Phase 2c Dose Comparison Study of MP4OX in Trauma

Trauma Clinical Trial

Official title:

A Multi-center, Multinational, Randomized, Double-blind, Controlled, Dose Comparison Study to Evaluate Safety and Efficacy of MP4OX Plus Standard Treatment, in Severely Injured Trauma Subjects With Lactic Acidosis Due to Hemorrhagic Shock

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01973504
• Other study ID #: TRA-207
• Status: Withdrawn
• Phase: Phase 2
• First received: August 20, 2013
• Last updated: October 25, 2013
• Start date: December 2013
• Est. completion date: March 2016

Study information

• Verified date: October 2013
• Source: Sangart
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Department of Health and Ageing Therapeutic Goods AdministrationBelgium: Federal Agency for Medicines and Health Products, FAMHPBrazil: National Health Surveillance AgencyFrance: Agence Nationale de Sécurité du Médicament et des produits de santéGermany: Paul-Ehrlich-InstitutIsrael: Ministry of HealthLebanon: Ministry of Public HealthMexico: Federal Commission for Sanitary Risks ProtectionNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)New Zealand: MedsafeNorway: Norwegian Medicines AgencySouth Africa: Medicines Control CouncilSwitzerland: SwissmedicUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

MP4OX is being developed as an ischemic rescue therapy to perfuse and oxygenate tissues at risk during hemorrhagic shock. MP4OX is a pegylated hemoglobin-based colloid designed to improve perfusion and target delivery of oxygen to ischemic tissues. This study will evaluate safety and efficacy of MP4OX treatment, in addition to standard therapy, in trauma patients suffering from lactic acidosis due to severe hemorrhagic shock.

Description:

Acute trauma, including both blunt and penetrating injury, is often associated with uncontrolled bleeding that leads to hemorrhagic shock. During shock, inadequate blood flow results in local ischemia and tissue hypoxia (insufficient oxygenation) of critical organs with resulting lactic acidosis. More than 10% of trauma victims who reach hospital alive will die, and many will suffer from organ failure. The primary goal when treating traumatic hemorrhage is to control blood loss, support ventilation and oxygenation, and maintain cardiovascular function to maintain organ perfusion.

Despite optimal care, organ dysfunction is present in many patients as evidenced by persistent lactic acidosis. Blood transfusions are intended to improve circulation of oxygen-carrying red blood cells, but are frequently insufficient, even when the hemoglobin level is optimized. The severity of lactic acidosis in trauma victims has also been shown to correlate with worse outcome.

Support for the proposed application for MP4OX as a therapeutic adjunct to standard treatment of severe hemorrhage shock, is based on multiple preclinical studies in different animal models of hemorrhagic shock resuscitation. These preclinical studies demonstrated that survival was greater and restoration of acid-base status and hemodynamics were improved with MP4OX. The benefits of MP4OX in animals were observed with or without co-administration of autologous blood, demonstrating that red cell transfusion alone was insufficient, and that the effects of MP4OX were additive.

The hypothesis for the current study is that MP4OX will enhance perfusion and oxygenation of ischemic organs and thereby prevent and reduce the duration of organ failure and improve morbidity and mortality outcome measures.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: March 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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)

Exclusion Criteria:

• Massive injury incompatible with life

• Normalization of lactate prior to dosing (= 2.2 mmol/L)

• Evidence of severe traumatic brain injury (TBI) as defined by ANY one of the following: Known non-survivable head injury or open brain injury; Known AIS (head region) = 4 by an appropriate imaging methodology; Contemplated CNS surgery; Abnormal physical exam indicative of severe CNS or any spinal cord injury above T5 level; or Glasgow Coma Score (GCS) = 3, 4 or 5.

• Cardiac arrest prior to randomization

• Known 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

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
• Hemorrhagic Shock
• Lactic Acidosis
• Shock, Hemorrhagic
• Trauma
• Wounds and Injuries

Intervention

Drug:
• MP4OX
4.3 g/dL pegylated hemoglobin in balanced lactate-electrolyte solution
• Control
Crystalloid solution IV infusion drip to keep vein open

Locations

Country	Name	City	State
Australia	Liverpool Hospital	Liverpool
Australia	John Hunter Hospital	Newcastle
Belgium	Erasme University Hospital	Brussels
Belgium	University Hospital Antwerpen	Edegem
Brazil	Faculdade de Medicina de S. J. Do Rio Preto	São José do Rio Preto
Brazil	Hopital Universitário, Centro de Estudos em Emergências em Saúde, USP Ribeirão Preto	São Paulo
Brazil	Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo - FMUSP	São Paulo
France	Hôpital Beaujon	Clichy
France	Hôpital du Kremlin Bicêtre	Le Kremlin Bicêtre Cedex
France	Hôpital Roger Salengro, CHRU Lille	Lille Cedex
France	CHU Dupuytren	Limoges
France	Hôpital Edouard Herriot	Lyon
France	Hôpital Pitié-Salpêtrière	Paris Cedex
Germany	Universitätsklinikum der Rheinisch-Westfälische Technische Hochschule Aachen	Aachen
Germany	Campus Virchow Klinikum Charité Berlin	Berlin
Germany	Kliniken der Stadt Köln gGmbH Krankenhaus Merheim	Cologne
Germany	Klinikum der J.-W.-Goethe-Universität Frankfurt a.M.	Franfurt
Germany	BG Klinik Ludwigshafen	Ludwigshafen
Israel	Soroka University Medical Center	Be'er-Sheva
Israel	Rambam Health Care Campus	Haifa
Israel	Hadassah Medical Organization, Hadassah University Hospital, Ein-Karem	Jerusalem
New Zealand	Auckland City Hospital	Auckland
Norway	Oslo University Hospital Ullevaal	Oslo
South Africa	Netcare Union Hospital	Alberton
South Africa	Vincent Palotti Dr Christiaan Barnard Memorial Hospital	Cape Town
South Africa	Charlotte Maxeke Johannesburg Academic Hospita	Johannesburg
South Africa	Netcare Milpark Hospital	Johannesburg
South Africa	Chris Hani Baragwanath Hospital	Soweto
Switzerland	CHU Vaudois	Lausanne
Switzerland	UniversitätsSpital Zürich	Zurich
United Kingdom	The Royal London Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
Sangart

