Phase IIa Study of MP4OX in Traumatic Hemorrhagic Shock Patients
Primary Purpose
Shock, Hemorrhagic, Shock, Traumatic, Acidosis, Lactic
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
MP4OX
MP4OX
Ringers Lactate solution
Sponsored by
About this trial
This is an interventional treatment trial for Shock, Hemorrhagic focused on measuring Trauma, Hemorrhage, Hemorrhagic shock, Lactic acidosis, Oxygen carriers, Oxygen therapeutics, Hemoglobin solutions, Hemoglobin substitutes, Red cell substitutes, PEG-hemoglobin
Eligibility 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 (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
Sites / Locations
- Centre Hospitalier de Bicêtre
- CHRU de Lille - Hôpital Claude Huriez
- Hôpital Dupuytren
- Hôpital Pitié-Salpêtrière
- Charité Campus Virchow Klinikum
- Klinikum der Johann-Wolfgang-Goethe-Universität
- Netcare Union Hospital
- Charlotte Maxeke Johannesburg Hospital
- Netcare Milpark Hospital
- Netcare Unitas Hospital, Centurian
- Steve Biko Academic Hospital
- Chris Hani Baragwanath Hospital
- The Royal London Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Active Comparator
Arm Label
MP4OX - 250
MP4OX - 500
Ringers Lactate solution
Arm Description
250 mL dose
500 mL dose
500 mL dose
Outcomes
Primary Outcome Measures
Serum lactate clearance
Secondary Outcome Measures
All-cause mortality
Ventilator-free days
ICU-free days
Hospital-free days
Sepsis-related Organ Failure Assessment (SOFA) score
Modified Denver score
Composite endpoint of Time to Complete Organ Failure Resolution (CTCOFR)
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01004198
Brief Title
Phase IIa Study of MP4OX in Traumatic Hemorrhagic Shock Patients
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
August 2013
Overall Recruitment Status
Completed
Study Start Date
December 2009 (undefined)
Primary Completion Date
June 2010 (Actual)
Study Completion Date
June 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sangart
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Shock, Hemorrhagic, Shock, Traumatic, Acidosis, Lactic
Keywords
Trauma, Hemorrhage, Hemorrhagic shock, Lactic acidosis, Oxygen carriers, Oxygen therapeutics, Hemoglobin solutions, Hemoglobin substitutes, Red cell substitutes, PEG-hemoglobin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
51 (Actual)
8. Arms, Groups, and Interventions
Arm Title
MP4OX - 250
Arm Type
Experimental
Arm Description
250 mL dose
Arm Title
MP4OX - 500
Arm Type
Experimental
Arm Description
500 mL dose
Arm Title
Ringers Lactate solution
Arm Type
Active Comparator
Arm Description
500 mL dose
Intervention Type
Drug
Intervention Name(s)
MP4OX
Other Intervention Name(s)
MP4, MalPEG-Hb, PEG-Hb, Pegylated-Hb
Intervention Description
4.3 g/dL PEG-Hb solution in lactated electrolyte solution
Intervention Type
Drug
Intervention Name(s)
MP4OX
Other Intervention Name(s)
MP4, MalPEG-Hb, PEG-Hb, Pegylated-Hb
Intervention Description
4.3 g/dL PEG-Hb solution in lactated electrolyte solution
Intervention Type
Drug
Intervention Name(s)
Ringers Lactate solution
Other Intervention Name(s)
Lactated Ringers, Hartmann's solution
Intervention Description
Ringers Lactate solution for Injection
Primary Outcome Measure Information:
Title
Serum lactate clearance
Time Frame
2 hours
Secondary Outcome Measure Information:
Title
All-cause mortality
Time Frame
28 days
Title
Ventilator-free days
Time Frame
28 days
Title
ICU-free days
Time Frame
28 days
Title
Hospital-free days
Time Frame
28 days
Title
Sepsis-related Organ Failure Assessment (SOFA) score
Time Frame
Daily
Title
Modified Denver score
Time Frame
Daily
Title
Composite endpoint of Time to Complete Organ Failure Resolution (CTCOFR)
Time Frame
At 14 and 21 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility 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 (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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Karim Brohi, MD
Organizational Affiliation
The Royal London Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Centre Hospitalier de Bicêtre
City
Le Kremlin Bicetre
Country
France
Facility Name
CHRU de Lille - Hôpital Claude Huriez
City
Lille
Country
France
Facility Name
Hôpital Dupuytren
City
Limoges
Country
France
Facility Name
Hôpital Pitié-Salpêtrière
City
Paris
Country
France
Facility Name
Charité Campus Virchow Klinikum
City
Berlin
Country
Germany
Facility Name
Klinikum der Johann-Wolfgang-Goethe-Universität
City
Frankfurt
Country
Germany
Facility Name
Netcare Union Hospital
City
Alberton
Country
South Africa
Facility Name
Charlotte Maxeke Johannesburg Hospital
City
Johannesburg
Country
South Africa
Facility Name
Netcare Milpark Hospital
City
Johannesburg
Country
South Africa
Facility Name
Netcare Unitas Hospital, Centurian
City
Pretoria
Country
South Africa
Facility Name
Steve Biko Academic Hospital
City
Pretoria
Country
South Africa
Facility Name
Chris Hani Baragwanath Hospital
City
Soweto
Country
South Africa
Facility Name
The Royal London Hospital
City
London
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
17122578
Citation
Olofsson C, Ahl T, Johansson T, Larsson S, Nellgard P, Ponzer S, Fagrell B, Przybelski R, Keipert P, Winslow N, Winslow RM. A multicenter clinical study of the safety and activity of maleimide-polyethylene glycol-modified Hemoglobin (Hemospan) in patients undergoing major orthopedic surgery. Anesthesiology. 2006 Dec;105(6):1153-63. doi: 10.1097/00000542-200612000-00015.
