Phase III Study of Hemospan® for Treating Hypotension in Hip Arthroplasty

A Randomized, Double-Blind, Phase III Study of the Efficacy and Safety of an Oxygen-Carrying Plasma Expander, Hemospan®, Compared With Voluven® toTreat Hypotension in Patients Undergoing Primary Hip Arthroplasty With Spinal Anesthesia

The purpose of this study is to determine whether Hemospan is superior to Voluven for treatment of hypotensive episodes during the perioperative period (from induction of spinal anesthesia until 6 hours after skin closure), and for reducing the incidence of operative and postoperative complications including organ dysfunction and failure until follow-up at one month following surgery. An independent Data Safety Monitoring Board (DSMB) will periodically evaluate the safety data collected during this trial

Study Overview

• Status: Completed
• Conditions: Ischemia; Hypotension
• Intervention / Treatment: Drug: Hemospan (MP4OX); Drug: Voluven (HES 130/0.4)

Detailed Description

Hemospan is a novel hemoglobin-based oxygen carrier developed to perfuse and oxygenate tissue at risk for ischemia and hypoxia. As a result of its molecular size and oxygen binding characteristics, Hemospan selectively off-loads oxygen in tissues predisposed to low oxygen tension. Preclinical evidence suggests that Hemospan provides rapid and effective plasma expansion and tissue perfusion, and that the properties of Hemospan target oxygen release in the microcirculation.

Spinal anesthesia is the preferred choice for hip arthroplasty procedures in elderly patients, but is associated with a functional hypovolemia due to loss of vascular tone that frequently causes acute hypotensive episodes. Hypotension represents a surrogate marker of hypovolemia that may be further exacerbated by surgical bleeding, which can result in decreased cardiac output, insufficient perfusion and inadequate tissue oxygenation. Ischemia resulting from hypotension can adversely affect vital organ function and may result in complications and postoperative morbidity. As the population ages and more patients become candidates for orthopedic reconstruction or joint replacement surgery, the number of patients at risk is increasing. The ideal IV solution for treating hypovolemia-associated hypotension and improving hemodynamic stability would be an effective plasma expander that promotes tissue perfusion and delivers oxygen to ischemic or marginally hypoxic tissue.

Preclinical animal studies have shown that Hemospan may be well-suited to this application and may even be better than blood in some situations. Data from Sangart's Phase II orthopedic surgery study (No. 6055), published recently by Olofsson et al. (Anesthesiology 2006; 105(6):1153-63) support the safety and potential benefit of Hemospan for preventing and treating hypotension in orthopedic surgery patients undergoing hip replacement surgery under spinal anesthesia.

• Study Type: Interventional
• Enrollment (Actual): 462
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • CHU Brugmann
  • Genk, Belgium
    • Z.O.L. Genk
  • Roeselare, Belgium
    • Stedelijk Ziekenhuis Roeselare
• Czech Republic
  • Hradec Kralove, Czech Republic
    • Fakultni nemocnice Hradec Kralove
  • Prague, Czech Republic
    • Fakultni nemocnice Na Bulovce
  • Prague, Czech Republic
    • Fakultni nemocnice Motol, I. Ortopedicka klinika
  • Prague, Czech Republic
    • Fakultni nemocnice Motol, II. Ortopedicka klinika
• Netherlands
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Hilversum, Netherlands
    • Tergooi Ziekenhuizen, locatie Hilversum
  • Nijmegen, Netherlands
    • Sint Maartenskliniek
  • Rotterdam, Netherlands
    • UMC Erasmus
• Poland
  • Bialystok, Poland
    • Samodzielny Publiczny Szpital Kliniczny AM
  • Piekary Śląskie, Poland
    • SP Wojewódzki Szpital Chirurgii Urazowej
  • Sosnowiec, Poland
    • Wojewódzki Szpital Specjalistyczny nr 5
  • Warsaw, Poland
    • SK Dzieciątka Jezus
  • Warsaw, Poland
    • Instytut Reumatologii, Klinika Reumoortopedii
• Sweden
  • Gävle, Sweden
    • Länssjukhuset Gävle
  • Kalmar, Sweden
    • Kalmar Hospital
  • Motala, Sweden
    • Lasarettet Motala
  • Stockholm, Sweden
    • Danderyd Sjukhus
  • Stockholm, Sweden
    • Söder Hospital
  • Uddevalla, Sweden
    • Uddevalla Sjukhus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients scheduled to undergo elective primary hip arthroplasty (based on an osteoarthritis diagnosis) under spinal anesthesia
• Adult male or female (surgically sterile or post-menopausal), aged 50 years or older
• American Society of Anesthesiology (ASA) Class II or III
• Physical examination, laboratory status, vital signs, and ECG within acceptable limits for the planned surgery, as judged by the investigator
• Have been given written and verbal information by the investigator about Hemospan and the protocol, and have had the opportunity to ask questions about the study
• Patients must sign an Informed Consent form that has been reviewed and approved by the independent Ethics Committee

