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

NCT02148367 | Withdrawn Phase 2 DMC

• 2 other identifiers: T-N-2695306135-7.01-60855
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Traumatic Brain Injury

Keywords

Traumatic brain injury; Endothelial progenitor cells; Cerebrovascular reactivity; Angiogenesis

Outcome Measures

Primary Outcomes (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).

  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.

  Four weeks of treatment

Secondary Outcomes (3)

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

  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)

  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.

  Four weeks of treatment

Other Outcomes (1)

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

  5 weeks and 6 months after the TBI

Study Arms (2)

Erythropoietin (EPO)

ACTIVE COMPARATOR

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

PLACEBO COMPARATOR

Participants (n=10) will receive placebo s.c. once weekly for 4 weeks

Drug: Erythropoietin

Interventions

Erythropoietin DRUG

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

Erythropoietin (EPO); placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• GCS 3 - 12 on first presentation to medical attention
• Post-traumatic amnesia \> 24 hours
• TBI-related abnormality on neuroimaging
• Persistent post-concussive symptoms
• 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

You may not qualify if:

• Contraindication to EPO therapy:
• Known allergy to EPO, hypersensitivity to mammalian cell-derived products, or hypersensitivity to albumin
• 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
• 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
• 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).

Sponsors & Collaborators

• Uniformed Services University of the Health Sciences: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

National Institutes of Health, Clinical Center.

Bethesda, Maryland, 20814, United States

Location

Related Publications (3)

• 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.

  PMID: 14525788 BACKGROUND

• 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.

  PMID: 19226208 BACKGROUND

• 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.

  PMID: 21135380 BACKGROUND

MeSH Terms

Conditions

Brain Injuries, Traumatic

Interventions

Erythropoietin; Epoetin Alfa

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Ramon Diaz-Arrastia, MD, PhD

  Uniformed Services University of the Health Sciences

  PRINCIPAL INVESTIGATOR

• Eric Wassermann, MD

  National Institutes of Health (NIH)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology

Study Record Dates

• First Submitted: May 22, 2014
• First Posted: May 28, 2014
• Study Start: September 1, 2014
• Primary Completion: June 1, 2016
• Study Completion: December 1, 2016
• Last Updated: January 18, 2019

Record last verified: 2019-01

Locations

US (1)