WithdrawnNCT02148367TBI-EPOUpdated Jan 18, 2019

Effect of Recombinant Erythropoietin on Numbers of Circulating Endothelial Progenitor Cells in Subacute TBI

A Phase 2 interventional study of Erythropoietin in Traumatic Brain Injury, sponsored by Uniformed Services University of the Health Sciences. Withdrawn at 1 site in United States. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2019-01-18.

Sponsored by Uniformed Services University of the Health Sciences · Phase 2, Interventional, and Prevention

Why this study was withdrawn

Publication of recent trials showing no effect of EPO in TBI.

Phase: Phase 2
Study type: Interventional
Enrollment: 0
Allocation: Randomized
Ages: 18 Years to 70 Years
Sex: All

Study summary

Traumatic brain injury (TBI) is the leading cause of death and disability in people under age 45 in industrialized countries. Significant numbers of US veterans from the wars in Iraq and Afghanistan return with TBI. However, to date, there are no specific neuroprotective treatment options with proven clinical efficacy.
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) and promotes angiogenesis and neovascularization after TBI. EPO also promotes neurogenesis and improves functional recovery in animals after experimental stroke and TBI. 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.

Read the detailed description

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-1α); 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.

Conditions studied

Traumatic Brain Injury

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Keywords

Traumatic brain injury
Endothelial progenitor cells
Cerebrovascular reactivity
Angiogenesis

In context

Brain Injuries

2,113 studies on the registry are indexed under Brain Injuries; 384 are open to participants now.

Browse Brain Injuries studies →

Lead sponsor

Uniformed Services University of the Health Sciences is the lead sponsor of 45 studies on the registry; 13 are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 70 Years
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Age 18 - 70 years, inclusive
History of having sustained a TBI > 3 days and \< 7 days prior to enrollment. This evidence will be any one of the following:
1. GCS 3 - 12 on first presentation to medical attention
2. Post-traumatic amnesia > 24 hours
3. TBI-related abnormality on neuroimaging
Persistent post-concussive symptoms
1. Three of more of the following symptoms, which started shortly after the trauma and persist for at least up to the time of enrollment:
  - Fatigueability
  - Disordered sleep
  - Headache
  - Vertigo or dizziness
  - Irritability or aggression
  - Anxiety, depression, or affective instability
  - Changes in personality (e.g., social or sexual inappropriateness)
  - Apathy or lack of spontaneity
2. Symptoms had their onset after trauma, or there is a significant worsening or pre-existing symptoms after trauma.
Ability to give consent by the participant himself
Willingness of women of childbearing potential to use effective contraception during this

Exclusion criteria

Exclusion Criteria:

Contraindication to EPO therapy:
1. Known allergy to EPO, hypersensitivity to mammalian cell-derived products, or hypersensitivity to albumin
2. Serum hemoglobin > 16 g/dL in a male patient or > 14 g/dL in a female patient; or a platelet count > 400,000/mm3 or serum hemoglobin \< 10 g/dL in either a male or female patient
3. liver or kidney disease; the former will be operationally defined as a serum bilirubin > 4 mg/dL, alkaline phosphatase (AP) > 250 U/L, aspartate aminotransferase (SGOT, AST) > 150 U/L, alanine aminotransferase (SGPT, ALT) >150 U/L, or Moderately decreased GFR 30-59 ml/min/1.73m2
4. Pregnancy or lactating; note that a negative pregnancy test will be required if the patient is a female of childbearing potential
Use of EPO one month prior to the randomization
Suspicion of a coagulation disorder associated with bleeding (PTT>45 or INR>1.7, spontaneously out of normal range)
Pre-existing and active major disabling psychiatric disorder (e.g., schizophrenia or bipolar disorder), or other neurological disease (epilepsy, multiple sclerosis, developmental disorder) not related to TBI
History of heart disease or heart attack, congestive heart failure, stroke, venous thromboembolism.
History of disorders that predispose to coagulation (e.g. polycythemia vera, essential thrombocytosis, or thrombotic thrombocytopenic purpura).
Uncontrolled hypertension, defined as above 140/90 mm Hg in three measurements in two separate visits despite antihypertensive therapy.
Known malignant conditions, e.g., melanoma, breast, brain, lung tumor or prostate cancer
Terminal medical diagnosis consistent with survival \< 1 year
Planned surgical procedure during duration of the study
Current use of Coumadin or other blood thinners (e.g. Pradaxa, Heparin, Lovenox).
Any history of previous deep venous thrombosis (DVT), pulmonary embolization (PE), or other thromboembolic event
Current participation in other interventional clinical trial
Current use of iron supplements
Evidence of penetrating brain injury
Contraindication to MRI scanning
No adherence to use of effective method of contraception for females of childbearing potential for time from enrollment to the study until 2 weeks after completion of the study drug

