Clinical trial NCT00647998: The Darbepoetin Alfa for Ischemic Surgical Complications (DISC) Dose Finding Trial
Official title: Phase 2 Dose Finding Trial of Prophylactic Darbepoetin Alfa to Improve Outcomes From Ischemic Complications of Surgery
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Spinal Ischemia
Stroke
Neuroprotection
Keywords: Surgical complications
Spinal ischemia
Stroke
Neuroprotection
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
First posted: 2008-04-01
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: 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
timeFrame: Discharge from the hospital
Secondary outcomes:
measure: CSF S100beta
timeFrame: 48 hours
measure: Hemoglobin
timeFrame: 24 hours post-surgery
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: The Hospital of the University of Pennsylvania
state: Pennsylvania
Study officials:
References:
citation: Messe SR, McGarvey ML, Bavaria JE, Pochettino A, Szeto WY, Cheung AT, Leitner E, Miller SW, Kasner SE. A pilot study of darbepoetin alfa for prophylactic neuroprotection in aortic surgery. Neurocrit Care. 2013 Feb;18(1):75-80. doi: 10.1007/s12028-012-9710-4.