Phase IIb Study of MP4OX in Traumatic Hemorrhagic Shock Patients
NCT ID: NCT01262196
Last Updated: 2013-08-22
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE2
348 participants
INTERVENTIONAL
2011-05-31
2012-11-30
Brief Summary
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Detailed Description
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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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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MP4OX
250-mL dose
MP4OX
4.3 g/dL pegylated hemoglobin in balanced lactate-electrolyte solution
Control
250-mL of normal saline solution
Saline
Normal saline (0.9%) solution
Interventions
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MP4OX
4.3 g/dL pegylated hemoglobin in balanced lactate-electrolyte solution
Saline
Normal saline (0.9%) solution
Other Intervention Names
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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) arterial or venous
Exclusion Criteria
* 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
ALL
No
Sponsors
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Sangart
INDUSTRY
Responsible Party
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Principal Investigators
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Karim Brohi, MD
Role: PRINCIPAL_INVESTIGATOR
The Royal London Hospital
Locations
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Liverpoool Hospital NSW
Liverpool, , Australia
John Hunter Hospital
Newcastle, , Australia
Graz University Hospital
Gratz, , Austria
Faculdade de Medicina de S. J. Do Rio Preto
São José do Rio Preto, , Brazil
Hospital das Clínicas - USP
São Paulo, , Brazil
Hospital Universitário - USP Ribeirão Preto
São Paulo, , Brazil
Fundacion Valle de Lili
Cali, , Colombia
Hôpital Beaujon
Clichy, , France
Hôpital Michallon
Grenoble, , France
Hôpital du Kremlin Bicêtre
Le Kremlin-Bicêtre, , France
Hôpital Roger Salengro, CHRU Lille
Lille, , France
Hôpital Dupuytren, CHU Limoges
Limoges, , France
Hôpital Edouard Herriot
Lyon, , France
Hôpital Lyon sud
Lyon, , France
Hôpital Pitié-Salpêtrière
Paris, , France
Universitätsklinikum der RWTH Aachen
Aachen, , Germany
Charite - Campus Virchow Klinikum
Berlin, , Germany
Kliniken der Stadt Köln Merheim
Cologne, , Germany
Klinikum der Johann-Wolfgang-Goethe-Universität Frankfurt a.M.
Frankfurt, , Germany
BG Klinik Ludwigshafen
Ludwigshafen, , Germany
Soroka University Medical Center
Beersheba, , Israel
Rambam Hospital
Haifa, , Israel
Hadassah Medical Center
Jerusalem, , Israel
Auckland Hospital
Auckland, , New Zealand
Oslo university hospital
Oslo, , Norway
National University Hospital
Singapore, , Singapore
Singapore General Hospital
Singapore, , Singapore
Tan Tock Seng Hospital
Singapore, , Singapore
Netcare Union Hospital
Alberton, , South Africa
Vincent Pallotti Hospital
Cape Town, , South Africa
Netcare Unitas Hospital
Centurion, , South Africa
Charlotte Maxeke Johannesburg Hospital
Johannesburg, , South Africa
Netcare Milpark Hospital
Johannesburg, , South Africa
Chris Baragwanath Hospital
Soweto, , South Africa
Hospital 12 de Octubre, Madrid
Madrid, , Spain
Centre Hospitalier Universitaire Vaudois CHUV
Lausanne, , Switzerland
Universitätsspital Zürich
Zurich, , Switzerland
King's College Hospital, London
London, , United Kingdom
The Royal London Hospital
London, , United Kingdom
John Radcliffe Hospital, Oxford
Oxford, , United Kingdom
Countries
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References
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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.
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.
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.
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.
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.
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.
Svergun DI, Ekstrom F, Vandegriff KD, Malavalli A, Baker DA, Nilsson C, Winslow RM. Solution structure of poly(ethylene) glycol-conjugated hemoglobin revealed by small-angle X-ray scattering: implications for a new oxygen therapeutic. Biophys J. 2008 Jan 1;94(1):173-81. doi: 10.1529/biophysj.107.114314. Epub 2007 Sep 7.
Winslow RM, Lohman J, Malavalli A, Vandegriff KD. Comparison of PEG-modified albumin and hemoglobin in extreme hemodilution in the rat. J Appl Physiol (1985). 2004 Oct;97(4):1527-34. doi: 10.1152/japplphysiol.00404.2004. Epub 2004 Jun 18.
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.
Tsai AG, Vandegriff KD, Intaglietta M, Winslow RM. Targeted O2 delivery by low-P50 hemoglobin: a new basis for O2 therapeutics. Am J Physiol Heart Circ Physiol. 2003 Oct;285(4):H1411-9. doi: 10.1152/ajpheart.00307.2003. Epub 2003 Jun 12.
Olofsson CI, Gorecki AZ, Dirksen R, Kofranek I, Majewski JA, Mazurkiewicz T, Jahoda D, Fagrell B, Keipert PE, Hardiman YJ, Levy H; Study 6084 Clinical Investigators. Evaluation of MP4OX for prevention of perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anesthesia: a randomized, double-blind, multicenter study. Anesthesiology. 2011 May;114(5):1048-63. doi: 10.1097/ALN.0b013e318215e198.
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.
Related Links
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Sangart Inc. (San Diego, CA) web site
Other Identifiers
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TRA-205
Identifier Type: -
Identifier Source: org_study_id