Study design

Phase: Phase 2
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Double (Participant, Investigator)
Enrollment: 0 participants (actual)

Study arms

Active comparator
Erythropoietin (EPO)
Participants (n=20) will receive EPO with a dose of 40,000 IU EPO subcutaneously (s.c.) once weekly for 4 weeks.
Drug: Erythropoietin
Placebo comparator
placebo
Participants (n=10) will receive placebo s.c. once weekly for 4 weeks
Drug: Erythropoietin

Interventions

DrugErythropoietin
This is a double blind randomized placebo-cotrolled study. Randomization and blinding will be done by the NIH Pharmacy. Participants and study staff will be blinded as to group assignment.Participants randomized into the placebo group will receive placebo once weekly for 4 weeks. In total, 10 participants will be randomized in this group. Participants randomized into the experimental group will receive active drug. In total, 20 participants will be randomized in this group. A clinic nurse or physician will administer the study drug, EPO or placebo, to the study participants at the Clinical Center. The study drug is administered by injection under the skin in the arm, leg, or buttock.
Also known as: Procrit, Epogen

What researchers measure

Primary outcomes

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).
Study participants (n=20) will receive EPO once weekly 40,000 IU for 4 weeks. Blood will be collected for EPC assays during each visit. EPC numbers determined after the drug administration will be compared to EPC numbers obtained at the baseline visit.
Time frame: Four weeks of treatment

Secondary outcomes

Comparison of the change of numbers of circulating EPC's between EPO and placebo groups.
Numbers of EPC in treatment group will be compared numbers of EPC determined in placebo group during four weeks of drug/placebo administration.
Time frame: Four weeks of treatment
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-1α); and matrix metalloproteinase-9 (MMP-9)
Biomarkers of of angiogenesis and inflammation will be evaluated in the treatment and placebo groups.
Time frame: Four weeks of threatment
Effect of 4 weeks of placebo administration on numbers of circulating EPCs in patients with persistent symptoms during the subacute period after TBI.
EPC numbers will be studied in TBI participants receiving placebo to elucidate natural history of temporal profiles of EPC after TBI.
Time frame: Four weeks of treatment

Other outcomes

Relationship between EPC levels at baseline and after 4 weeks and neuropsychological performance following TBI.
Neuropsychological performance using subset of Common Data Elements will be studied 5 weeks and 6 months after TBI. These neuropshychological outcomes will be related to levels of EPC on admission and after 4 weeks of the drug administration.
Time frame: 5 weeks and 6 months after the TBI

Study locations

1 site

National Institutes of Health, Clinical Center.
Bethesda, Maryland 20814, United States

References and documents

Publications

Bahlmann FH, De Groot K, Spandau JM, Landry AL, Hertel B, Duckert T, Boehm SM, Menne J, Haller H, Fliser D. Erythropoietin regulates endothelial progenitor cells. Blood. 2004 Feb 1;103(3):921-6. doi: 10.1182/blood-2003-04-1284. Epub 2003 Oct 2. PubMed 14525788 ↗
Guo X, Liu L, Zhang M, Bergeron A, Cui Z, Dong JF, Zhang J. Correlation of CD34+ cells with tissue angiogenesis after traumatic brain injury in a rat model. J Neurotrauma. 2009 Aug;26(8):1337-44. doi: 10.1089/neu.2008.0733. PubMed 19226208 ↗
Bogoslovsky T, Chaudhry A, Latour L, Maric D, Luby M, Spatz M, Frank J, Warach S. Endothelial progenitor cells correlate with lesion volume and growth in acute stroke. Neurology. 2010 Dec 7;75(23):2059-62. doi: 10.1212/WNL.0b013e318200d741. PubMed 21135380 ↗

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Jan 18, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT02148367
Lead sponsor: Uniformed Services University of the Health Sciences
Collaborators: National Institutes of Health (NIH)
Responsible party: Ramon Diaz-Arrastia (Professor of Neurology, Uniformed Services University of the Health Sciences) — Principal investigator
First posted: May 28, 2014
Start date: Sep 2014
Primary completion: Jun 2016 (estimated)
Completion: Dec 2016 (estimated)
Last update: Jan 18, 2019

Study contacts

Ramon Diaz-Arrastia, MD, PhD

principal investigator · Uniformed Services University of the Health Sciences

Eric Wassermann, MD

principal investigator · National Institutes of Health (NIH)

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

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This study is withdrawn, as verified in Jan 2019. You cannot join it, but the record below documents what was studied.

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