Clinical trial NCT01004198: 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
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
Hemoglobin substitutes
Red cell substitutes
PEG-hemoglobin
Lead sponsor: Sangart
Sponsor class: INDUSTRY
First posted: 2009-10-29
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Serum lactate clearance
timeFrame: 2 hours
Secondary outcomes:
measure: All-cause mortality
timeFrame: 28 days
measure: Ventilator-free days
timeFrame: 28 days
measure: ICU-free days
timeFrame: 28 days
measure: Hospital-free days
timeFrame: 28 days
measure: Sepsis-related Organ Failure Assessment (SOFA) score
timeFrame: Daily
measure: Modified Denver score
timeFrame: Daily
measure: Composite endpoint of Time to Complete Organ Failure Resolution (CTCOFR)
timeFrame: At 14 and 21 days
Other outcomes:
Locations:
city: Le Kremlin Bicetre
country: France
facility: Centre Hospitalier de Bicêtre
city: Lille
country: France
facility: CHRU de Lille - Hôpital Claude Huriez
city: Limoges
country: France
facility: Hôpital Dupuytren
city: Paris
country: France
facility: Hôpital Pitié-Salpêtrière
city: Berlin
country: Germany
facility: Charité Campus Virchow Klinikum
city: Frankfurt
country: Germany
facility: Klinikum der Johann-Wolfgang-Goethe-Universität
city: Alberton
country: South Africa
facility: Netcare Union Hospital
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesburg Hospital
city: Johannesburg
country: South Africa
facility: Netcare Milpark Hospital
city: Pretoria
country: South Africa
facility: Netcare Unitas Hospital, Centurian
city: Pretoria
country: South Africa
facility: Steve Biko Academic Hospital
city: Soweto
country: South Africa
facility: Chris Hani Baragwanath Hospital
city: London
country: United Kingdom
facility: The Royal London Hospital
Study officials:
affiliation: The Royal London Hospital
name: Karim Brohi, MD
role: PRINCIPAL_INVESTIGATOR
References:
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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.
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: 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: 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.