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

Study Overview
=================
Brief Summary
-----------------
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

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.

Official Title
-----------------
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

Conditions
-----------------
Hypotension, Ischemia

Intervention / Treatment
-----------------
* Drug: Hemospan (MP4OX)
* Drug: Voluven (HES 130/0.4)


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 
| 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 | 
| Duration of the longest period of hypotension recorded |  | 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 | 
| Incidence of postoperative intervention with a diuretic for volume-overload or inadequate urine output |  | Post-operative day 3 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hip arthroplasty, Anesthesia, spinal, Hypotension, Ischemia, Blood substitutes, Plasma expanders