Exclusion Criteria:

• Hip fracture patients and nail/pin extraction procedures
• Clinical evidence of uncontrolled cardiovascular, infectious, psychiatric, metabolic or systemic disorders including diabetes and rheumatoid arthritis
• Evidence of significant hypertension with SBP >180 mmHg, or a difference in SBP obtained in each arm that is >15 mmHg (measured in the supine position in both arms, at screening)
• Recent history or evidence of MI or stroke (within 6 months)
• Known alcohol or drug dependency
• Currently taking oral anti-coagulant therapy; except for low-dose aspirin (acetylsalicylic acid), <200 mg/day
• History of coagulopathy
• Involved in any investigational drug or device trial within 30 days prior to this study
• Professional or ancillary personnel involved with this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hemospan (MP4OX); 4.3 g/dL MalPEG-Hb solution	Drug: Hemospan (MP4OX); 250 mL unit dose, up to 500 mL total dose as needed at protocol-defined dosing triggers; Other Names: MP4OX solution; 4.3 g/dL MalPEG-Hb; PEGylated Hb
Active Comparator: Control; Voluven (HES 130/0.4)	Drug: Voluven (HES 130/0.4); 250 mL unit dose, up to 500 mL total dose as needed at protocol-defined dosing triggers; Other Names: Voluven; 6% hetastarch solution; 6% HES 130/0.4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Total duration of all hypotensive episodes occurring during anesthesia/surgery and throughout the postoperative period (defined as the first 6 hours following skin closure)	Up to 6 hours after skin closure

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of serious operative and postoperative complications, combined into a Composite Morbidity Outcome that includes acute heart failure, acute MI, ischemic stroke, and renal failure	30 days
Incidence of operative and postoperative organ dysfunction related to ischemia and/or tissue hypoxia, as a Composite Ischemia Outcome that includes clinical evidence of cerebral ischemia, myocardial ischemia, and renal dysfunction	30 days
Duration of the longest period of hypotension recorded	Up to 6 hours after skin closure
Incidence of postoperative intervention with a diuretic for volume-overload or inadequate urine output	Post-operative day 3
Mortality (In-hospital, and all-cause at 30 days)	30 days
Time to resolve/correct the initial hypotensive episode that led to the first dosing trigger	Intraoperative
Time to the second dosing trigger from the first dosing trigger	Intraoperative
Proportion of patients treated successfully with one dose	Intraoperative
Incidence of hypotension	Up to 6 hours after skin closure
Incidence of intervention with a pressor agent to treat hypotensive episodes	Up to 6 hours after skin closure

Collaborators and Investigators

• Sponsor: Sangart
• Investigators: Principal Investigator: Philippe van der Linden, MD, PhD, CHU Brugmann, Brussels

Publications and helpful links

General Publications

• 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.
• 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.
• Bjorkholm M, Fagrell B, Przybelski R, Winslow N, Young M, Winslow RM. A phase I single blind clinical trial of a new oxygen transport agent (MP4), human hemoglobin modified with maleimide-activated polyethylene glycol. Haematologica. 2005 Apr;90(4):505-15.
• Winslow RM. Red cell substitutes. Semin Hematol. 2007 Jan;44(1):51-9. doi: 10.1053/j.seminhematol.2006.09.013.
• Cabrales P, Tsai AG, Winslow RM, Intaglietta M. Effects of extreme hemodilution with hemoglobin-based O2 carriers on microvascular pressure. Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2146-53. doi: 10.1152/ajpheart.00749.2004. Epub 2005 Jan 6.
• Winslow RM. Current status of oxygen carriers ('blood substitutes'): 2006. Vox Sang. 2006 Aug;91(2):102-10. doi: 10.1111/j.1423-0410.2006.00789.x.
• Olofsson C, Ahl T, Johansson T, Larsson S, Nellgard P, Ponzer S, Fagrell B, Przybelski R, Keipert P, Winslow N, Winslow RM. A multicenter clinical study of the safety and activity of maleimide-polyethylene glycol-modified Hemoglobin (Hemospan) in patients undergoing major orthopedic surgery. Anesthesiology. 2006 Dec;105(6):1153-63. doi: 10.1097/00000542-200612000-00015.
• 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.

Helpful Links

• Click here for more information about Sangart, Inc.

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (Actual): March 1, 2008
• Study Completion (Actual): April 1, 2008

Study Registration Dates

• First Submitted: January 9, 2007
• First Submitted That Met QC Criteria: January 9, 2007
• First Posted (Estimate): January 11, 2007

Study Record Updates

• Last Update Posted (Estimate): August 19, 2013
• Last Update Submitted That Met QC Criteria: August 15, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: Hypotension; Ischemia; Hip arthroplasty; Anesthesia, spinal; Blood substitutes; Plasma expanders
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Ischemia; Hypotension; Plasma Substitutes; Blood Substitutes; Pharmaceutical Solutions; Hydroxyethyl Starch Derivatives
• Other Study ID Numbers: 6090