The COGNI-REHAB Trial is a single-site, phase O/I, randomized, double-blind, placebo-controlled study of human chorionic gonadotropin (hCG; choriogonadotropin alfa, Ovidrel®) in men with post-acute, moderate to severe traumatic brain injury (msTBI). Its objective is to assess the safety and efficacy of a 24-week regimen of Ovidrel (125 micrograms twice weekly) compared to placebo on treatment-emergent adverse events (TEAEs), cognitive and functional recovery, and circulating sex hormones.

This project aims to re-purpose a safe, well-tolerated, already-approved medication: human chorionic gonadotropin (hCG; choriogonadotropin alfa, Ovidrel®) for use in the post-acute rehabilitation of moderate to severe traumatic brain injury (msTBI). Ovidrel is currently FDA-approved for use in ovulation induction and Assisted Reproductive Technologies (ART). The rationale for using Ovidrel comes from a convergence of evidence indicating that hCG has neurodevelopmental and neuroregenerative properties, and from preclinical studies demonstrating that hCG reverses TBI-induced suppression of sex hormone production (i.e., reverses hypogonadism) and improves recovery of sensorimotor and spatial learning and memory in rodents following a focal injury to the medial prefrontal cortex. Recovery from a TBI is typically a very slow process because innate neuronal regeneration is a slow process; thus, Ovidrel (125 µg twice weekly) treatment will be evaluated over 24-weeks in patients that are 1-6 months post-TBI.

Inclusion Criteria:

• Male subjects aged 18-65
• Subject is 1-month but < 6-month post-TBI with a msTBI defined as Glasgow Coma Scale (GCS) 4-12 (inclusive) at the time of the TBI, and/or at the time of screening (Visit 1)
• Stable doses of any medication, supplement or medical food that may affect brain function, unless deemed medically necessary by the patient's physician for optimal healthcare
• Fluent in English
• Reasonable expectation of availability to receive the 24-week course of therapy and be available for follow up evaluations

Exclusion Criteria:

• Significantly depressed (Geriatric Depression Scale > 10)
• Patients considered to be at risk for suicidality or homicidality according to the Columbia Suicide Severity Rating Scale (CSSRS)
• Primary hypogonadism (unrelated to trauma)
• Renal disease; Asthma; known endocrine or germ cell tumor
• Taking other medications known to affect serum sex hormone or gonadotropin concentrations such as testosterone for hormone replacement therapy, goserelin or danazol, in the past three (3) months
• Presence of significant systemic illness likely to interfere with participation in or completion of the study or to affect study results
• Receiving other investigational drugs within 30 d or 5 half-lives prior to randomization, whichever longer
• Male patients with known/documented elevated PSA levels, or a PSA level of 4ng/mL at screening
• History of deep venous thrombosis (DVT) or venous thromboembolism (VTE)
• Clinically significant peripheral edema
• History of sleep apnea
• Severe symptoms of benign prostatic hyperplasia (BPH), i.e., International Prostate Symptom Score greater than or equal to 20 points
• Patients with known hypercoagulability, including cardiolipin/antiphospholipid antibody syndrome
• Allergy or other contraindication to hCG
• Uncontrolled hypertension, defined as blood pressure persistently above 140 mm Hg systolic or 95 mm Hg diastolic despite antihypertensive therapy
• Uncontrolled thyroid, adrenal or pituitary dysfunction
• An uncontrolled organic intracranial lesion such as a pituitary tumor
• History of breast or prostate cancer; sex hormone dependent tumors of the reproductive organs or accessory sex glands
• Taking hCG, or any condition known to elevate hCG, active in the prior 24 mo. e.g., choriocarcinoma or germ cell tumor
• Patients who have 6 or more symptoms for substance use disorder according to DSM-5 criteria
• Patients with evidence of an active or previous thrombotic event

The data and resources sharing plan for this project is in accordance with the Veterans Administration Data Sharing Policies. All raw clinical, genetic, and imaging data from this project will be available upon written request. Deidentified data may be uploaded to one or more of several available data sharing sites designed for this purpose. The final data will be available in acceptable formats such as presentations and publications.

Research data and results that document and support the study aims will be available after the final results are accepted for publication. The data to be shared will be anonymized and there will be no fees or other restrictions.

Research data and results that document and support the study aims will be available after the final results are accepted for publication.

Approval from PI

Double blind