Countries where clinical trial is conducted

Australia,  Belgium,  Brazil,  France,  Germany,  Israel,  New Zealand,  Norway,  South Africa,  Switzerland,  United Kingdom, 

References & Publications (20)

Abramson D, Scalea TM, Hitchcock R, Trooskin SZ, Henry SM, Greenspan J. Lactate clearance and survival following injury. J Trauma. 1993 Oct;35(4):584-8; discussion 588-9. — View Citation

Cole RH, Vandegriff KD, Szeri AJ, Savas O, Baker DA, Winslow RM. A quantitative framework for the design of acellular hemoglobins as blood substitutes: implications of dynamic flow conditions. Biophys Chem. 2007 Jun;128(1):63-74. Epub 2007 Mar 13. — View Citation

Cole RH, Vandegriff KD. MP4, a vasodilatory PEGylated hemoglobin. Adv Exp Med Biol. 2011;701:85-90. doi: 10.1007/978-1-4419-7756-4_12. — View 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. Epub 2004 Jan 16. — View Citation

Husain FA, Martin MJ, Mullenix PS, Steele SR, Elliott DC. Serum lactate and base deficit as predictors of mortality and morbidity. Am J Surg. 2003 May;185(5):485-91. — View Citation

McCarthy MR, Vandegriff KD, Winslow RM. The role of facilitated diffusion in oxygen transport by cell-free hemoglobins: implications for the design of hemoglobin-based oxygen carriers. Biophys Chem. 2001 Aug 30;92(1-2):103-17. — View Citation

McNelis J, Marini CP, Jurkiewicz A, Szomstein S, Simms HH, Ritter G, Nathan IM. Prolonged lactate clearance is associated with increased mortality in the surgical intensive care unit. Am J Surg. 2001 Nov;182(5):481-5. — View Citation

Régnier MA, Raux M, Le Manach Y, Asencio Y, Gaillard J, Devilliers C, Langeron O, Riou B. Prognostic significance of blood lactate and lactate clearance in trauma patients. Anesthesiology. 2012 Dec;117(6):1276-88. doi: 10.1097/ALN.0b013e318273349d. — View Citation

Svergun DI, Ekström 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. Epub 2007 Sep 7. — 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

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. Epub 2003 Jun 12. — View Citation

Vandegriff KD, Bellelli A, Samaja M, Malavalli A, Brunori M, Winslow RM. Kinetics of NO and O2 binding to a maleimide poly(ethylene glycol)-conjugated human haemoglobin. Biochem J. 2004 Aug 15;382(Pt 1):183-9. — 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, Malavalli A, Wooldridge J, Lohman J, Winslow RM. MP4, a new nonvasoactive PEG-Hb conjugate. Transfusion. 2003 Apr;43(4):509-16. — 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

Wettstein R, Tsai AG, Erni D, Winslow RM, Intaglietta M. Resuscitation with polyethylene glycol-modified human hemoglobin improves microcirculatory blood flow and tissue oxygenation after hemorrhagic shock in awake hamsters. Crit Care Med. 2003 Jun;31(6):1824-30. — View 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. Epub 2004 Jun 18. — 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

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Daily modified Denver Score		Day 7	Yes
Other	Proportion of patients with persistent renal dysfunction		Day 60	Yes
Other	Duration of ICU stay for survivors		Day 28 and Day 60	No
Other	Proportion of subjects who normalize lactate		4 hours	No
Primary	Proportion of subjects discharged from hospital through Day 28 and alive at the Day 28 Follow up visit		28 days	No
Secondary	Hospital-free, ICU-free, and Ventilator-free days		Through 28 and 60 days	No
Secondary	Proportion of subjects remaining in hospital, ICU or on ventilator		Through 28 and 60 days	No
Secondary	Days in hospital, in ICU, or on Ventilator		Through 28 and 60 days	No
Secondary	All-cause Mortality		At 48 hours and 28 or 60 days	Yes
Secondary	Time to discharge from ICU, hospital discharge, or liberation from ventilation		Through 28 or 60 days	No
Secondary	Composite of Time to Complete Organ Failure Resolution (CTCOFR)		Day 21	No

External Links

•   Sangart Inc. (San Diego, CA) web site [Study SPONSOR]