Phase IIb Study of MP4OX in Traumatic Hemorrhagic Shock Patients

August 20, 2013 updated by: Sangart

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

MP4OX is a novel oxygen therapeutic agent being developed as an ischemic rescue therapy to enhance perfusion and oxygenation of tissues at risk during hemorrhagic shock. MP4OX is a pegylated hemoglobin-based colloid. Due to its molecular size and unique oxygen dissociation characteristics, MP4OX targets delivery of oxygen to ischemic tissues. This study will evaluate the safety and efficacy of MP4OX treatment in trauma patients suffering from lactic acidosis due to severe hemorrhagic shock. The study hypothesis is that MP4OX will reverse the lactic acidosis by enhancing perfusion and oxygenation of ischemic tissues and thereby prevent and reduce the duration of organ failure and improve outcome in these patients.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Acute traumatic injury, including both blunt and penetrating injury, is often associated with severe uncontrolled bleeding which can lead to hemorrhagic shock. During shock, inadequate blood flow results in local ischemia and tissue hypoxia (insufficient oxygenation) of critical organs, which can be detected by an increase in serum lactate levels in these trauma victims. 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.

The primary treatment of trauma is to support ventilation and oxygenation, limit blood loss, and maintain cardiovascular function so that organs are perfused. The patient's airway may be intubated to allow oxygenated airflow to the lungs. Mechanical ventilation is used if the patient cannot maintain oxygenation and carbon dioxide elimination. Damage-control surgery is used to limit blood loss and to intentionally delay definitive repair until the patient can better tolerate procedures. Blood transfusions are provided to maintain the oxygen-carrying capacity of the circulation. Platelets and coagulation factors are infused to correct any coagulopathy from dilution of blood and consumption of clotting factors. Vasopressor and inotropic agents may be used to support low cardiac output or blood pressure. Renal replacement therapy may be instituted if kidney failure occurs.

Despite optimal care, organ dysfunction is present in many patients. Hypoperfusion and anaerobic metabolism of organs and tissues can be detected by the presence of lactic acidosis. Current therapy is aimed at supporting failing organs, but an agent that accelerates the repayment of an oxygen debt and prevents or shortens the duration of organ failure is sought. Blood transfusion improves circulation of oxygen-carrying red blood cells but is insufficient if lactic acidosis is present, even when the hemoglobin level has been restored. Studies in critically ill intensive care patients have demonstrated that elevated initial and 24-hour lactate levels are significantly correlated with mortality, and prolonged elevation of blood lactate levels after trauma has been correlated with increased organ failure and mortality.

Support for the efficacy of MP4OX in resuscitation of severe hemorrhage shock comes from several preclinical studies in hamster, rat, and swine. Using a swine model of uncontrolled hemorrhage and resuscitation, survival was greater and restoration of hemodynamics and acid-base status were improved with MP4OX relative to 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 more effectively than control fluids. Importantly, these benefits of MP4OX were observed with or without co-administration of autologous blood, suggesting that blood alone is not sufficient to achieve resuscitation, and that the effects of MP4OX are additional to those of blood.

Additional support comes from a recently completed phase IIa trauma study in 51 patients with lactic acidosis due to severe hemorrhage. MP4OX treatment was associated with a more rapid and sustained reduction of high lactate levels, and a greater proportion of MP4OX-treated patients who normalized lactate by four hours after dosing. There was also a trend toward shorter median hospital stay and a greater proportion of MP4OX-treated patients being discharged from hospital alive by Day 28. These phase IIa results suggest improved oxygen delivery and utilization by ischemic tissues in the MP4OX-treated patients, based on the reversal of lactic acidosis, and support the positive results from the preclinical models of hemorrhagic shock resuscitation.

Study Type

Interventional

Enrollment (Actual)

