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Clinical Trial Details — Status: Withdrawn

Administrative data

NCT number NCT01973504
Other study ID # TRA-207
Secondary ID
Status Withdrawn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


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 allClick 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
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