Phase IIb Study of MP4OX in Traumatic Hemorrhagic Shock Patients

Shock, Traumatic Clinical Trial

Official title:

A Multi-center, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of MP4OX Treatment, in Addition to Standard Treatment, in Severely Injured Trauma Patients With Lactic Acidosis Due to Hemorrhagic Shock

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01262196
• Other study ID #: TRA-205
• Status: Completed
• Phase: Phase 2
• First received: December 15, 2010
• Last updated: August 20, 2013
• Start date: May 2011
• Est. completion date: November 2012

Study information

• Verified date: August 2013
• Source: Sangart
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Agency for Health and Food SafetyAustralia: Department of Health and Ageing Therapeutic Goods AdministrationBrazil: National Health Surveillance AgencyCanada: Health CanadaColombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y AlimentosFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Paul-Ehrlich-InstitutIsrael: Israeli Health Ministry Pharmaceutical AdministrationNew Zealand: Ministry of HealthNorway: Norwegian Medicines AgencySingapore: Health Sciences AuthoritySouth Africa: Medicines Control CouncilSpain: Spanish Agency of MedicinesSwitzerland: SwissmedicUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

Description:

Acute traumatic injury, including both blunt and penetrating injury, is often associated with severe uncontrolled bleeding which can lead to hemorrhagic shock. During shock, inadequate blood flow results in local ischemia and tissue hypoxia (insufficient oxygenation) of critical organs, which can be detected by an increase in serum lactate levels in these trauma victims. 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.

The primary treatment of trauma is to support ventilation and oxygenation, limit blood loss, and maintain cardiovascular function so that organs are perfused. The patient's airway may be intubated to allow oxygenated airflow to the lungs. Mechanical ventilation is used if the patient cannot maintain oxygenation and carbon dioxide elimination. Damage-control surgery is used to limit blood loss and to intentionally delay definitive repair until the patient can better tolerate procedures. Blood transfusions are provided to maintain the oxygen-carrying capacity of the circulation. Platelets and coagulation factors are infused to correct any coagulopathy from dilution of blood and consumption of clotting factors. Vasopressor and inotropic agents may be used to support low cardiac output or blood pressure. Renal replacement therapy may be instituted if kidney failure occurs.

Despite optimal care, organ dysfunction is present in many patients. Hypoperfusion and anaerobic metabolism of organs and tissues can be detected by the presence of lactic acidosis. Current therapy is aimed at supporting failing organs, but an agent that accelerates the repayment of an oxygen debt and prevents or shortens the duration of organ failure is sought. Blood transfusion improves circulation of oxygen-carrying red blood cells but is insufficient if lactic acidosis is present, even when the hemoglobin level has been restored. Studies in critically ill intensive care patients have demonstrated that elevated initial and 24-hour lactate levels are significantly correlated with mortality, and prolonged elevation of blood lactate levels after trauma has been correlated with increased organ failure and mortality.

Support for the efficacy of MP4OX in resuscitation of severe hemorrhage shock comes from several preclinical studies in hamster, rat, and swine. Using a swine model of uncontrolled hemorrhage and resuscitation, survival was greater and restoration of hemodynamics and acid-base status were improved with MP4OX relative to 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 more effectively than control fluids. Importantly, these benefits of MP4OX were observed with or without co-administration of autologous blood, suggesting that blood alone is not sufficient to achieve resuscitation, and that the effects of MP4OX are additional to those of blood.

