Traumatic Brain Injury
Conditions
Keywords
Traumatic brain injury, Human chorionic gonadotropin
Brief summary
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.
Detailed description
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.
Interventions
DRUGOvidrel
Ovidrel, recombinant human chorionic gonadotropin, comes in a prefilled syringe for subcutaneous injection, is the investigational agent that will be used in this trial. Ovidrel® PreFilled Syringe is a sterile, liquid intended for subcutaneous (s.c.) injection. Each Ovidrel® PreFilled Syringe is filled with 0.515 mL containing 257.5 micrograms of choriogonadotropin alfa, 28.1 mg mannitol, 505 g 85% O-phosphoric acid, 103 g L-methionine, 51.5 g Poloxamer 188, Sodium Hydroxide (for pH adjustment), and Water for Injection to deliver 125 micrograms of choriogonadotropin alfa in 0.25 mL twice weekly. The pH of the solution is 6.5 to 7.5.
OTHERPlacebo
Prefilled syringe of 0.250 mL normal saline.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind
Intervention model description
Placebo controlled.
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent change in Treatment-Emergent Adverse Events | Baseline, 26 Weeks | The frequency and type of individual TEAEs, discontinuations due to TEAEs, serious TEAEs, and clinically significant changes in laboratory test values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent change in modified Functional Independence Measure (FIM) | Baseline, 24 Weeks | The FIM is a standardized rating of motor and cognitive disability is commonly used to guide and track progress during rehabilitation, drilling down into level of assistance required for various daily tasks. |
| Glasgow Outcome Scale-Extended (GOSE) | Baseline, 24 Weeks | The GOSE is a brief standardized tool developed for assessing TBI severity and recovery, offering a useful global indicator of disability severity. |
| Percent Change in Neuropsychiatric Inventory (NPI) | Baseline, 24 Weeks | The NPI measures psychopathology in patients with neurological disorders, this tool allows brief screening of different conditions. When a screening item is positive, it follows up with more detail of symptom types, frequency, severity, and how distressing it is to caregivers. This makes for a very efficient and useful tool, providing a more comprehensive assessment of symptoms when they are present, and can be used to track recovery. |
| Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) | Baseline, 24 Weeks | This standardized self-rated scale detects presence and severity of PTSD symptoms and is used for monitoring during recovery. This is widely used in the veteran TBI literature as PTSD is frequently comorbid with TBI and can complicate recovery. This is a necessary complement to the NPI, which doesn't assess PTSD. |
| Percent change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Baseline, 24 Weeks | RBANS is used in msTBI to assess cognitive impairment and track recovery in rehabilitation, this performance-based test generates a Total cognition score, which is made up of indices of Attention, Learning, Memory, Language, and Visuospatial skills. Each index can be broken down into two or more different aspects of the given cognitive domain. This allows for both global and more fine-grained analysis of cognitive impairment and recovery. |
| Percent change in Automated Neuropsychological Assessment Metrics Military (ANAM) | Baseline, 24 Weeks | ANAM is used by the US military to assess cognitive function in service members for pre-deployment screening, post-injury monitoring, TBI detection and recovery. This test complements the RBANS by offering a measure of reaction time and more robust assessment of processing speed and executive functions. |
| Percent change in Trail Making Test (TMT) | Baseline, 24 Weeks | TMT is a test of simple psychomotor speed and complex attention / executive control. It requires less manual dexterity than the RBANS and is less complicated by reaction time than the ANAM, so is useful in a mixed msTBI population as some participants may also have motor disability. |
| Columbia-Suicide Severity Rating Scale (C-SSRS) | Baseline, 26 Weeks | The "Columbia Protocol" is a brief tool used by healthcare professionals to identify if a person is at risk for suicide. |
Countries
United States
Contacts
CONTACTCraig Atwood, PhD
CONTACTRobert Kotloski, MD
PRINCIPAL_INVESTIGATORCraig Atwood, PhD
William S. Middleton Memorial Veterans Hospital, Madison, WI
Outcome results
None listed