A Phase II, randomized controlled trial of recombinant human Growth Hormone (rhGH) during rehabilitation from Traumatic Brain Injury

Ramon Diaz-Arrastia, MD, PhD Principal Investigator

Mary Carlile. MD Co-Principal Investigator

Growth Hormone (GH) deficiency, defined by insufficient GH response to a variety of stimulating compounds, is found in 15 - 35% of adults who suffer traumatic brain injuries (TBI) requiring inpatient rehabilitation. However, there is no accepted gold standard for diagnosing GH deficiency in this population. Further, the major effector molecule of the somatotropic axis, Insulin-Like Growth Factor-1 (IGF-1) has recently been recognized as an important neurotrophic agent . Since most repair and regeneration after TBI occurs within the first few months after injury, absolute or relative deficiencies of GH and IGF-1 in the subacute period after TBI may be contributing factors in the limited recovery seen in some patients. 

The proposed study is a Phase II, randomized, double-blind, placebo-controlled trial of rhGH, starting at 1 month post TBI and continuing for 6 months thereafter to determine if treatment with recombinant human Growth Hormone (rhGH) in the subacute period after TBI results in improved functional outcome after injury. The study also hopes to determine if treatment with rhGH results in increased IGF-1 levels; if the benefits of rhGH treatment persist up to 1 year after injury; if low GH response to L-arginine stimulation at baseline is associated with poor functional outcome; if low IGF-1 levels at baseline are associated with poor functional outcomes; if rhGH treatment is more effective in patients who have low GH response to LArginine stimulation at baseline; and if rhGH treatment is more effective in patients who have low IGF-1 levels at baseline.

Neuroimaging Biomarkers of Diffuse Axonal Injury

Ramon Diaz-Arrastia, MD, PhD Principal Investigator

Michael Devous, MD Co-Principal Investigator

A common mechanism of TBI which is not well reproduced in the most widely studied animal models is Diffuse Axonal Injury (DAI).  DAI is characterized by microscopic axonal lesions that commonly appear in subcortical white matter of patients with acceleration-deceleration type TBI. DAI is the predominant mechanism of injury in 40 – 50% of TBIs requiring hospital admission, and it is likely that DAI is a component of injury in all cases of TBI resulting from high-speed motor vehicle collisions. DAI is poorly imaged by CT scanning, and conventional MRI, the current method of choice, has not been carefully studied and is of uncertain sensitivity and specificity. The inability to accurately identify and measure DAI during life is a major limitation in the clinical management of TBI.  Additionally, clinical trials of neuro-protective and axono-protective therapies directed at DAI are unlikely to be successful unless there are reliable and validated biomarkers which will allow subphenotyping of injury mechanisms. 

The goal of our study is to develop and validate Diffusion Tensor Imaging (DTI) as a biomarker of DAI.  Preliminary data from our group indicates that DTI is more sensitive than conventional structural MRI for identifying DAI lesions. A secondary objective is to determine if other neuroimaging measures are useful biomarkers. This proposal is designed to identify DTI measures that can be reliably utilized in clinical trials of DAI-directed therapies. We will accomplish our objectives through the following three specific aims: 1)Obtain MRI scans on patients with DAI in the subacute period (within 1 week after injury). 2) Obtain repeat MRI scans and outcome information 6-months after injury. Obtain pathologic confirmation of the DAI lesions identified by DTI in the acute scans.