Phase IIb Study of MP4OX in Traumatic Hemorrhagic Shock Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sangart
ClinicalTrials.gov Identifier:
NCT01262196
First received: December 15, 2010
Last updated: August 20, 2013
Last verified: August 2013
  Purpose

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.


Condition Intervention Phase
Shock, Hemorrhagic
Shock, Traumatic
Acidosis, Lactic
Drug: MP4OX
Drug: Saline
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Sangart:

Primary Outcome Measures:
  • Proportion of patients discharged from hospital through day 28 and alive at the Day 28 follow-up visit [ Time Frame: 28 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Hospital-free, ICU-free, and ventilator-free days [ Time Frame: Through 28 days ] [ Designated as safety issue: No ]
  • Composite endpoint of Time to Complete Organ Failure Resolution (CTCOFR) [ Time Frame: At 14 and 21 days ] [ Designated as safety issue: No ]
  • Proportion of patients who normalize (≤ 2.2 mmol/L) lactate levels [ Time Frame: 2, 4, 6, 8 and 12 hours ] [ Designated as safety issue: No ]
  • Proportion of patients remaining: (1) in hospital, (2) in ICU, and (3) on ventilator through Day 28 [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • Number of days: (1) in hospital, (2) in ICU, and (3) on the ventilator [ Time Frame: Through 28 days ] [ Designated as safety issue: No ]
  • All-cause mortality [ Time Frame: At 48 hours and at 28 days ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]
  • Sequential organ failure assessment (SOFA score) [ Time Frame: Daily ] [ Designated as safety issue: Yes ]
  • Modified Denver score [ Time Frame: Daily ] [ Designated as safety issue: Yes ]

Enrollment: 348
Study Start Date: May 2011
Study Completion Date: November 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
  • Saline solution
  • Sodium chloride 0.9%

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01262196

  Show 40 Study Locations
Sponsors and Collaborators
Sangart
Investigators
Principal Investigator: Karim Brohi, MD The Royal London Hospital
  More Information

Additional Information:
Publications:

Responsible Party: Sangart
ClinicalTrials.gov Identifier: NCT01262196     History of Changes
Other Study ID Numbers: TRA-205
Study First Received: December 15, 2010
Last Updated: August 20, 2013
Health Authority: Austria: Agency for Health and Food Safety
Australia: Department of Health and Ageing Therapeutic Goods Administration
Brazil: National Health Surveillance Agency
Canada: Health Canada
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Paul-Ehrlich-Institut
Israel: Israeli Health Ministry Pharmaceutical Administration
New Zealand: Ministry of Health
Norway: Norwegian Medicines Agency
Singapore: Health Sciences Authority
South Africa: Medicines Control Council
Spain: Spanish Agency of Medicines
Switzerland: Swissmedic
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Sangart:
Trauma
Hemorrhage
Hemorrhagic shock
Lactic acidosis
Oxygen carriers
Oxygen therapeutics
Hemoglobin solutions
Red cell substitutes
PEG-hemoglobin

Additional relevant MeSH terms:
Shock
Acidosis
Shock, Hemorrhagic
Shock, Traumatic
Acidosis, Lactic
Pathologic Processes
Acid-Base Imbalance
Metabolic Diseases
Hemorrhage
Wounds and Injuries
Pharmaceutical Solutions
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 02, 2014