Clinical trial NCT01262196: Phase IIb Study of MP4OX in Traumatic Hemorrhagic Shock Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Shock, Hemorrhagic
Shock, Traumatic
Acidosis, Lactic
Keywords: Trauma
Hemorrhage
Hemorrhagic shock
Lactic acidosis
Oxygen carriers
Oxygen therapeutics
Hemoglobin solutions
Red cell substitutes
PEG-hemoglobin
Lead sponsor: Sangart
Sponsor class: INDUSTRY
First posted: 2010-12-17
Enrollment: 348
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Proportion of patients discharged from hospital through day 28 and alive at the Day 28 follow-up visit
timeFrame: 28 days
Secondary outcomes:
measure: Hospital-free, ICU-free, and ventilator-free days
timeFrame: Through 28 days
measure: Composite endpoint of Time to Complete Organ Failure Resolution (CTCOFR)
timeFrame: At 14 and 21 days
measure: Proportion of patients who normalize (≤ 2.2 mmol/L) lactate levels
timeFrame: 2, 4, 6, 8 and 12 hours
measure: Proportion of patients remaining: (1) in hospital, (2) in ICU, and (3) on ventilator through Day 28
timeFrame: 28 days
measure: Number of days: (1) in hospital, (2) in ICU, and (3) on the ventilator
timeFrame: Through 28 days
measure: All-cause mortality
timeFrame: At 48 hours and at 28 days
measure: Time (days) from randomization to: (1) death, (2) discharge from hospital, (3) discharge from ICU, and (4) liberation from mechanical ventilation
timeFrame: Through 28 days
measure: Sequential organ failure assessment (SOFA score)
timeFrame: Daily
measure: Modified Denver score
timeFrame: Daily
Other outcomes:
Locations:
city: Liverpool
country: Australia
facility: Liverpoool Hospital NSW
city: Newcastle
country: Australia
facility: John Hunter Hospital
city: Gratz
country: Austria
facility: Graz University Hospital
city: Sao Paolo
country: Brazil
facility: Hospital das Clínicas - USP
city: Sao Paolo
country: Brazil
facility: Hospital Universitário - USP Ribeirão Preto
city: São José do Rio Preto
country: Brazil
facility: Faculdade de Medicina de S. J. Do Rio Preto
city: Cali
country: Colombia
facility: Fundacion Valle de Lili
city: Clichy
country: France
facility: Hôpital Beaujon
city: Grenoble
country: France
facility: Hôpital Michallon
city: Le Kremlin Bicetre
country: France
facility: Hôpital du Kremlin Bicêtre
city: Lille
country: France
facility: Hôpital Roger Salengro, CHRU Lille
city: Limoges
country: France
facility: Hôpital Dupuytren, CHU Limoges
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Lyon
country: France
facility: Hôpital Lyon sud
city: Paris
country: France
facility: Hôpital Pitié-Salpêtrière
city: Aachen
country: Germany
facility: Universitätsklinikum der RWTH Aachen
city: Berlin
country: Germany
facility: Charite - Campus Virchow Klinikum
city: Cologne
country: Germany
facility: Kliniken der Stadt Köln Merheim
city: Frankfurt
country: Germany
facility: Klinikum der Johann-Wolfgang-Goethe-Universität Frankfurt a.M.
city: Ludwigshafen
country: Germany
facility: BG Klinik Ludwigshafen
city: Beersheba
country: Israel
facility: Soroka University Medical Center
city: Haifa
country: Israel
facility: Rambam Hospital
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Auckland
country: New Zealand
facility: Auckland Hospital
city: Oslo
country: Norway
facility: Oslo university hospital
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Alberton
country: South Africa
facility: Netcare Union Hospital
city: Cape Town
country: South Africa
facility: Vincent Pallotti Hospital
city: Centurion
country: South Africa
facility: Netcare Unitas Hospital
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesburg Hospital
city: Johannesburg
country: South Africa
facility: Netcare Milpark Hospital
city: Soweto
country: South Africa
facility: Chris Baragwanath Hospital
city: Madrid
country: Spain
facility: Hospital 12 de Octubre, Madrid
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois CHUV
city: Zurich
country: Switzerland
facility: Universitätsspital Zürich
city: London
country: United Kingdom
facility: King's College Hospital, London
city: London
country: United Kingdom
facility: The Royal London Hospital
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital, Oxford
Study officials:
affiliation: The Royal London Hospital
name: Karim Brohi, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
citation: 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.
citation: 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.
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.
citation: 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.
citation: 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.
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.