding-related Adverse Event During the Treatment Period (Continued)

All suspected bleeding events were to be reported by the investigator as either an adverse event or serious adverse event or and adjudicated by the Independent Central Adjudication Committee (ICAC). Definitions of bleeding outcomes: Acute clinically overt bleeding =new onset, visible bleeding, or signs or symptoms suggestive of bleeding with confirmatory imaging techniques that could detect the presence of blood. All acute clinically overt bleeding events were adjudicated by the ICAC as a major bleeding event or a clinically relevant nonmajor bleeding event; suspected minor bleeding events were not sent for adjudication.

Time frame: First dose of study drug (presurgery) through 2 days after the last dose of study drug

Number of Participants With Neurologic Adverse Events With Onset During the Treatment Period

Neurologic events were based on Medical Dictionary for Regulatory Activities search categories.For new or worsening events that were not related to the site of surgery, additional information was collected on a specific form. In addition, neurology consultation was to be obtained for these patients.

Time frame: First dose of study drug (presurgery) through 2 days after the last dose of study drug

Number of Participants With Marked Abnormalities (MA) in Clinical Laboratory Test Results During the Treatment Period

preRx=predose; LLN=lower limit of normal; ULN=upper limit of normal. MA criteria: Hemoglobin: \>2 g/dL decrease from preRx or value ≤ 8 g/dL; hematocrit (%): \<0.75\*preRx; platelet count (\*10\^9 cells/L): \<100,000/mm\^3; erythrocytes (\*10\^6 cells/μL): \<0.75\*preRx level; leukocytes (\*10\^3 cells/μL): \< 0.75\*LLN or \>1.25\*ULN, or if preRx LLN use \< 0.8\*preRx or \>ULN if preRx \>ULN use \>1.2\*preRx or \<LLN; basophils (\*10\^3 cells/μL): \>400/mm\^3; eosinophils (\*10\^3 cells/μL): \> 0.75\*10\^3 cells/μL; lymphocytes (\*10\^3 cells/μL): \>0.75\*10\^3 cells/μL; monocytes (\*10\^3 cells/μL): \>2000/mm\^3; neutrophils (\*10\^3 cells/μL): \<1.0;

Time frame: First dose of study drug (presurgery) through 2 days after the last dose of study drug

Number of Participants With Marked Abnormalities (MA) in Clinical Laboratory Test Results During the Treatment Period (Continued)

preRx=predose; LLN=lower limit of normal; ULN=upper limit of normal. Alanine aminotransferase (ALT) (U/L): \>3 \*ULN: alkaline phosphatase (ALP) (U/L): \>2\* ULN; aspartate aminotransferase (ASP) (U/L): \>3 \*ULN; bilirubin, direct (mg/dL): \>2\*ULN; bilirubin, total (mg/dL): \>2\*ULN; BUN (mg/dL): \>2\*ULN; creatinine (mg/dL): \>1.5\*ULN; calcium (mg/dL): \< 0.8\*LLN or \>1.2 \*ULN, or if preRx \<LLN use \<0.75\* preRx or \>ULN if preRx \>ULN use \> 1.25\*preRx or \<LLN; chloride (mEq/L): \<0.9\*LLN or \>1.1\*ULN, or if preRx \<LLN use \<0.9\*preRx or \>ULN if preRx \>ULN use \>1.1\* preRx or \<LLN; bicarbonate (mEq/L): \< 0.75\* LLN or \>1.25\*ULN, or if preRx \<LLN use \<0.75\*preRx or \>ULN if preRx \>ULN use \>1.25\*preRx or \<LLN; potassium (mEq/L): \< 0.9\*LLN or \>1.1\*ULN, or if preRx \<LLN use \<0.9\*preRx or \>ULN if preRx \>ULN use \>1.1\* preRx or \< LLN; sodium (mEq/L): \<0.95\* LLN or \>1.05×ULN, or if preRx \<LLN use \<0.95\* predose or \>ULN if preRx \>ULN use \>1.05 \*preRx or \< LLN.

Time frame: First dose of study drug (presurgery) through 2 days after the last dose of study drug

Number of Participants With Marked Abnormalities (MA) in Clinical Laboratory Test Results During the Treatment Period (Continued)

preRx=predose; LLN=lower limit of normal; ULN=upper limit of normal. Glucose, fasting (mg/dL): \<.8\*LLN or \>1.5\*ULN, or if preRx \<LLN use \<.8\*preRx or \>ULN if preRx \>ULN use \>2\*preRx or \<LLN; protein, total (g/L): If missing preRx use ≥2, or if value ≥4 or preRx =0 or .5 use ≥2, or if preRx=1 use ≥3, or if preRx =2 or 3 use ≥4; creatine kinase (U/L): \>5\*ULN; uric acid (mg/dL): \>.5\* ULN, or if preRx \>ULN use \>2\*preRx; blood, urine: If missing preRx use ≥2, or if value ≥4, or if preRx=0 or 0.5 use ≥2, or if preRx=1 use ≥3, or if preRx =2 or 3 use ≥4; glucose, urine : If missing preRx use ≥2, or if value ≥4, or if preRx=0 or .5 use ≥2, or if preRx=1 use ≥3, or if preRx=2 or 3 use ≥4; RBC, urine (hpf): If missing preRx use ≥2, or if value ≥4, or if preRx=0 or 0.5 use ≥2, or if preRx dose= 1 use ≥3, or if preRx=2 or 3 use ≥4; WBC, urine (h): If missing preRx use ≥2, or if value ≥4, or if preRx =0 or .5 use ≥2, or if preRx =1 use ≥3, or if preRx=2 or 3 use ≥4.

Time frame: First dose of study drug (presurgery) through 2 days after the last dose of study drug

Number of Participants With Adverse Events Related to Elevations in Liver Function Test Results With Onset During the Treatment Period

Treatment guidelines were provided for jaundice and elevated results of liver function tests.

Time frame: First dose of study drug (presurgery) through 30 days after the last dose of study drug

Rates of Adjudicated Myocardial Infarction (MI)/Stroke, MI, Stroke, and Thrombocytopenia During the Intended Treatment Period

Event rate=Number of events divided by the number of patients evaluated. All suspected events were reported by investigator. Acute MI=the presence of a clinical situation (eg, abnormal history, physical examination, new electrocardiogram changes) suggestive of an MI and at least 1 of the following: elevated creatine kinase (CK)-MB or troponin T or troponin I ≥2\*upper limit of normal (ULN); if CK-MB or troponin values not available, total CK ≥2\*ULN; or new significant (≥0.04 sec) Q waves in ≥2 contiguous leads. Stroke=a new focal neurologic deficit of sudden onset lasting at least 24 hours that was not due to a readily identifiable nonvascular cause. Adjudication classified each reported stroke as primary hemorrhagic, nonhemorrhagic, infarction with hemorrhagic conversion, or unknown type. Thrombocytopenia=after 3 days as drop in platelet count to \<100,000/mm\^3 for patients with a baseline value \>150,000/mm\^3 or a \>50% decline, if the baseline value was ≤150,000/mm\^3.

Time frame: Day 1 (first dose of study drug) to later of 2 days after last dose or 38 days after first dose