Effect of Recombinant Erythropoietin on Numbers of Circulating Endothelial Progenitor Cells in People With Persistent Symptoms During the Subacute Period After Traumatic Brain Injury

Traumatic Brain Injury Clinical Trial

Official title: Effect of Administration of Recombinant Erythropoietin on Numbers of Circulating Endothelial Progenitor Cells in Patients With Persistent Symptoms During the Subacute Period After TBI

Status Withdrawn

Clinical Trial Summary

Background:

• Traumatic brain injury (TBI) injures blood vessels in the brain. Endothelial progenitor cells (EPCs) help the body form new blood vessels. The drug erythropoietin (EPO) helps the body make more blood cells and might help make blood vessels. Researchers want to see if EPO helps people with TBI.

Objective:

• To see whether erythropoietin increases the number of endothelial progenitor cells circulating in the blood and changes reactivity of brain vessels.

Eligibility:

• Adults age 18 70 who had a TBI 3 7 days ago and still have symptoms.

Design:

• Participants will be screened with medical history and blood tests. Vital signs will be taken.

• Visit 1:

• Medical history, physical exam, and blood sample.

• Neuropsychological tests of memory, attention, and thinking. These include written and spoken questions, tests on paper or computer, and simple actions.

• Magnetic resonance imaging (MRI) scan with carbon dioxide. Participants will lie on a table that slides in and out of a metal cylinder. For part of the scan, participants will wear a breathing mask like a snorkel and wear a nose clip.

• Study drug or placebo injection under the skin of the arm, leg, or buttock.

• Visits 2, 3, and 4 will be 1 week apart.

• Blood sample.

• Review of TBI symptoms and any drug side effects.

• Study drug or placebo injection under the skin.

• Visit 5 will be 1 week after visit 4. Visit 6 will be 6 months after participants start the study.

• Blood sample.

• Review of TBI symptoms and any drug side effects.

• Neuropsychological tests.

• MRI with carbon dioxide.

Clinical Trial Description

Objective

Traumatic brain injury (TBI) is the leading cause of death and disability in people under age 45 in industrialized countries 5;6. Significant numbers of US veterans from the wars in Iraq and Afghanistan return with TBI7. However, to date, there are no specific neuroprotective treatment options with proven clinical efficacy 8. Erythropoietin (EPO) is approved by the FDA to treat anemia and has comprehensive preclinical data supporting its neuroprotective and neuroregenerative efficacy following traumatic (TBI) and a wide range of other acquired brain insults. Injury to small and medium-sized cerebral blood vessels is a well recognized consequence of TBI. EPO increases production of endothelial progenitor cells (EPCs) 4;9 and promotes angiogenesis and neovascularization after TBI. EPO also promotes neurogenesis and improves functional recovery in animals after experimental stroke10-12 and TBI.13;14 Neovascularization is coupled with neurogenesis, and augmentation of both processes by EPO may result in lessened cognitive deficits. Neovascularization by EPO may prevent post-traumatic deficits in cerebrovascular reactivity (CVR), which can be measured noninvasively using magnetic resonance imaging (MRI).

This proposal is for a randomized, placebo-controlled pilot clinical trial designed to obtain data on the effects of EPO in humans with persistent post-concussive symptoms after TBI. The primary objective is to evaluate effect of 4 week administration of recombinant erythropoietin on numbers of circulating endothelial progenitor cells in patients with persistent symptoms during the subacute period after TBI. This information will guide the design of a future definitive study.

Study Population

The study population will include 30 males and females with persistent post-concussive symptoms continuing up to 7 days after TBI. Participants will be military service members or civilians presenting as outpatients for clinical management of TBI or post-concussive symptoms at the Center for Neuroscience and Regenerative Medicine (CNRM)-affiliated hospitals. These include the Walter Reed National Military Medical Center (WRNMMC), Suburban Hospital (SH), and Washington Hospital Center (WHC).

Design

Participants will be referred to the NIH Clinical Center (CC) from participating hospitals or will be recruited by advertisements through CNRM Recruitment core to receive EPO or placebo. Telephone screening will be carried out to determine tentative eligibility. At the baseline visit, participants will be screened, consented and randomized 2:1 to receive either EPO or placebo with a dose of 40,000 IU EPO subcutaneously (s.c.) (n=20) once weekly for 4 weeks or placebo (n=10). Each participant will have 6 outpatient visits (visits 1-6) performed at the NIH CC. Placebo or active drug will be administered s.c. based on the randomization at visits 1-4; blood will be collected for EPC assays and safety laboratory measurements during each visit. Brain MRI and neuropsychological tests will be performed during visit 1 (before administering EPO or placebo), and visit 5 (one week after final drug administration) and visit 6 (6 months after study enrollment).

Outcome Measures

Primary outcome:

1. . Effect of 4 weeks of EPO administration on numbers of circulating EPCs in patients with persistent symptoms during the subacute period after TBI (within subject comparison).

Secondary outcomes:

2. . Comparison of the change of numbers of circulating EPC s between EPO and placebo groups.

3. . Effect of 4 weeks of EPO administration on MRI biomarkers of TBI recovery (such as CVR on hypercapnia and global and regional brain volumes by MRI).

4. . Effect of 4 weeks of EPO administration on plasma biomarkers of angiogenesis and inflammation, such as stem cell factor (SCF), vascular endothelial growth factor (VEGF), stromal-derived factor (SDF-1 ); and matrix metalloproteinase-9 (MMP-9).

5. . Effect of 4 weeks of placebo administration on numbers of circulating EPCs in patients with persistent symptoms during the subacute period after TBI.

Tertiary outcome:

6. . Relationship between EPC levels at baseline and after 4 weeks and neuropsychological performance following TBI. ;

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Traumatic Brain Injury
• Wounds and Injuries

• NCT number: NCT02226848
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Withdrawn
• Phase: Phase 2
• Start date: August 15, 2014
• Completion date: May 31, 2017