Phase Iii Studies

The Phase I studies, using phlebotomy and volume replacement as a model of 'surgical blood loss', laid the foundation for entry into Phase I/II studies in surgical patients and patients with sickle cell anemia. To evaluate increased doses, an elective surgery study was performed in which the initial dose was comparable to doses tested in the Phase I studies, but with subsequent dosing that was two- to three-fold higher.

Sprung et al. (2002) evaluated the tolerability of HBOC-201 in a randomized, single-blind, dose-escalation, RL controlled, multicenter study in 81 patients undergoing non-cardiac surgery who were expected to receive allogeneic blood. Patients were randomized 2:1 to receive a single intraoperative dose of either HBOC-201 (n = 55) (0.6g Hb/kg, 0.9g Hb/kg, 1.2g Hb/kg, 1.5g Hb/kg, 2g Hb/kg or 2.5g Hb/kg) or an equivalent volume of RL solution (n = 26) after an estimated 500-ml or more surgical blood loss. A 5-ml test dose of clinical trial material (either HBOC-201 or RL) was administered prior to anesthesia induction to assess tolerability.The efficacy of treatment with HBOC-201 was evaluated by assessing the number of allogeneic RBC units administered per patient. Safety and tolerability outcomes (evaluated by comparing treatment emergent signs and symptoms) were used to permit progression to the next higher dose level.

The mean number of units of RBC transfused was similar in the two groups. There was no apparent relationship between dose of HBOC-201 and the number of units of allogeneic RBC transfused in a patient. The investigators noted that this was due primarily to study design because only single HBOC-201 doses were investigated; not the consecutive administration of HBOC-201 that was shown in later surgical studies to reduce the use of RBC transfusion.

Intraoperative doses of HBOC-201 (up to a maximum of 245 g) were well tolerated. There were no patient deaths or withdrawals during the study. Adverse events were similar in both treatment groups in type of event and frequency of occurrence; most were not associated with either treatment. Nausea, hypertension, oliguria, skin discoloration after large doses, and rash occurred somewhat more frequently in the HBOC-201 group; fever, hypotension, constipation, insomnia, gastrointestinal disorder and hypomagnesemia occurred somewhat more frequently in the RL group. Administration of HBOC-201 was associated with a dose-dependent increase in methemoglobin concentrations (3.7 per cent ± 3.2 per cent). Systolic blood pressure was approximately 12 per cent higher in the HBOC-201 treated patients than controls following recovery room discharge; other vital signs were not different. Isolated transient increases in aspartate aminotransferase and/or lipase activities (that returned to normal levels prior to hospital discharge) were observed in a few patients. One serious adverse event (mast cell degranulation syndrome) occurred in a hyperimmune patient with systemic mastocytosis who received only a test dose of HBOC-201; the event was considered of unknown association with HBOC-201. Other serious adverse events were not associated with treatment.

Two additional, controlled, perioperative Phase I/II studies, conducted in Europe, assessed the safety of HBOC-201 in acute normovolemic hemo-dilution. These low-dose studies (Kasper et al., 1996, 1998; Brauer et al., 1998; Standl et al., 1998) demonstrated that HBOC-201 was well tolerated during acute normovolemic hemodilution (in patients undergoing liver resection and elective surgery for aortic abdominal aneurysms).

In the patients undergoing preoperative hemo-dilution prior to elective abdominal aortic surgery, Kasper et al. (1996, 1998) investigated the effects of HBOC-201 on hemodynamics and oxygen transport in a single-blind, randomized, single-center, escalating single-dose, hydroxy-ethylstarch (HES) controlled pilot trial (n = 13) and two subsequent studies (total n = 24). Patients (randomized 1 to 1) received a single infusion of HBOC-201 (doses of 0.4g Hb/kg to 1.2g Hb/kg) or an equal volume of hydroxyethyl starch (HES) during hemodilution with RL after anesthesia induction and approximately one hour before surgery. Infusion of HBOC-201 caused an increase in systemic and pulmonary vascular resistance and decrease in cardiac index while maintaining arterial oxygen content at near baseline levels. Base excess, which remained unchanged in the HES treated group, was improved significantly in the HBOC-201 groups 30 minutes after infusion while oxygen consumption was similar in both groups. The improvement in arterial base excess and maintenance of arterial oxygen content in these patients suggest enhanced tissue oxygen transport, despite reduced cardiac output.

