Phase IIb Study of MP4OX in Traumatic Hemorrhagic Shock Patients

Sponsor

Sangart (Industry)

Overall Status

Completed

CT.gov ID

NCT01262196

Collaborator

(none)

348

Enrollment

Locations

Arms

18.1

Duration (Months)

8.7

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Shock, Hemorrhagic Shock, Traumatic Acidosis, Lactic	Drug: MP4OX Drug: Saline	Phase 2

Detailed 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

348 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Study Start Date :

May 1, 2011

Actual Primary Completion Date :

Oct 1, 2012

Actual Study Completion Date :

Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MP4OX 250-mL dose	Drug: MP4OX 4.3 g/dL pegylated hemoglobin in balanced lactate-electrolyte solution Other Names: Hemoglobin pegylated MalPEG-Hb MP4 PEG-Hb Pegylated-Hb
Placebo Comparator: Control 250-mL of normal saline solution	Drug: Saline Normal saline (0.9%) solution Other Names: Normal saline Saline solution Sodium chloride 0.9%

Arm

Intervention/Treatment

Experimental: MP4OX

250-mL dose

Drug: MP4OX

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

Other Names:

Hemoglobin pegylated

MalPEG-Hb

MP4

PEG-Hb

Pegylated-Hb

Placebo Comparator: Control

250-mL of normal saline solution

Drug: Saline

Normal saline (0.9%) solution

Other Names:

Normal saline

Saline solution

Sodium chloride 0.9%

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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]
All-cause mortality [At 48 hours and at 28 days]
Time (days) from randomization to: (1) death, (2) discharge from hospital, (3) discharge from ICU, and (4) liberation from mechanical ventilation [Through 28 days]
Sequential organ failure assessment (SOFA score) [Daily]
Modified Denver score [Daily]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country
1	Liverpoool Hospital NSW	Liverpool	Australia
2	John Hunter Hospital	Newcastle	Australia
3	Graz University Hospital	Gratz	Austria
4	Hospital das Clínicas - USP	Sao Paolo	Brazil
5	Hospital Universitário - USP Ribeirão Preto	Sao Paolo	Brazil
6	Faculdade de Medicina de S. J. Do Rio Preto	São José do Rio Preto	Brazil
7	Fundacion Valle de Lili	Cali	Colombia
8	Hôpital Beaujon	Clichy	France
9	Hôpital Michallon	Grenoble	France
10	Hôpital du Kremlin Bicêtre	Le Kremlin Bicetre	France
11	Hôpital Roger Salengro, CHRU Lille	Lille	France
12	Hôpital Dupuytren, CHU Limoges	Limoges	France
13	Hôpital Edouard Herriot	Lyon	France
14	Hôpital Lyon sud	Lyon	France
15	Hôpital Pitié-Salpêtrière	Paris	France
16	Universitätsklinikum der RWTH Aachen	Aachen	Germany
17	Charite - Campus Virchow Klinikum	Berlin	Germany
18	Kliniken der Stadt Köln Merheim	Cologne	Germany
19	Klinikum der Johann-Wolfgang-Goethe-Universität Frankfurt a.M.	Frankfurt	Germany
20	BG Klinik Ludwigshafen	Ludwigshafen	Germany
21	Soroka University Medical Center	Beersheba	Israel
22	Rambam Hospital	Haifa	Israel
23	Hadassah Medical Center	Jerusalem	Israel
24	Auckland Hospital	Auckland	New Zealand
25	Oslo university hospital	Oslo	Norway
26	National University Hospital	Singapore	Singapore
27	Singapore General Hospital	Singapore	Singapore
28	Tan Tock Seng Hospital	Singapore	Singapore
29	Netcare Union Hospital	Alberton	South Africa
30	Vincent Pallotti Hospital	Cape Town	South Africa
31	Netcare Unitas Hospital	Centurion	South Africa
32	Charlotte Maxeke Johannesburg Hospital	Johannesburg	South Africa
33	Netcare Milpark Hospital	Johannesburg	South Africa
34	Chris Baragwanath Hospital	Soweto	South Africa
35	Hospital 12 de Octubre, Madrid	Madrid	Spain
36	Centre Hospitalier Universitaire Vaudois CHUV	Lausanne	Switzerland
37	Universitätsspital Zürich	Zurich	Switzerland
38	King's College Hospital, London	London	United Kingdom
39	The Royal London Hospital	London	United Kingdom
40	John Radcliffe Hospital, Oxford	Oxford	United Kingdom