Phase III Study of Hemospan® to Prevent Hypotension in Hip Arthroplasty

Hypotension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00421200
• Other study ID #: 6084
• Status: Completed
• Phase: Phase 3
• First received: January 9, 2007
• Last updated: August 15, 2013
• Start date: February 2007
• Est. completion date: June 2008

Study information

• Verified date: August 2013
• Source: Sangart
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicines and Health Products, FAMHPCzech Republic: State Institute for Drug ControlNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsSweden: Medical Products AgencyUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether Hemospan is superior to Voluven for preventing 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.

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 preventing 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 hypotension in orthopedic surgery patients undergoing hip replacement surgery under spinal anesthesia.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 375
• Est. completion date: June 2008
• Est. primary completion date: May 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypotension
• Ischemia

Intervention

Drug:
• Hemospan (MP4OX)
250 ml unit dose, up to 500 mL total dose, as needed at protocol-defined dosing triggers
• Voluven (HES 130/0.4)
250 ml unit dose, up to 500 mL total dose, as needed at protocol-defined dosing triggers

Locations

Country	Name	City	State
Belgium	Univ. Ziekenhuis Antwerp	Antwerp
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	ZOL Campus Sint-Jan	Genk
Belgium	AZ St. Lucas Hospital	Ghent
Czech Republic	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czech Republic	Oblastni nemocnice Kladno	Kladno
Czech Republic	Fakultni nemocnice Motol	Prague
Czech Republic	Fakultni nemocnice Na Bulovce	Prague
Netherlands	Sint Maartenskliniek	Nijmegen
Netherlands	Universitair Medisch Centrum St. Radboud	Nijmegen
Poland	SPSK nr 4, Klinika Ortopedii, Traumatologii i Rehabilitacji AM	Lublin
Poland	SP Wojewódzki Szpital Chirurgii Urazowej	Piekary Slaskie
Poland	Wojewódzki Szpital Specjalistyczny nr 5	Sosnowiec
Poland	SK Dzieciatka Jezus	Warsaw
Sweden	Skaraborg Hospital	Skövde
Sweden	Karolinska Hospital	Stockholm
Sweden	S:t Görans Hospital	Stockholm
United Kingdom	Univ. Hospital - Queen's Medical Center	Nottingham

Sponsors (1)

Lead Sponsor	Collaborator
Sangart

Countries where clinical trial is conducted

Belgium,  Czech Republic,  Netherlands,  Poland,  Sweden,  United Kingdom, 

References & Publications (8)

Björkholm 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. — View Citation

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. Epub 2005 Jan 6. — View Citation

Olofsson C, Ahl T, Johansson T, Larsson S, Nellgård 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. — 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 pr — 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

Winslow RM. Current status of oxygen carriers ('blood substitutes'): 2006. Vox Sang. 2006 Aug;91(2):102-10. Review. — View Citation

Winslow RM. Red cell substitutes. Semin Hematol. 2007 Jan;44(1):51-9. Review. — 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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients who develop at least one hypotensive episode during anesthesia/surgery and throughout the postoperative period (the first 6 hours following skin closure)		Up to 6 hours after skin closure	No
Secondary	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	No
Secondary	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	No
Secondary	Mortality (in-hospital, and all-cause at 30 days)		30 days	No
Secondary	Time to the first hypotensive episode (SBP < 90 mmHg or < 75% of BL) following completion of the dosing regimen		Intraoperative	No
Secondary	Time to administration of the second dose		Intraoperative	No
Secondary	Proportion of patients that only receive/require one dose and avoid hypotension		Up to 6 hours after skin closure	No
Secondary	Total duration of all hypotensive episodes		Up to 6 hours after skin closure	No
Secondary	Duration of the longest period of hypotension recorded		Up to 6 hours after skin closure	No
Secondary	Incidence of intervention with a pressor agent to treat hypotension		Up to 6 hours after skin closure	No
Secondary	Incidence of postoperative intervention with a diuretic for volume-overload or inadequate urine output		Post-operative day 3	No

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