VA Cooperative Studies Program (CSP)
CSP #2018 - Growth Hormone Replacement Therapy (GRIT)
Growth Hormone Replacement Therapy in Veterans with mild Traumatic Brain Injury (mTBI) and Adult Growth Hormone Deficiency (AGHD); The GRIT Study
OVERVIEW
CSP #2018 is a placebo-controlled, double-blind, parallel-group randomized clinical trial (RCT) of recombinant human growth hormone (rhGH) replacement therapy vs. placebo in Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn (OIF/OEF/OND) Veterans with a history of adult growth hormone deficiency (AGHD) and deployment-related mild traumatic brain injury (mTBI). This study will assess the efficacy of rhGH as well as treatment safety and compliance. The primary hypothesis is that participants receiving rhGH will show improvement in quality of life, as measured by the Quality of Life Assessment for GHD in Adults questionnaire (QoL-AGHDA) scale, a well-validated tool commonly used to test the efficacy of rhGH in AGHD patients. This study is well aligned both with the Department of Veterans Affairs focus on patient-centered approaches as well as the NIH initiative on patient-reported outcomes.
BACKGROUND
Traumatic brain injury (TBI) occurs in approximately 10% of military personnel deployed to Iraq and Afghanistan (OIF/OEF/OND), of which 80% are mild in severity (mTBI). It is estimated that approximately 200,000 of these Veterans have suffered at least one mTBI. It is further estimated that up to 25% of mTBI patients suffer from concomitant AGHD, which presents with similar symptoms as TBI and is therefore often over-looked and untreated. There is thus incumbency for treating clinicians to recognize AGHD as prevalent in the mTBI patient population, and to institute screening. Furthermore, there is urgent need to identify safe and effective treatment for these patients.
The symptoms of mTBI, and the symptoms of AGHD, include fatigue, sleep disturbances, cognitive deficits, and chronic pain, leading to increased disability and poor quality of life (QoL). Other problems commonly seen among these Veterans include metabolic changes (e.g. obesity and dyslipidemia) and autonomic alterations (e.g. arterial hypertension and reduced heart variability) associated with higher cardiovascular risk and increased mortality. In addition, AGHD is associated with objective markers of “metabolic aging” such as increase in truncal fat mass or “central obesity”, reduction in lean body mass (LBM), reduced exercise capacity, dyslipidemia, arterial hypertension, and left ventricular systolic dysfunction. Furthermore, there is also evidence that patients with AGHD have objective deficits in cognitive functioning including memory and executive tasks.
Growth hormone replacement therapy (GHRT) reverses body composition changes, increases exercise capacity and bone density, improves dyslipidemia, and enhances quality of life in non-TBI civilian patients with AGHD. In addition, preliminary studies suggest a possible benefit of GHRT on cognition and quality of life among civilian patients with severe TBI. However, additional studies are needed in patients with a history of mTBI since GHRT has not been evaluated in this setting. In addition, the safety, efficacy, and compliance of GH in military personnel have not been evaluated before.
OBJECTIVES
The aim of CSP #2018 is to study the efficacy and safety of GHRT as a treatment option for patients with a history of mTBI and AGHD. Specifically, this study is designed to determine the efficacy of rhGH, compared to placebo, in improving quality of life. Key secondary outcomes include biological markers of body composition and cardiovascular health, fatigue, chronic pain, and depression. Participants in the study will receive standard medical treatment for other associated hormonal deficiencies, neurological and psychiatric disorders, and other comorbidities.
RESEARCH PLAN
Participants will be recruited from 20 sites, over 33 months, with each participant being followed for 6 months. All participants will be screened for eligibility including AGHD diagnosis, stability regarding hormonal replacement for other deficiencies when present, as well as stability in prescribed psychotropic medications, and treatment for any chronic conditions. Otherwise, the eligibility criteria are posed with an interest in capturing a largely representative sample.
Participants (n=172) will be randomized in a 1:1 ratio to rhGH (n=86) versus placebo (n=86) for six months, stratified by participating site. Both study participants and the study team will be blinded to treatment assignment. All participants will complete in-clinic follow-ups at Days 14, 40, 65, and 90 (3 months) and at day 180 (6 months). The primary outcome will be the mean difference in QoL-AGHDA scores between treatment arms at 6 months follow-up. Patients will discontinue the study intervention at 6 months, and will be followed-up two weeks subsequent, in order to assure patient safety and wellness, and to ensure maximal facilitation of patient transition back into routine care.
We hypothesize that rhGH will result in a 3.5-point lower (better) mean difference in QoL-AGHDA total score versus placebo, corresponding to a clinically meaningful improvement in QoL. Using an ANCOVA with a two-sided type-I error α=0.05, and baseline QoL score as a covariate, the present design will test this hypothesis with 95% power, adjusted for cross-overs and losses (12.5%).
IMPACT
The impact of GHRT on a Veteran population in the setting of AGHD and mTBI has never been studied in a RCT. This study could therefore have a major impact on public health, irrespective of its findings. If GHRT is found to be safe, and effective in improving the outcomes measured, this study is likely to transform clinical practice by delivering a new treatment option to a patient population that may number in the tens of thousands within the VA, and hundreds of thousands worldwide (Section I.B.12). If the hypothesized effect is not shown, the study’s impact will benefit VA clinical care by providing the VA precious opportunity to consider the appropriateness of this time-consuming diagnostic work-up and treatment. Regardless of outcome, this study will break ground by providing a suite of epidemiological data related to the symptom burden of patients with a history of mTBI, the prevalence of AGHD among these patients, and the standards of practice surrounding their diagnosis and care.
Updated March 2023
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