Although Kasper et al. (1996, 1998) concluded that hemodilution with HBOC-201 (at the doses used in these studies) provided no advantage over hemodilution with HES, they did not directly measure tissue oxygenation. Characteristically, treatment with HBOC-201 results in a decrease in cardiac output associated with small increases in systemic vascular resistance however, this is associated with marked and sustained increases in oxygen extraction and increases in tissue oxygenation as demonstrated by preclinical studies performed by Standl et al. (1997). These studies showed a primary effect of an increased oxygen extraction ratio associated with a transient decrease in cardiac index.This physiology, which is supported by data from Page et al. (1998), highlights the fact that hemoglobin solutions increase diffusive oxygen transport as well as convective oxygen transport. Therefore, HBOC-201 causes a primary effect on tissue oxygen extraction because of its unique ability to transport high concentrations of oxygen in the plasma that is readily transported to tissues. Autoregulatory mechanisms then result in an appropriate decrease in cardiac output caused by the increased oxygen extraction. The Standl experiments further define this relationship and show that these changes are associated with normal or above normal tissue oxygen levels as measured by the Eppendorf microelectrode technique. The Kasper studies (1996, 1998) demonstrated that HBOC-201 maintained oxygen through a higher extraction ratio and a lower cardiac output whereas the HES group maintained oxygen consumption by increasing cardiac output without an increase in the oxygen extraction ratio.

Liver resection

Standl et al. (1998) investigated the use of HBOC-201 in a randomized, single-blind, single-center, single-dose, HES-controlled study to evaluate the safety and tolerance of HBOC-201 in patients undergoing preoperative hemodilution prior to elective liver resection surgery. Patients were randomized 1 :1 to receive a single infusion of HBOC-201 (0.4g/kg, ~ 1 unit) or HES (equal volume) during hemodilution with RL prior to surgery. There were no differences in heart rate, respiratory rate, temperature, pulse oximetry, blood-gas tensions, or blood chemistry parameters between the two groups throughout the 3-month monitoring period. Patients in the HBOC-201 group had a higher MAP than the control group upon admission to the intensive care unit (95 versus 83 mmHg, respectively; P = 0.037) and more pronounced leukocytosis and reticulocyto-sis during the early postoperative days compared to the HES treated patients. There was a slight increase in methemoglobin with HBOC-201, but the increase remained within a clinically acceptable range. HBOC-201 was not associated with toxic effects nor was it associated with any allergic reactions. In addition, no adverse events were considered by the investigator to be associated with treatment with either HBOC-201 or HES.The authors concluded that HBOC-201 was well tolerated in this patient population and appeared to be safe as a substitute fluid for preoperative hemodilution.

As part of this study in patients undergoing liver resection, Brauer et al. (1998) used transcranial doppler sonography (TCD) to measure cerebral blood flow before and after infusion of HBOC-201 or HES. After treatment there was a slight increase (not statistically significant) inTCD mean flow velocity compared with baseline measurements, which was not different between the two treatment groups and was likely due to hemodilution (decreased hematocrit). These data demonstrate that infusion of HBOC-201 did not result in any specific cerebrovascular side effects compared to control.

Sickle cell disease

Due to its unique oxygen transport characteristics (circulation in the plasma, and its effects on oxygen-diffusing capacity), HBOC-201 may be beneficial for managing the vaso-occlusive crises in patients with sickle cell disease (SCD). Gonzalez et al. (1997) and Orringer et al. (1995) measured local perfusion in sickle cell anemia patients not in crisis in a randomized, single-blind, single-dose, dose-escalation, saline-controlled, single-center study. Patients were randomized 2: 1 to treatment with HBOC-201 (at 0.2, 0.4 or 0.6g Hb/kg) or an equal volume of saline. The study monitored treatment-emergent signs and symptoms, and determined the functional capacity of selected muscle groups by grip strength and aerobic selected muscle group evaluations. Pulmonary function tests were performed on patients in the two higher-dose groups.

HBOC-201 was well tolerated at all doses. Systolic and diastolic blood pressures were nearly identical at all time points, and there were only minor changes in hematological and chemical laboratory parameters. One patient receiving 0.2 g Hb/kg of HBOC-201 experienced a painful sickle cell crisis attributed to the 4-hour post-infusion exercise test but this was not considered associated with HBOC-201. There were no significant differences between the two groups in handgrip testing. However, when subjects underwent graded exercise testing, heart rate during aerobic exercise was significantly lower in the HBOC-201 group (P = 0.0061) even though exercise intensity was similar in both patient groups. By 48 hours post-infusion, heart rate was similar in both the HBOC-201 and placebo patients. The investigators hypothesized that HBOC-201 may facilitate oxygen delivery and help overcome the rheologic abnormality of sickle erythrocytes in SCD patients.

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