Adjuvant Treatment of Pulmonary Embolism With Drotrecogin Alfa (Activated): Phase II Exploratory Study

Study Overview
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Brief Summary
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An exploratory, multicenter, randomized, placebo-controlled, double blind, dose escalation study comparing a standard therapy for submassive pulmonary embolism (Enoxaparin sodium) to a combined therapy of Drotrecogin alfa (activated) plus Enoxaparin sodium.

Official Title
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Drotrecogin Alfa (Activated) (LY203638)] Exploratory, Safety Study, Multi-Center, Randomized, Placebo-Controlled, Dose Escalating Study Design, Comparing a Standard Therapy (Enoxaparin Sodium) for Submassive Pulmonary Embolism to a Combined Therapy of Drotrecogin Alfa (Activated) Plus Enoxaparin Sodium.

Conditions
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Submassive Pulmonary Embolism

Intervention / Treatment
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* Drug: Drotrecogin Alfa (Activated)
* Drug: Enoxaparin
* Drug: Placebo
* Drug: Drotrecogin Alfa (Activated)
* Drug: Drotrecogin Alfa (Activated)
* Drug: Drotrecogin Alfa (Activated)


Participation Criteria
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Eligibility Criteria
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Patients with symptoms of acute pulmonary embolism (PE), without an indication for fibrinolytic therapy but with echocardiographic evidence of right ventricular dysfunction (submassive PE) within 48 hours of onset of symptoms Inclusion Criteria: Clinical symptoms of Pulmonary embolism for less than 48 hours Exclusion Criteria: Patients with symptoms of Pulmonary embolism for more than 48 hours

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Drotrecogin Alfa (Activated)<br>* 6 micrograms/kilograms/hour (ug/kg/hr), intravenous (IV), one infusion, over 12 hours<br>* Other names: Xigris, LY203638;Drug: Enoxaparin<br>* 1 milligram/kilogram (mg/kg), subcutaneous, every 12 hours until the target International Normalized Ratio (INR) is reached, minimum of 5 days<br>|
| Experimental: 2<br> | Drug: Enoxaparin<br>* 1 milligram/kilogram (mg/kg), subcutaneous, every 12 hours until the target International Normalized Ratio (INR) is reached, minimum of 5 days<br>Drug: Drotrecogin Alfa (Activated)<br>* 12 micrograms/kilograms/hour (ug/kg/hr), intravenous (IV), one infusion, over 12 hours<br>* Other names: Xigris, LY203638;|
| Experimental: 3<br> | Drug: Enoxaparin<br>* 1 milligram/kilogram (mg/kg), subcutaneous, every 12 hours until the target International Normalized Ratio (INR) is reached, minimum of 5 days<br>Drug: Drotrecogin Alfa (Activated)<br>* 18 micrograms/kilograms/hour (ug/kg/hr), intravenous (IV), one infusion, over 12 hours<br>* Other names: Xigris, LY203638;|
| Experimental: 4<br> | Drug: Enoxaparin<br>* 1 milligram/kilogram (mg/kg), subcutaneous, every 12 hours until the target International Normalized Ratio (INR) is reached, minimum of 5 days<br>Drug: Drotrecogin Alfa (Activated)<br>* 24 micrograms/kilograms/hour (ug/kg/hr), intravenous (IV), one infusion, over 12 hours<br>* Other names: Xigris, LY203638;|
| Placebo Comparator: 5<br> | Drug: Enoxaparin<br>* 1 milligram/kilogram (mg/kg), subcutaneous, every 12 hours until the target International Normalized Ratio (INR) is reached, minimum of 5 days<br>Drug: Placebo<br>* intravenous (IV), one infusion, over 12 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Major Bleeding Events | Number of patients with major bleeding events, defined as: Reduction in hemoglobin of 2 to 5 grams per deciliter (g/dL) within 24 hours; Transfusion of 2 to 4 units of packed red blood cells within 24 hours; Hematoma requiring prolonged hospitalization or surgical intervention; Intracranial or retroperitoneal hemorrhage. | baseline through day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Right Ventricular Enddiastolic Area/Left Ventricular Enddiastolic Area (RVEDA/LVEDA) Ratios | Change of right ventricular function measured as difference of right ventricular enddiastolic area/left ventricular enddiastolic area (RVEDA/LVEDA) ratios by echocardiography | baseline, day 6, day 90 | 
| Chronic Respiratory Questionnaire Self-Administered Standardized Format (CRQ-SAS of the McMaster University Canada) | Scores in each of the 4 domains (dyspnea, fatigue, emotional, and mastery) ranged from 1 (maximum impairment) to 7 (no impairment). | baseline and day 90 (follow-up) | 
| Difference in Pulmonary Artery (PA) Pressure | Investigator decided estimate of pulmonary artery pressure by echocardiography would not be useful and no data on pulmonary artery pressure were collected. | baseline, day 6, day 90 |