Results Reference
background
PubMed Identifier
18279190
Citation
Olofsson C, Nygards EB, Ponzer S, Fagrell B, Przybelski R, Keipert PE, Winslow N, Winslow RM. A randomized, single-blind, increasing dose safety trial of an oxygen-carrying plasma expander (Hemospan) administered to orthopaedic surgery patients with spinal anaesthesia. Transfus Med. 2008 Feb;18(1):28-39. doi: 10.1111/j.1365-3148.2007.00811.x.
Results Reference
background
PubMed Identifier
18948027
Citation
Young MA, Lohman J, Malavalli A, Vandegriff KD, Winslow RM. Hemospan improves outcome in a model of perioperative hemodilution and blood loss in the rat: comparison with hydroxyethyl starch. J Cardiothorac Vasc Anesth. 2009 Jun;23(3):339-47. doi: 10.1053/j.jvca.2008.08.006. Epub 2008 Oct 22.
Results Reference
background
PubMed Identifier
18212644
Citation
Young MA, Riddez L, Kjellstrom BT, Winslow RM. Effect of maleimide-polyethylene glycol hemoglobin (MP4) on hemodynamics and acid-base status after uncontrolled hemorrhage in anesthetized swine: comparison with crystalloid and blood. J Trauma. 2007 Dec;63(6):1234-44. doi: 10.1097/TA.0b013e31815bd7b0.
Results Reference
background
PubMed Identifier
16096458
Citation
Young MA, Riddez L, Kjellstrom BT, Bursell J, Winslow F, Lohman J, Winslow RM. MalPEG-hemoglobin (MP4) improves hemodynamics, acid-base status, and survival after uncontrolled hemorrhage in anesthetized swine. Crit Care Med. 2005 Aug;33(8):1794-804. doi: 10.1097/01.ccm.0000172648.55309.13.
Results Reference
background
PubMed Identifier
14729723
Citation
Drobin D, Kjellstrom BT, Malm E, Malavalli A, Lohman J, Vandegriff KD, Young MA, Winslow RM. Hemodynamic response and oxygen transport in pigs resuscitated with maleimide-polyethylene glycol-modified hemoglobin (MP4). J Appl Physiol (1985). 2004 May;96(5):1843-53. doi: 10.1152/japplphysiol.00530.2003. Epub 2004 Jan 16.
Results Reference
background
PubMed Identifier
19178457
Citation
Vandegriff KD, Winslow RM. Hemospan: design principles for a new class of oxygen therapeutic. Artif Organs. 2009 Feb;33(2):133-8. doi: 10.1111/j.1525-1594.2008.00697.x.
Results Reference
background
PubMed Identifier
18837531
Citation
Vandegriff KD, Malavalli A, Mkrtchyan GM, Spann SN, Baker DA, Winslow RM. Sites of modification of hemospan, a poly(ethylene glycol)-modified human hemoglobin for use as an oxygen therapeutic. Bioconjug Chem. 2008 Nov 19;19(11):2163-70. doi: 10.1021/bc8002666.
Results Reference
background
PubMed Identifier
16857991
Citation
Tsai AG, Cabrales P, Manjula BN, Acharya SA, Winslow RM, Intaglietta M. Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers. Blood. 2006 Nov 15;108(10):3603-10. doi: 10.1182/blood-2006-02-005272. Epub 2006 Jul 20.
Results Reference
background
PubMed Identifier
21317165
Citation
van der Linden P, Gazdzik TS, Jahoda D, Heylen RJ, Skowronski JC, Pellar D, Kofranek I, Gorecki AZ, Fagrell B, Keipert PE, Hardiman YJ, Levy H; 6090 Study Investigators. A double-blind, randomized, multicenter study of MP4OX for treatment of perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. Anesth Analg. 2011 Apr;112(4):759-73. doi: 10.1213/ANE.0b013e31820c7b5f. Epub 2011 Feb 11.
Results Reference
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Phase IIa Study of MP4OX in Traumatic Hemorrhagic Shock Patients
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