Phase IIa Study of MP4OX in Traumatic Hemorrhagic Shock Patients

Shock, Traumatic Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01004198
• Other study ID #: TRA-204
• Status: Completed
• Phase: Phase 2
• First received: October 28, 2009
• Last updated: August 15, 2013
• Start date: December 2009
• Est. completion date: June 2010

Study information

• Verified date: August 2013
• Source: Sangart
• Contact: n/a
• Is FDA regulated: No
• Health authority: South Africa: Medicines Control CouncilUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Paul-Ehrlich-Institut
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: June 2010
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Acidosis
• Acidosis, Lactic
• Shock
• Shock, Hemorrhagic
• Shock, Traumatic

Intervention

Drug:
• MP4OX
4.3 g/dL PEG-Hb solution in lactated electrolyte solution
• MP4OX
4.3 g/dL PEG-Hb solution in lactated electrolyte solution
• Ringers Lactate solution
Ringers Lactate solution for Injection

Locations

Country	Name	City	State
France	Centre Hospitalier de Bicêtre	Le Kremlin Bicetre
France	CHRU de Lille - Hôpital Claude Huriez	Lille
France	Hôpital Dupuytren	Limoges
France	Hôpital Pitié-Salpêtrière	Paris
Germany	Charité Campus Virchow Klinikum	Berlin
Germany	Klinikum der Johann-Wolfgang-Goethe-Universität	Frankfurt
South Africa	Netcare Union Hospital	Alberton
South Africa	Charlotte Maxeke Johannesburg Hospital	Johannesburg
South Africa	Netcare Milpark Hospital	Johannesburg
South Africa	Netcare Unitas Hospital, Centurian	Pretoria
South Africa	Steve Biko Academic Hospital	Pretoria
South Africa	Chris Hani Baragwanath Hospital	Soweto
United Kingdom	The Royal London Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
Sangart

Countries where clinical trial is conducted

France,  Germany,  South Africa,  United Kingdom, 

References & Publications (10)

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. Epub 2004 Jan 16. — View Citation

Olofsson C, Ahl T, Johansson T, Larsson S, Nellgård 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. — View Citation

Olofsson C, Nygårds 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. — View 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. Epub 2006 Jul 20. — View Citation

van der Linden P, Gazdzik TS, Jahoda D, Heylen RJ, Skowronski JC, Pellar D, Kofranek I, Górecki 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. — View 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. — View 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. — View 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. — View Citation

Young MA, Riddez L, Kjellström 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. — View Citation

Young MA, Riddez L, Kjellström 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum lactate clearance		2 hours	No
Secondary	All-cause mortality		28 days	Yes
Secondary	Ventilator-free days		28 days	No
Secondary	ICU-free days		28 days	No
Secondary	Hospital-free days		28 days	No
Secondary	Sepsis-related Organ Failure Assessment (SOFA) score		Daily	Yes
Secondary	Modified Denver score		Daily	Yes
Secondary	Composite endpoint of Time to Complete Organ Failure Resolution (CTCOFR)		At 14 and 21 days	Yes

External Links

•   www.Sangart.com