Additional support comes from a recently completed phase IIa trauma study in 51 patients with lactic acidosis due to severe hemorrhage. MP4OX treatment was associated with a more rapid and sustained reduction of high lactate levels, and a greater proportion of MP4OX-treated patients who normalized lactate by four hours after dosing. There was also a trend toward shorter median hospital stay and a greater proportion of MP4OX-treated patients being discharged from hospital alive by Day 28. These phase IIa results suggest improved oxygen delivery and utilization by ischemic tissues in the MP4OX-treated patients, based on the reversal of lactic acidosis, and support the positive results from the preclinical models of hemorrhagic shock resuscitation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 348
• Est. completion date: November 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

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

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

Exclusion Criteria:

• 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

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 pegylated hemoglobin in balanced lactate-electrolyte solution
• Saline
Normal saline (0.9%) solution

Locations

Country	Name	City	State
Australia	Liverpoool Hospital NSW	Liverpool
Australia	John Hunter Hospital	Newcastle
Austria	Graz University Hospital	Gratz
Brazil	Faculdade de Medicina de S. J. Do Rio Preto	São José do Rio Preto
Brazil	Hospital das Clínicas - USP	Sao Paolo
Brazil	Hospital Universitário - USP Ribeirão Preto	Sao Paolo
Colombia	Fundacion Valle de Lili	Cali
France	Hôpital Beaujon	Clichy
France	Hôpital Michallon	Grenoble
France	Hôpital du Kremlin Bicêtre	Le Kremlin Bicetre
France	Hôpital Roger Salengro, CHRU Lille	Lille
France	Hôpital Dupuytren, CHU Limoges	Limoges
France	Hôpital Edouard Herriot	Lyon
France	Hôpital Lyon sud	Lyon
France	Hôpital Pitié-Salpêtrière	Paris
Germany	Universitätsklinikum der RWTH Aachen	Aachen
Germany	Charite - Campus Virchow Klinikum	Berlin
Germany	Kliniken der Stadt Köln Merheim	Cologne
Germany	Klinikum der Johann-Wolfgang-Goethe-Universität Frankfurt a.M.	Frankfurt
Germany	BG Klinik Ludwigshafen	Ludwigshafen
Israel	Soroka University Medical Center	Beersheba
Israel	Rambam Hospital	Haifa
Israel	Hadassah Medical Center	Jerusalem
New Zealand	Auckland Hospital	Auckland
Norway	Oslo university hospital	Oslo
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital	Singapore
Singapore	Tan Tock Seng Hospital	Singapore
South Africa	Netcare Union Hospital	Alberton
South Africa	Vincent Pallotti Hospital	Cape Town
South Africa	Netcare Unitas Hospital	Centurion
South Africa	Charlotte Maxeke Johannesburg Hospital	Johannesburg
South Africa	Netcare Milpark Hospital	Johannesburg
South Africa	Chris Baragwanath Hospital	Soweto
Spain	Hospital 12 de Octubre, Madrid	Madrid
Switzerland	Centre Hospitalier Universitaire Vaudois CHUV	Lausanne
Switzerland	Universitätsspital Zürich	Zurich
United Kingdom	King's College Hospital, London	London
United Kingdom	The Royal London Hospital	London
United Kingdom	John Radcliffe Hospital, Oxford	Oxford

Sponsors (1)

Lead Sponsor	Collaborator
Sangart

Countries where clinical trial is conducted

Australia,  Austria,  Brazil,  Colombia,  France,  Germany,  Israel,  New Zealand,  Norway,  Singapore,  South Africa,  Spain,  Switzerland,  United Kingdom, 

References & Publications (12)

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 CI, Górecki 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. — 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

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

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 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients 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 days	No
Secondary	Composite endpoint of Time to Complete Organ Failure Resolution (CTCOFR)		At 14 and 21 days	No
Secondary	Proportion of patients who normalize (= 2.2 mmol/L) lactate levels		2, 4, 6, 8 and 12 hours	No
Secondary	Proportion of patients remaining: (1) in hospital, (2) in ICU, and (3) on ventilator through Day 28		28 days	No
Secondary	Number of days: (1) in hospital, (2) in ICU, and (3) on the ventilator		Through 28 days	No
Secondary	All-cause mortality		At 48 hours and at 28 days	Yes
Secondary	Time (days) from randomization to: (1) death, (2) discharge from hospital, (3) discharge from ICU, and (4) liberation from mechanical ventilation		Through 28 days	No
Secondary	Sequential organ failure assessment (SOFA score)		Daily	Yes
Secondary	Modified Denver score		Daily	Yes

External Links

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