Clinical trial NCT00421200: Phase III Study of Hemospan® to Prevent Hypotension in Hip Arthroplasty
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypotension
Ischemia
Keywords: Hip arthroplasty
Anesthesia, spinal
Hypotension
Ischemia
Blood substitutes
Plasma expanders
Lead sponsor: Sangart
Sponsor class: INDUSTRY
First posted: 2007-01-11
Enrollment: 375
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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)
timeFrame: Up to 6 hours after skin closure
Secondary outcomes:
measure: 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
timeFrame: 30 days
measure: 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
timeFrame: 30 days
measure: Mortality (in-hospital, and all-cause at 30 days)
timeFrame: 30 days
measure: Time to the first hypotensive episode (SBP < 90 mmHg or < 75% of BL) following completion of the dosing regimen
timeFrame: Intraoperative
measure: Time to administration of the second dose
timeFrame: Intraoperative
measure: Proportion of patients that only receive/require one dose and avoid hypotension
timeFrame: Up to 6 hours after skin closure
measure: Total duration of all hypotensive episodes
timeFrame: Up to 6 hours after skin closure
measure: Duration of the longest period of hypotension recorded
timeFrame: Up to 6 hours after skin closure
measure: Incidence of intervention with a pressor agent to treat hypotension
timeFrame: Up to 6 hours after skin closure
measure: Incidence of postoperative intervention with a diuretic for volume-overload or inadequate urine output
timeFrame: Post-operative day 3
Other outcomes:
Locations:
city: Antwerp
country: Belgium
facility: Univ. Ziekenhuis Antwerp
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Genk
country: Belgium
facility: ZOL Campus Sint-Jan
city: Ghent
country: Belgium
facility: AZ St. Lucas Hospital
city: Hradec Kralove
country: Czech Republic
facility: Fakultni nemocnice Hradec Kralove
city: Kladno
country: Czech Republic
facility: Oblastni nemocnice Kladno
city: Prague
country: Czech Republic
facility: Fakultni nemocnice Motol
city: Prague
country: Czech Republic
facility: Fakultni nemocnice Na Bulovce
city: Nijmegen
country: Netherlands
facility: Sint Maartenskliniek
city: Nijmegen
country: Netherlands
facility: Universitair Medisch Centrum St. Radboud
city: Lublin
country: Poland
facility: SPSK nr 4, Klinika Ortopedii, Traumatologii i Rehabilitacji AM
city: Piekary Śląskie
country: Poland
facility: SP Wojewódzki Szpital Chirurgii Urazowej
city: Sosnowiec
country: Poland
facility: Wojewódzki Szpital Specjalistyczny nr 5
city: Warsaw
country: Poland
facility: SK Dzieciątka Jezus
city: Skövde
country: Sweden
facility: Skaraborg Hospital
city: Stockholm
country: Sweden
facility: Karolinska Hospital
city: Stockholm
country: Sweden
facility: S:t Görans Hospital
city: Nottingham
country: United Kingdom
facility: Univ. Hospital - Queen's Medical Center
Study officials:
affiliation: Karolinska University Hospital
name: Christina I. Olofsson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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. doi: 10.1152/ajpheart.00749.2004. Epub 2005 Jan 6.
citation: 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.
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. doi: 10.1182/blood-2006-02-005272. Epub 2006 Jul 20.
citation: 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.
citation: 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.
citation: Winslow RM. Red cell substitutes. Semin Hematol. 2007 Jan;44(1):51-9. doi: 10.1053/j.seminhematol.2006.09.013.
citation: 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.