Phase 2c Dose Comparison Study of MP4OX in Trauma

Study Overview
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Brief Summary
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MP4OX is being developed as an ischemic rescue therapy to perfuse and oxygenate tissues at risk during hemorrhagic shock. MP4OX is a pegylated hemoglobin-based colloid designed to improve perfusion and target delivery of oxygen to ischemic tissues. This study will evaluate safety and efficacy of MP4OX treatment, in addition to standard therapy, in trauma patients suffering from lactic acidosis due to severe hemorrhagic shock.

Detailed Description
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Acute trauma, including both blunt and penetrating injury, is often associated with uncontrolled bleeding that leads to hemorrhagic shock. During shock, inadequate blood flow results in local ischemia and tissue hypoxia (insufficient oxygenation) of critical organs with resulting lactic acidosis. More than 10% of trauma victims who reach hospital alive will die, and many will suffer from organ failure. The primary goal when treating traumatic hemorrhage is to control blood loss, support ventilation and oxygenation, and maintain cardiovascular function to maintain organ perfusion. Despite optimal care, organ dysfunction is present in many patients as evidenced by persistent lactic acidosis. Blood transfusions are intended to improve circulation of oxygen-carrying red blood cells, but are frequently insufficient, even when the hemoglobin level is optimized. The severity of lactic acidosis in trauma victims has also been shown to correlate with worse outcome. Support for the proposed application for MP4OX as a therapeutic adjunct to standard treatment of severe hemorrhage shock, is based on multiple preclinical studies in different animal models of hemorrhagic shock resuscitation. These preclinical studies demonstrated that survival was greater and restoration of acid-base status and hemodynamics were improved with MP4OX. The benefits of MP4OX in animals were observed with or without co-administration of autologous blood, demonstrating that red cell transfusion alone was insufficient, and that the effects of MP4OX were additive. The hypothesis for the current study is that MP4OX will enhance perfusion and oxygenation of ischemic organs and thereby prevent and reduce the duration of organ failure and improve morbidity and mortality outcome measures.

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

Conditions
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Trauma, Hemorrhagic Shock, Lactic Acidosis

Intervention / Treatment
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* Drug: MP4OX
* Drug: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Trauma injury (blunt and/or penetrating) resulting in lactic acidosis due to hemorrhagic shock Acidosis (blood lactate level ≥ 5 mmol/L; equivalent to 45 mg/dL) Exclusion Criteria: Massive injury incompatible with life Normalization of lactate prior to dosing (≤ 2.2 mmol/L) Evidence of severe traumatic brain injury (TBI) as defined by ANY one of the following: Known non-survivable head injury or open brain injury; Known AIS (head region) ≥ 4 by an appropriate imaging methodology; Contemplated CNS surgery; Abnormal physical exam indicative of severe CNS or any spinal cord injury above T5 level; or Glasgow Coma Score (GCS) = 3, 4 or 5. Cardiac arrest prior to randomization Known age below the legal age for consenting Estimated time from injury to randomization > 4 hours Estimated time from hospital admission to randomization > 2 hours Known pregnancy Use of any oxygen carrier other than RBCs Known previous participation in this study Professional or ancillary personnel involved with this study Known receipt of any investigational drug(s) within 30 days prior to study

Ages Eligible for Study
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Minimum Age: 18 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 500-mL<br>500-mL dose of MP4OX | Drug: MP4OX<br>* 4.3 g/dL pegylated hemoglobin in balanced lactate-electrolyte solution<br>* Other names: Pegylated-Hb;|
| Experimental: MP4OX 750-mL<br>750-mL dose of MP4OX | Drug: MP4OX<br>* 4.3 g/dL pegylated hemoglobin in balanced lactate-electrolyte solution<br>* Other names: Pegylated-Hb;|
| Sham Comparator: Control<br>Standard crystalloid Keep Vein Open (KVO) infusion | Drug: Control<br>* Crystalloid solution IV infusion drip to keep vein open<br>* Other names: Sham infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects discharged from hospital through Day 28 and alive at the Day 28 Follow up visit |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital-free, ICU-free, and Ventilator-free days |  | Through 28 and 60 days | 
| Proportion of subjects remaining in hospital, ICU or on ventilator |  | Through 28 and 60 days | 
| Days in hospital, in ICU, or on Ventilator |  | Through 28 and 60 days | 
| All-cause Mortality |  | At 48 hours and 28 or 60 days | 
| Time to discharge from ICU, hospital discharge, or liberation from ventilation |  | Through 28 or 60 days | 
| Composite of Time to Complete Organ Failure Resolution (CTCOFR) |  | Day 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trauma, Hemorrhagic shock, Hemorrhage, Lactic acidosis, Oxygen therapeutics, Oxygen carriers, Ischemic rescue therapy, Hemoglobin solutions, PEGylated hemoglobin