Phase 2c Dose Comparison Study of MP4OX in Trauma

NCT01973504 | Withdrawn Phase 2 DMC

• 1 other identifier: TRA-207
• Study Type: interventional
• Target: N/A
• Locations: 11 countries
• Sites: 31

Brief 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.

Conditions

Trauma; Hemorrhagic Shock; Lactic Acidosis

Keywords

Trauma; Hemorrhagic shock; Hemorrhage; Lactic acidosis; Oxygen therapeutics; Oxygen carriers; Ischemic rescue therapy; Hemoglobin solutions; PEGylated hemoglobin

Outcome Measures

Primary Outcomes (1)

• Proportion of subjects discharged from hospital through Day 28 and alive at the Day 28 Follow up visit

  28 days

Secondary Outcomes (6)

• Hospital-free, ICU-free, and Ventilator-free days

  Through 28 and 60 days

• Proportion of subjects remaining in hospital, ICU or on ventilator

  Through 28 and 60 days

• Days in hospital, in ICU, or on Ventilator

  Through 28 and 60 days

• All-cause Mortality

  At 48 hours and 28 or 60 days

• Time to discharge from ICU, hospital discharge, or liberation from ventilation

  Through 28 or 60 days

Other Outcomes (4)

• Daily modified Denver Score

  Day 7

• Proportion of patients with persistent renal dysfunction

  Day 60

• Duration of ICU stay for survivors

  Day 28 and Day 60

Study Arms (3)

MP4OX 500-mL

EXPERIMENTAL

500-mL dose of MP4OX

Drug: MP4OX

MP4OX 750-mL

EXPERIMENTAL

750-mL dose of MP4OX

Drug: MP4OX

Control

SHAM COMPARATOR

Standard crystalloid Keep Vein Open (KVO) infusion

Drug: Control

Interventions

MP4OX DRUG

4.3 g/dL pegylated hemoglobin in balanced lactate-electrolyte solution

Also known as: Hemoglobin pegylated, MalPEG-Hb, MP4, PEG-Hb, Pegylated-Hb

MP4OX 500-mL; MP4OX 750-mL

Control DRUG

Crystalloid solution IV infusion drip to keep vein open

Also known as: Keep vein open (KVO) infusion, Sham infusion

Control

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Sangart: lead

Study Sites (31)

Liverpool Hospital

Liverpool, Australia

Location

John Hunter Hospital

Newcastle, Australia

Location

Erasme University Hospital

Brussels, Belgium

Location

University Hospital Antwerpen

Edegem, Belgium

Location

Faculdade de Medicina de S. J. Do Rio Preto

São José do Rio Preto, Brazil

Location

Hopital Universitário, Centro de Estudos em Emergências em Saúde, USP Ribeirão Preto

São Paulo, Brazil

Location

Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo - FMUSP

São Paulo, Brazil

Location

Hôpital Beaujon

Clichy, France

Location

Hôpital du Kremlin Bicêtre

Le Kremlin-Bicêtre, France

Location

Hôpital Roger Salengro, CHRU Lille

Lille, France

Location

CHU Dupuytren

Limoges, France

Location

Hôpital Edouard Herriot

Lyon, France

Location

Hôpital Pitié-Salpêtrière

Paris, France

Location

Universitätsklinikum der Rheinisch-Westfälische Technische Hochschule Aachen

Aachen, Germany

Location

Campus Virchow Klinikum Charité Berlin

Berlin, Germany

Location

Kliniken der Stadt Köln gGmbH Krankenhaus Merheim

Cologne, Germany

Location

Klinikum der J.-W.-Goethe-Universität Frankfurt a.M.

Franfurt, Germany

Location

BG Klinik Ludwigshafen

Ludwigshafen, Germany

Location

Soroka University Medical Center

Beersheba, Israel

Location

Rambam Health Care Campus

Haifa, Israel

Location

Hadassah Medical Organization, Hadassah University Hospital, Ein-Karem

Jerusalem, Israel

Location

Auckland City Hospital

Auckland, New Zealand

Location

Oslo University Hospital Ullevaal

Oslo, Norway

Location

Netcare Union Hospital

Alberton, South Africa

Location

Vincent Palotti Dr Christiaan Barnard Memorial Hospital

Cape Town, South Africa

Location

Charlotte Maxeke Johannesburg Academic Hospita

Johannesburg, South Africa

Location

Netcare Milpark Hospital

Johannesburg, South Africa

Location

Chris Hani Baragwanath Hospital

Soweto, South Africa

Location

CHU Vaudois

Lausanne, Switzerland

Location

UniversitätsSpital Zürich

Zurich, Switzerland

Location

The Royal London Hospital

London, United Kingdom

Location

Related Publications (20)

• 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.

  PMID: 21445773 BACKGROUND

• 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.

  PMID: 18948027 BACKGROUND

• 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.

  PMID: 19178457 BACKGROUND

• 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.

  PMID: 18837531 BACKGROUND

• 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.

  PMID: 17827244 BACKGROUND

• 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. doi: 10.1016/j.bpc.2007.03.004. Epub 2007 Mar 13.

  PMID: 17418478 BACKGROUND

• 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.

  PMID: 16096458 BACKGROUND

• 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.

  PMID: 14729723 BACKGROUND

• 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.

  PMID: 15208289 BACKGROUND

• 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. doi: 10.1042/BJ20040156.

  PMID: 15175010 BACKGROUND

• 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.

  PMID: 12805024 BACKGROUND

• Vandegriff KD, Malavalli A, Wooldridge J, Lohman J, Winslow RM. MP4, a new nonvasoactive PEG-Hb conjugate. Transfusion. 2003 Apr;43(4):509-16. doi: 10.1046/j.1537-2995.2003.00341.x.

  PMID: 12662285 BACKGROUND

• 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. doi: 10.1016/s0301-4622(01)00194-6.

  PMID: 11527583 BACKGROUND

• 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.

  PMID: 18212644 BACKGROUND

• 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. doi: 10.1097/01.CCM.0000069340.16319.F2.

  PMID: 12794426 BACKGROUND

• 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. doi: 10.1016/s0002-9610(03)00044-8.

  PMID: 12727572 BACKGROUND

• Regnier 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.

  PMID: 23168430 BACKGROUND

• 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. doi: 10.1016/s0002-9610(01)00755-3.

  PMID: 11754855 BACKGROUND

• 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. doi: 10.1097/00005373-199310000-00014.

  PMID: 8411283 BACKGROUND

• 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.

  PMID: 16857991 BACKGROUND

Related Links

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

MeSH Terms

Conditions

Wounds and Injuries; Shock, Hemorrhagic; Acidosis, Lactic; Hemorrhage

Interventions

polynitroxylated pegylated hemoglobin; maleimide-polyethylene glycol-modified hemoglobin, MP4; PEG-hemoglobin

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Acidosis; Acid-Base Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Karim Brohi, MD

  The Royal London Hospital

  PRINCIPAL INVESTIGATOR

• Frank V. Booth, BCh, FACS

  Sangart, Inc.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 20, 2013
• First Posted: October 31, 2013
• Study Start: December 1, 2013
• Primary Completion: December 1, 2015
• Study Completion: March 1, 2016
• Last Updated: October 31, 2013

Record last verified: 2013-10

Locations

DE (5); ZA (5); BE (2); GB (1); CH (2); AU (2); BR (3); NO (1); IL (3); NZ (1); FR (6)