Phase IIa Study of MP4OX in Traumatic Hemorrhagic Shock Patients

Study Overview
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Brief Summary
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MP4OX is a novel oxygen therapeutic agent specifically developed to perfuse and oxygenate tissue at risk for ischemia and hypoxia. MP4OX is a pegylated hemoglobin-based colloid and and as a result of its molecular size and unique oxygen dissociation characteristics, targets oxygen delivery to ischemic tissues by selectively off-loading oxygen in tissues predisposed to low oxygen tension. Sangart is currently evaluating MP4OX to reduce organ dysfunction and failure in trauma patients with lactic acidosis due to severe hemorrhagic shock.

Detailed Description
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Acute traumatic injury, including both blunt and penetrating injury, is often associated with severe bleeding which can lead to hemorrhagic shock. During shock, inadequate perfusion of critical organs can lead to local ischemia and tissue hypoxia (insufficient oxygenation), which can be detected by an increase in serum lactate levels. Despite optimal care, more than 10% of trauma victims who reach hospital alive will die, and many will suffer from organ failure. Death and significant, persistent morbidity are consequences of trauma, and traumatic injuries are associated with lost productivity, reduced quality of life, and direct costs to patients and health care systems worldwide. Current therapies, which also include blood transfusion, are aimed at supporting failing organs, but a therapeutic agent that could help to quickly restore adequate oxygenation may be beneficial to prevent or shorten duration of organ failure and improve patient outcome. Direct support for the proposed clinical application to use MP4OX in resuscitation from hemorrhage is found in preclinical animal studies. Using a pig model of uncontrolled hemorrhage and resuscitation, survival was greater and restoration of hemodynamics and acid-base status were improved with MP4OX relative to an equivalent volume of crystalloid, pentastarch, or unmodified hemoglobin. Administration of MP4OX improved 24-hour survival, stabilized cardiac output and arterial pressure at nearly normal levels, and reduced lactate levels more effectively than the control fluids. Importantly, these benefits of MP4OX were observed with or without co-administration of autologous blood, suggesting that blood alone was not sufficient to achieve complete resuscitation, and that the effects of MP4OX appear to be additional to those of blood.

Official Title
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A Multi-center, Randomized, Double-blind, Controlled Dose-finding Study to Evaluate the Safety and Efficacy of MP4OX Treatment Plus Standard of Care in Severely Injured Trauma Patients With Lactic Acidosis Due to Hemorrhagic Shock

Conditions
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Shock, Hemorrhagic, Shock, Traumatic, Acidosis, Lactic

Intervention / Treatment
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* Drug: MP4OX
* Drug: MP4OX
* Drug: Ringers Lactate solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female (surgically sterile or post-menopausal or confirmed not to be pregnant) Trauma injury (blunt and/or penetrating) resulting in lactic acidosis due to hemorrhagic shock (blood lactate level ≥ 5 mmol/L; equivalent to ≥ 45 mg/dL) Informed consent obtained before any study-related activities Exclusion Criteria: Not expected to survive 24 hours after randomization Evidence of severe traumatic brain injury as defined by any one of the following: Known non-survivable head injury or open brain injury; Glasgow Coma Score (GCS) = 3, 4 or 5, or known AIS = 5 if GCS > 5; Immediate open intracranial operation; Abnormal physical exam indicative of severe CNS or spinal injury Significant ongoing uncontrolled hemorrhage where control of bleeding is not expected within 2 hours of randomization Cardiac arrest prior to dosing Estimated time from injury to dosing > 4 hours Estimated time from hospital admission to randomization > 2 hours Known or suspected pregnancy (confirmed by urine test) Previous participation in this study Professional or ancillary personnel involved with this study Receipt of any investigational drug(s) within 30 days prior to study

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MP4OX - 250<br>250 mL dose | Drug: MP4OX<br>* 4.3 g/dL PEG-Hb solution in lactated electrolyte solution<br>* Other names: Pegylated-Hb;|
| Experimental: MP4OX - 500<br>500 mL dose | Drug: MP4OX<br>* 4.3 g/dL PEG-Hb solution in lactated electrolyte solution<br>* Other names: Pegylated-Hb;|
| Active Comparator: Ringers Lactate solution<br>500 mL dose | Drug: Ringers Lactate solution<br>* Ringers Lactate solution for Injection<br>* Other names: Hartmann's solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum lactate clearance |  | 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality |  | 28 days | 
| Ventilator-free days |  | 28 days | 
| ICU-free days |  | 28 days | 
| Hospital-free days |  | 28 days | 
| Sepsis-related Organ Failure Assessment (SOFA) score |  | Daily | 
| Modified Denver score |  | Daily | 
| Composite endpoint of Time to Complete Organ Failure Resolution (CTCOFR) |  | At 14 and 21 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trauma, Hemorrhage, Hemorrhagic shock, Lactic acidosis, Oxygen carriers, Oxygen therapeutics, Hemoglobin solutions, Hemoglobin substitutes, Red cell substitutes, PEG-hemoglobin