The Darbepoetin Alfa for Ischemic Surgical Complications (DISC) Dose Finding Trial

Phase 2

Completed

Conditions: Spinal Ischemia
Stroke
Neuroprotection

Interventions: Drug: Darbepoetin alfa
Other: Standard care

Registration Number: NCT00647998

Lead Sponsor: University of Pennsylvania

Brief Summary: Numerous neuroprotectants have been effective when given prior to ischemic stroke in animals, yet they have all have failed when given after ischemic stroke in humans. A novel approach to ischemic neuroprotection is needed. Many patients who undergo cardiac, vascular, and neurosurgical procedures develop ischemic central nervous system (CNS) complications. These high risk surgeries present a unique opportunity to administer neuroprotectant medication prior to the injury, greatly increasing the likelihood that it will have a positive impact on outcomes. Patients undergoing descending thoracic aortic (DTA) and thoracoabdominal aortic (TAA) surgery have a particularly high rate of both brain and spine ischemia. In addition, these surgeries require placement of a lumbar cerebrospinal fluid (CSF) drain, allowing access to CSF in order to monitor markers of injury and penetration of medication into the CNS. We are performing a pilot dose finding trial of prophylactic darbepoetin alfa, a long-acting erythropoiesis medication with putative neuroprotectant properties, in patients undergoing DTA and TAA surgery.

Detailed Description: Numerous neuroprotectants have been effective when given prior to ischemic stroke in animals, yet they have all have failed when given after ischemic stroke in humans. A novel approach to ischemic neuroprotection is needed. Many patients who undergo cardiac, vascular, and neurosurgical procedures develop ischemic central nervous system (CNS) complications. These high risk surgeries present a unique opportunity to administer neuroprotectant medication prior to the injury, greatly increasing the likelihood that it will have a positive impact on outcomes. Patients undergoing descending thoracic aortic (DTA) and thoracoabdominal aortic (TAA) surgery have a particularly high rate of both brain and spine ischemia. In addition, these surgeries require placement of a lumbar cerebrospinal fluid (CSF) drain, allowing access to CSF in order to monitor markers of injury and penetration of medication into the CNS. We performed a pilot dose finding trial of prophylactic darbepoetin alfa, a long-acting erythropoiesis medication with putative neuroprotectant properties, in patients undergoing DTA and TAA surgery. This dose finding trial was stopped early after 9 patients were enrolled at the request of the FDA after an unrelated trial of erythropoietin in acute stroke performed in Germany was negative and showed possible harm in those patients who received intravenous tissue plasminogen activaor (tPA). We then enrolled 9 additional patients who did not receive any intervention in order to compare them to the patients who received darbepoetin.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 18

Inclusion Criteria

Are men and women between the ages of 18 - 100 years old (inclusive)
Require descending thoracic or thoracoabdominal aorta surgical repair
Can provide informed consent

Exclusion Criteria

Have a traumatic aortic dissection
Have a baseline NIHSS > 1 or modified Rankin Scale > 1
Have a history of stroke or myocardial infarction within the past 30 days
Have a preoperative hemoglobin < 9 or > 14
Have a history of polycythemia vera or essential thrombocytosis
Have a history of hematologic malignancy
Have a history of arterial or venous thrombosis in the past three months
Have uncontrolled hypertension
Have active malignancy requiring treatment
Are receiving hemodialysis
Are currently using recombinant human erythropoietin or darbepoetin alfa, or have an expectation to require these medications within 30 days of surgery.
Have a known allergy to recombinant human erythropoietin or darbepoetin alfa
Are pregnant or breast-feeding. Women of childbearing potential must have a negative pregnancy test (urine pregnancy test or serum beta-HCG)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Darbepoetin	Darbepoetin alfa	Patients received 1mg/kg IV Darbepoetin immediately prior to surgery
Darbepoetin	Standard care	Patients received 1mg/kg IV Darbepoetin immediately prior to surgery
Standard care	Standard care	No Darbepoetin

Primary Outcome Measures

Name	Time	Method
Death or Neurologic Disability, Defined as an National Institutes of Health Stroke Scale (NIHSS)>4 or American Spinal Injury Association (ASIA) Lower Extermity Motor Score <25	Discharge from the hospital	The NIHSS is a validated quasi-ordinal measure of stroke severity. An NIHSS \>4 is generally considered moderate or severe. The ASIA Lower Extremity Motor Score is a cumulative total of assessments of strength in 5 muscles in each leg, using the Medical Research Council 0-5 stroke score. ASIA score \< 25 is associated with impaired ambulation.

Secondary Outcome Measures