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

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

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.

Study Overview

• Status: Completed
• Conditions: Stroke; Neuroprotection; Spinal Ischemia
• Intervention / Treatment: Other: Standard care; Drug: Darbepoetin alfa

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Hospital of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Pennsylvania

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: March 27, 2008
• First Submitted That Met QC Criteria: March 31, 2008
• First Posted (Estimate): April 1, 2008

Study Record Updates

• Last Update Posted (Actual): June 5, 2017
• Last Update Submitted That Met QC Criteria: May 1, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Stroke; Neuroprotection; Surgical complications; Spinal ischemia
• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia; Hematinics; Darbepoetin alfa
• Other Study ID Numbers: DISC-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO