NCT02148367
Withdrawn
Phase 2
Effect of Administration of Recombinant Erythropoietin on Numbers of Circulating Endothelial Progenitor Cells in Patients With Persistent Symptoms During the Subacute Period After TBI
Uniformed Services University of the Health Sciences1 site in 1 countryStarted: September 2014Last updated:
Overview
- Phase
- Phase 2
- Status
- Withdrawn
- Locations
- 1
- Primary Endpoint
- 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).
Overview
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.
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- 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:
- •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
- •Vertigo or dizziness
Exclusion Criteria
- •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).
Arms & Interventions
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.
Intervention: Erythropoietin (Drug)
placebo
Placebo Comparator
Participants (n=10) will receive placebo s.c. once weekly for 4 weeks
Intervention: Erythropoietin (Drug)
Outcomes
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).
Time Frame: Four weeks of treatment
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.
Secondary Outcomes
- 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)
- Comparison of the change of numbers of circulating EPC's between EPO and placebo groups.(Four weeks of treatment)
Investigators
Ramon Diaz-Arrastia
Professor of Neurology
Uniformed Services University of the Health Sciences
Study Sites (1)
Loading locations...
Similar Trials
Withdrawn
Phase 2
Effect of Recombinant Erythropoietin on Numbers of Circulating Endothelial Progenitor Cells in People With Persistent Symptoms During the Subacute Period After Traumatic Brain InjuryTraumatic Brain InjuryNCT02226848National Institute of Neurological Disorders and Stroke (NINDS)
Active, not recruiting
Not Applicable
A study to see if erythropoietin can help patients recover better from headinjury.Traumatic brain injuryMedDRA version: 14.1Level: PTClassification code 10019196Term: Head injurySystem Organ Class: 10022117 - Injury, poisoning and procedural complicationsTherapeutic area: Diseases [C] - Symptoms and general pathology [C23]EUCTR2011-005235-22-DEMONASH UNIVERSITY606
Active, not recruiting
Not Applicable
A study to see if erythropoietin can help patients recover better from headinjury.EUCTR2011-005235-22-IEMONASH UNIVERSITY606
Completed
Not Applicable
The Prophylactic Hypothermia Trial to Lessen Traumatic Brain InjuryBrain Injuries, TraumaticNCT00987688Australian and New Zealand Intensive Care Research Centre511
Unknown
Not Applicable
TBI-Prognosis Multicenter Prospective StudyTraumatic Brain InjuryNCT02452541CHU de Quebec-Universite Laval315