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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase 2 Dose Finding Trial of Prophylactic Darbepoetin Alfa to Improve Outcomes From Ischemic Complications of Surgery

Conditions
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Spinal Ischemia, Stroke, Neuroprotection

Intervention / Treatment
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* Drug: Darbepoetin alfa
* Other: Standard care


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darbepoetin<br>Patients received 1mg/kg IV Darbepoetin immediately prior to surgery | Drug: Darbepoetin alfa<br>* Patients will receive one IV injection of Darbepoetin alfa at doses ranging from 1mcg/kg to 6.5 mcg/kg prior to surgery<br>* Other names: Aranesp;Other: Standard care<br> <br> |
| Placebo Comparator: Standard care<br>No Darbepoetin | Other: Standard care<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Discharge from the hospital | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CSF S100beta | Cerebrospinal fluid S100beta level | 48 hours | 
| Hemoglobin |  | 24 hours post-surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Surgical complications, Spinal ischemia, Stroke, Neuroprotection