Phase IIb Study of MP4OX in Traumatic Hemorrhagic Shock Patients

NCT01262196 | Completed Phase 2 DMC

• 1 other identifier: TRA-205
• Study Type: interventional
• Target: 348
• Locations: 13 countries
• Sites: 39

Brief Summary

MP4OX is a novel oxygen therapeutic agent being developed as an ischemic rescue therapy to enhance perfusion and oxygenation of tissues at risk during hemorrhagic shock. MP4OX is a pegylated hemoglobin-based colloid. Due to its molecular size and unique oxygen dissociation characteristics, MP4OX targets delivery of oxygen to ischemic tissues. This study will evaluate the safety and efficacy of MP4OX treatment in trauma patients suffering from lactic acidosis due to severe hemorrhagic shock. The study hypothesis is that MP4OX will reverse the lactic acidosis by enhancing perfusion and oxygenation of ischemic tissues and thereby prevent and reduce the duration of organ failure and improve outcome in these patients.

Conditions

Shock, Hemorrhagic; Shock, Traumatic; Acidosis, Lactic

Keywords

Trauma; Hemorrhage; Hemorrhagic shock; Lactic acidosis; Oxygen carriers; Oxygen therapeutics; Hemoglobin solutions; Red cell substitutes; PEG-hemoglobin

Outcome Measures

Primary Outcomes (1)

• Proportion of patients discharged from hospital through day 28 and alive at the Day 28 follow-up visit

  28 days

Secondary Outcomes (9)

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

  Through 28 days

• Composite endpoint of Time to Complete Organ Failure Resolution (CTCOFR)

  At 14 and 21 days

• Proportion of patients who normalize (≤ 2.2 mmol/L) lactate levels

  2, 4, 6, 8 and 12 hours

• Proportion of patients remaining: (1) in hospital, (2) in ICU, and (3) on ventilator through Day 28

  28 days

• Number of days: (1) in hospital, (2) in ICU, and (3) on the ventilator

  Through 28 days

Study Arms (2)

MP4OX

EXPERIMENTAL

250-mL dose

Drug: MP4OX

Control

PLACEBO COMPARATOR

250-mL of normal saline solution

Drug: Saline

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

Saline DRUG

Normal saline (0.9%) solution

Also known as: Normal saline, Saline solution, Sodium chloride 0.9%

Control

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Acidosis (blood lactate level ≥ 5 mmol/L; equivalent to 45 mg/dL) arterial or venous

You may not qualify if:

• Massive injury incompatible with life
• Normalization of lactate prior to dosing (≤ 2.2 mmol/L)
• Patients with 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; Known AIS (head region) ≥ 4 shown by an appropriate imaging methodology; Contemplated CNS surgery; or Abnormal physical exam indicative of severe CNS or any spinal cord injury above T5 level
• Cardiac arrest prior to randomization
• 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 (40)

Liverpoool Hospital NSW

Liverpool, Australia

Location

John Hunter Hospital

Newcastle, Australia

Location

Graz University Hospital

Gratz, Austria

Location

Faculdade de Medicina de S. J. Do Rio Preto

São José do Rio Preto, Brazil

Location

Hospital das Clínicas - USP

São Paulo, Brazil

Location

Hospital Universitário - USP Ribeirão Preto

São Paulo, Brazil

Location

Fundacion Valle de Lili

Cali, Colombia

Location

Hôpital Beaujon

Clichy, France

Location

Hôpital Michallon

Grenoble, France

Location

Hôpital du Kremlin Bicêtre

Le Kremlin-Bicêtre, France

Location

Hôpital Roger Salengro, CHRU Lille

Lille, France

Location

Hôpital Dupuytren, CHU Limoges

Limoges, France

Location

Hôpital Edouard Herriot

Lyon, France

Location

Hôpital Lyon sud

Lyon, France

Location

Hôpital Pitié-Salpêtrière

Paris, France

Location

Universitätsklinikum der RWTH Aachen

Aachen, Germany

Location

Charite - Campus Virchow Klinikum

Berlin, Germany

Location

Kliniken der Stadt Köln Merheim

Cologne, Germany

Location

Klinikum der Johann-Wolfgang-Goethe-Universität Frankfurt a.M.

Frankfurt, Germany

Location

BG Klinik Ludwigshafen

Ludwigshafen, Germany

Location

Soroka University Medical Center

Beersheba, Israel

Location

Rambam Hospital

Haifa, Israel

Location

Hadassah Medical Center

Jerusalem, Israel

Location

Auckland Hospital

Auckland, New Zealand

Location

Oslo university hospital

Oslo, Norway

Location

National University Hospital

Singapore, Singapore

Location

Singapore General Hospital

Singapore, Singapore

Location

Tan Tock Seng Hospital

Singapore, Singapore

Location

Netcare Union Hospital

Alberton, South Africa

Location

Vincent Pallotti Hospital

Cape Town, South Africa

Location

Netcare Unitas Hospital

Centurion, South Africa

Location

Charlotte Maxeke Johannesburg Hospital

Johannesburg, South Africa

Location

Netcare Milpark Hospital

Johannesburg, South Africa

Location

Chris Baragwanath Hospital

Soweto, South Africa

Location

Hospital 12 de Octubre, Madrid

Madrid, Spain

Location

Centre Hospitalier Universitaire Vaudois CHUV

Lausanne, Switzerland

Location

Universitätsspital Zürich

Zurich, Switzerland

Location

King's College Hospital, London

London, United Kingdom

Location

The Royal London Hospital

London, United Kingdom

Location

John Radcliffe Hospital, Oxford

Oxford, United Kingdom

Location

Related Publications (12)

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• Olofsson CI, Gorecki AZ, Dirksen R, Kofranek I, Majewski JA, Mazurkiewicz T, Jahoda D, Fagrell B, Keipert PE, Hardiman YJ, Levy H; Study 6084 Clinical Investigators. Evaluation of MP4OX for prevention of perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anesthesia: a randomized, double-blind, multicenter study. Anesthesiology. 2011 May;114(5):1048-63. doi: 10.1097/ALN.0b013e318215e198.

  PMID: 21455059 BACKGROUND

• 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.

  PMID: 21317165 BACKGROUND

Related Links

• Sangart Inc. (San Diego, CA) web site

MeSH Terms

Conditions

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

Interventions

polynitroxylated pegylated hemoglobin; maleimide-polyethylene glycol-modified hemoglobin, MP4; PEG-hemoglobin; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Karim Brohi, MD

  The Royal London Hospital

  PRINCIPAL INVESTIGATOR

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: December 15, 2010
• First Posted: December 17, 2010
• Study Start: May 1, 2011
• Primary Completion: October 1, 2012
• Study Completion: November 1, 2012
• Last Updated: August 22, 2013

Record last verified: 2013-08

Locations

AU (2); NO (1); CO (1); IL (3); ZA (6); DE (5); ES (1); CH (2); SG (3); BR (3); FR (8); NZ (1); GB (3)