The Treatment of Acute Pulmonary Thromboembolism (PE) of GSK576428 (Fondaparinux Sodium) in Japanese Patients

Study Overview
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Brief Summary
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The primary objective is to evaluate the efficacy (as measured by the rate of recurrent symptomatic Venous Thromboembolism [VTE] (i.e., Pulmonary thromboembolism [PE] and Deep Vein Thrombosis [DVT])) and safety of GSK576428 as the initial treatment in subjects with acute PE in an open-label design.

Official Title
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Clinical Evaluation of GSK576428 (Fondaparinux Sodium) in the Treatment of Acute Pulmonary Thromboembolism (PE)

Conditions
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Embolism, Pulmonary

Intervention / Treatment
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* Drug: Fondaparinux sodium
* Drug: unfractionated heparin (UFH)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with a confirmed diagnosis (by Multi detector-row CT [MDCT]) of acute symptomatic PE who are hemodynamically stable (i.e., the condition where anticoagulant therapy alone are indicated) (the time from onset should be no longer than 5 days, and subjects with or without symptomatic DVT are eligible) Age: >=20 years Gender: No restriction Female subjects must either be of non-childbearing potential (post-menopausal >1 year, hysterectomy, or sterilization), or of childbearing potential, has a negative pregnancy test at screening, and agree to use contraception throughout the study period. Hospitalization status: Subjects who are able to stay at the hospital at least during the initial treatment period. Written informed consent from the subject him/herself or his/her legally acceptable representative. Written informed consent from the subject's legally acceptable representative must be obtained if the subject is incapable of giving consent. Exclusion Criteria: Shock or hemodynamic instability*. *: Defined as shock or decreased blood pressure (systolic blood pressure <90 mmHg or >=40 mmHg) lasting for at least 15 minutes and does not represent hemodynamically unstable conditions due to newly emergent arrhythmia, dehydration or sepsis. Right cardiac function failure detected by echocardiography at screening. Requirement for surgical thrombectomy, catheter intervention and thrombolytic therapy for the current PE. Subjects (for example, with free-floating thrombus in the femoral vein or ilium by MDCT at screening) for whom insertion of inferior vena cava filter is indicated or subjects in whom inferior vena cava filter is present. Prior to entry into the study, therapeutic dosage of anticoagulants for more than 24 hours to treat the current episode. Active, clinically significant bleeding Thrombocytopenia (platelet count <10×10⁴/µL at screening) Concurrent conditions with bleeding risk (e.g., ulcer of the gastrointestinal tract, diverticulitis of the gastrointestinal tract, colitis, acute bacterial endocarditis, severe hypertension*, or severe diabetes) or bleeding tendency. *: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg Severe hepatic disorder Known hypersensitivity to heparin, low-molecular-weight heparin (LMWH) or warfarin Previous history of cerebral hemorrhage Brain, spinal, or ophthalmological surgery within 3 months prior to entry into this study Previous history of Heparin-induced thrombocytopenia Patients for whom anticoagulant therapy is contraindicated or who cannot be taken off anticoagulant therapy due to coexistent condition (e.g. prosthetic heart valve implant). Severe renal disorder (serum creatinine >2.0 mg/dL [180 µmol/L] at screening) in a well hydrated subject Documented hypersensitivity to contrast media Use of any contraindicated drug that cannot be combined with the injection of contrast medium [e.g., antihyperglycemic metformin hydrochloride (Glycoran®, Melbin®)] Participation in any other therapeutic drug study or a clinical study within 6 months prior to entry into this study Previous participation in a study of GSK576428 Drug or alcohol abuse Systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg Recent surgery within 3 days prior to entry into the study Life expectancy <3 months Pregnant women, nursing mothers, women who may be pregnant, or women contemplating pregnancy during the study period Others whom the investigator or subinvestigator considers not eligible for the study

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fondaparinux<br> | Drug: Fondaparinux sodium<br>* The dose of Fondaparinux will be determined based on a subject's body weight (<50 kg, 5 mg; 50 to 100 kg, 7.5 mg; >100 kg, 10 mg) and administered once daily by subcutaneous (SC) injection.<br>* Other names: GSK576428;|
| Other: unfractionated heparin<br> | Drug: unfractionated heparin (UFH)<br>* UFH therapy will be started on Day 1 while adjusting activated partial thromboplastin time (aPTT) to maintain aPTT 1.5 to 2.5 times control.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants With Recurrent or New Symptomatic Venous Thromboembolism (VTE) | VTE (pulmonary thromboembolism [PE] and/or deep vein thromboembolism [DVT]) was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). | From Day 1 to Day 90 (±7 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants With Recurrent or New Symptomatic/Asymptomatic Venous Thromboembolism (VTE) (by Type) | VTE (pulmonary thromboembolism [PE] and/or deep vein thromboembolism [DVT]) was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). | From Day 1 to Day 90 (±7 days) | 
| The Percentage of Participants With Perfusion Lung Scan Results Scored as Improved, no Change, or Worse | Improved, No change, or Worse was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). Each category is adjudicated by comparison with the perfusion score at baseline by the CIACE. | Baseline, Days 5-10 (the day when the medication [FPX or UFH] was finished /discontinued) (+/-1) | 
| Total Perfusion Score at Baseline and Mean Change From Baseline at Days 5-10 | The perfusion score (0: no perfusion; 0.25, 0.5, 0.75, 1: normal) in each of the six lobes of the lung was adjudicated blindly by the Central Independent Adjudication Committee of Efficacy (CIACE). Total perfusion score (r) was calculated as: r = (0.25 x right lower lobe) + (0.12 x right middle lobe) + (0.18 x right upper lobe) + (0.20 x left lower lobe) + (0.12 x lingula) + (0.13 x left upper lobe). | Baseline, Days 5-10 (the day when the medication [FPX or UFH] was finished /discontinued) (+/-1) | 
| The Percentage of Participants With a Bleeding Event | Bleeding events (major bleeding [clinically overt bleeding with: fatality, location in critical organ, a fall in hemoglobin >=2 g/dL, or a transfusion >=2 units], minor bleeding [clinically overt bleeding and not adjudicated as major bleeding]) were adjudicated blindly by the Central Independent Adjudication Committee of Safety (CIACS). | FPX or UFH treatment period (Days 5-10, on average) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fondaparinux sodium, contrast-enhanced MDCT, Deep Vein Thrombosis, Pulmonary thromboembolism