348

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
      • Liverpool, Australia
        • Liverpoool Hospital NSW
      • Newcastle, Australia
        • John Hunter Hospital
  • Austria
      • Gratz, Austria
        • Graz University Hospital
  • Brazil
      • Sao Paolo, Brazil
        • Hospital das Clínicas - USP
      • Sao Paolo, Brazil
        • Hospital Universitário - USP Ribeirão Preto
      • São José do Rio Preto, Brazil
        • Faculdade de Medicina de S. J. Do Rio Preto
  • Colombia
      • Cali, Colombia
        • Fundación Valle de Lili
  • France
      • Clichy, France
        • Hopital Beaujon
      • Grenoble, France
        • Hôpital Michallon
      • Le Kremlin Bicetre, France
        • Hôpital du Kremlin Bicetre
      • Lille, France
        • Hôpital Roger Salengro, CHRU Lille
      • Limoges, France
        • Hôpital Dupuytren, CHU Limoges
      • Lyon, France
        • Hôpital Edouard Herriot
      • Lyon, France
        • Hopital Lyon Sud
      • Paris, France
        • Hopital Pitie-Salpetriere
  • Germany
      • Aachen, Germany
        • Universitatsklinikum der RWTH Aachen
      • Berlin, Germany
        • Charité - Campus Virchow Klinikum
      • Cologne, Germany
        • Kliniken der Stadt Köln Merheim
      • Frankfurt, Germany
        • Klinikum der Johann-Wolfgang-Goethe-Universität Frankfurt a.M.
      • Ludwigshafen, Germany
        • BG Klinik Ludwigshafen
  • Israel
      • Beersheba, Israel
        • Soroka University Medical Center
      • Haifa, Israel
        • Rambam Hospital
      • Jerusalem, Israel
        • Hadassah Medical Center
  • New Zealand
      • Auckland, New Zealand
        • Auckland Hospital
  • Norway
      • Oslo, Norway
        • Oslo University Hospital
  • Singapore
      • Singapore, Singapore
        • National University Hospital
      • Singapore, Singapore
        • Singapore General Hospital
      • Singapore, Singapore
        • Tan Tock Seng Hospital
  • South Africa
      • Alberton, South Africa
        • Netcare Union Hospital
      • Cape Town, South Africa
        • Vincent Pallotti Hospital
      • Centurion, South Africa
        • Netcare Unitas Hospital
      • Johannesburg, South Africa
        • Netcare Milpark Hospital
      • Johannesburg, South Africa
        • Charlotte Maxeke Johannesburg Hospital
      • Soweto, South Africa
        • Chris Baragwanath Hospital
  • Spain
      • Madrid, Spain
        • Hospital 12 de Octubre, Madrid
  • Switzerland
      • Lausanne, Switzerland
        • Centre hospitalier universitaire vaudois CHUV
      • Zurich, Switzerland
        • UniversitätsSpital Zürich
  • United Kingdom
      • London, United Kingdom
        • The Royal London Hospital
      • London, United Kingdom
        • King's College Hospital, London
      • Oxford, United Kingdom
        • John Radcliffe Hospital, Oxford

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • ADULT
  • OLDER_ADULT
  • CHILD

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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
  • Acidosis (blood lactate level ≥ 5 mmol/L; equivalent to 45 mg/dL) arterial or venous

Exclusion Criteria:

  • Massive injury incompatible with life
  • Normalization of lactate prior to dosing (≤ 2.2 mmol/L)
  • Patients with 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; Known AIS (head region) ≥ 4 shown by an appropriate imaging methodology; Contemplated CNS surgery; or Abnormal physical exam indicative of severe CNS or any spinal cord injury above T5 level
  • Cardiac arrest prior to randomization
  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: MP4OX
250-mL dose
Drug: MP4OX
4.3 g/dL pegylated hemoglobin in balanced lactate-electrolyte solution
Other Names:
  • Hemoglobin pegylated
  • MalPEG-Hb
  • MP4
  • PEG-Hb
  • Pegylated-Hb
PLACEBO_COMPARATOR: Control
250-mL of normal saline solution
Drug: Saline
Normal saline (0.9%) solution
Other Names:
  • Normal saline
  • Saline solution
  • Sodium chloride 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Proportion of patients discharged from hospital through day 28 and alive at the Day 28 follow-up visit
Time Frame: 28 days
28 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Modified Denver score
Time Frame: Daily
Daily
Composite endpoint of Time to Complete Organ Failure Resolution (CTCOFR)
Time Frame: At 14 and 21 days
At 14 and 21 days
Hospital-free, ICU-free, and ventilator-free days
Time Frame: Through 28 days
Through 28 days
Proportion of patients who normalize (≤ 2.2 mmol/L) lactate levels
Time Frame: 2, 4, 6, 8 and 12 hours
2, 4, 6, 8 and 12 hours
Proportion of patients remaining: (1) in hospital, (2) in ICU, and (3) on ventilator through Day 28
Time Frame: 28 days
28 days
Number of days: (1) in hospital, (2) in ICU, and (3) on the ventilator
Time Frame: Through 28 days
Through 28 days
All-cause mortality
Time Frame: At 48 hours and at 28 days
At 48 hours and at 28 days
Time (days) from randomization to: (1) death, (2) discharge from hospital, (3) discharge from ICU, and (4) liberation from mechanical ventilation
Time Frame: Through 28 days
Through 28 days
Sequential organ failure assessment (SOFA score)
Time Frame: Daily
Daily

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sangart

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2011

Primary Completion (ACTUAL)

October 1, 2012

Study Completion (ACTUAL)

November 1, 2012

Study Registration Dates

First Submitted

December 15, 2010

First Submitted That Met QC Criteria

December 16, 2010

First Posted (ESTIMATE)

December 17, 2010

Study Record Updates

Last Update Posted (ESTIMATE)

August 22, 2013

Last Update Submitted That Met QC Criteria

August 20, 2013

Last Verified

August 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TRA-205

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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