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

- 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.

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:

- 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