Growth Hormone Replacement in Veterans With GWI and AGHD (GWIT)

Study Overview
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Brief Summary
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This is a placebo-controlled, double-blind, parallel, Randomized Controlled Trial of 6 months of Growth Hormone Replacement Therapy (GHRT) vs. placebo in Veterans with a history of Gulf War Illness (GWI) and Adult Growth Hormone Deficiency (AGHD). The investigators hypothesize that GHRT will reduce truncal fat mass percentage measured by DEXA (primary outcome). This could provide those veterans with GWI and AGHD a novel therapeutic option (GHRT). The study will also examine the feasibility and safety of a larger efficacy trial.

Detailed Description
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There is significant overlap between the symptoms of adult growth hormone deficiency (AGHD) and those of Gulf War Illness (GWI) such as fatigue, chronic pain, depression, anxiety, and cognitive dysfunction. AGHD is also associated with metabolic changes including increased truncal fat mass, dyslipidemia, and increased cerebrovascular risk which can lead to neuroinflammation, neurodegeneration, and functional decline. Growth hormone replacement therapy (GHRT) reverses body composition and metabolic changes. Studies on civilians with AGHD caused by other conditions such as brain tumors suggest GHRT improves fatigue, chronic pain, mood disturbance, cognitive function, and improves quality of life (QoL). This is a phase II, randomized, double-blind, placebo-controlled, futility trial testing the efficacy and safety of GHRT as a treatment option for patients with a history of AGHD and GWI. The primary outcome is to test the efficacy of GHRT versus placebo to change truncal fat mass percentage measured by dual energy x-ray absorptiometry (DEXA). The secondary objective is to gather high quality data to estimate the effect size of 6-months of GHRT versus placebo on 1) cardiometabolic risk factors; 2) lean body mass; 3) quality of life; 4) severity of fatigue symptoms; 5) severity of depression, anxiety, and stress symptoms; and 6) pain severity and pain interference.

Official Title
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Growth Hormone Replacement Therapy in Veterans With Gulf War Illness and Adult Growth Hormone Deficiency

Conditions
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Gulf War Syndrome, Adult Growth Hormone Deficiency

Intervention / Treatment
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* Drug: Recombinant human growth hormone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Being a veteran of the Gulf War conflict with a history of deployment to Operation Desert Storm or Desert Shield between 1990-91 age less than or equal to 64 years old have a diagnosis of Gulf War Illness assessed by study investigators have adult growth hormone deficiency diagnosed by glucagon stimulation test (cut point 3.0 mcg/L if BMI is less than or equal to 25 or 1.0 mcg/L if BMI is greater than 25) 4-week stability on any psychotropic medications 3-month stability on all hormone treatments able and willing to provide informed consent to participant in the study and complete study protocol Exclusion Criteria: history of a psychiatric disorder with substantial impact on functional status or quality of life (e.g., schizophrenia, schizoaffective disorder, bipolar, or other psychotic disorder) history of neurologic disorder other than traumatic brain injury with substantial impact on the quality of life other known cause for growth hormone deficiency (GHD) including history of childhood onset GHD, hypothalamic/pituitary disease, history of brain radiation, or genetic mutations known to lead to GHD active suicidal ideation as determined by a score of 2 points or higher on the Columbia Suicide Severity Rating Scale suicidal behavior in the past 6 months contraindication to recombinant human growth hormone (rhGH) such as hypersensitivity to rhGH or any of the components of the supplied product acute medical illness, active infection, cancer, or decompensated chronic medical illness (e.g., decompensated diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease) evidence of substance use disorder in the past 6 months other than mild alcohol or cannabis use disorder diagnosed by clinician at time of screening. urine toxicology evidence of illicit drug use (excluding cannabis) within the past 90 days prior to screening BMI > 35 or body weight > 350 lbs abnormal pituitary anatomy documented by an MRI using a Sella protocol women who are pregnant or of child-bearing potential who are unable/unwilling to use one of the following barrier contraceptives: condoms, diaphragm, cervical cap, or intrauterine device current use of the following: growth hormone, estrogen or estrogen-like dietary supplements, hormonal contraceptives, progestin, insulin growth factor 1 (IGF-1), or chronic glucocorticoid use in supraphysiologic doses 15) currently enrolled in any other interventional drug trials unless prior approval is provided by the study chairs and the study sponsor

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a phase II, randomized, double-blind, placebo-controlled, futility trial.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Growth Hormone Replacement Therapy<br>Drug: Somatropin After randomization patients will be started at a dose of 200-300 mcg/d of daily injections of GHRT. A biweekly titration period of 6 weeks will be performed in increments of 100 mcg/d as needed until IGF-1 levels are between +1 and +2 standard deviation score, up to a maximum dose of 2,000 mcg/d, provided the dose is well tolerated. Participants will be randomized in a 1:1 ratio to rhGH versus placebo for six months, stratified by participating site. Study participants and study team will be blinded to treatment assignment. Participants will complete in-clinic follow-up visits at Days 14, 40, 65, 90, and 180. The primary outcome will be the change in truncal fat mass percentage from baseline to six months measured by dual-energy x-ray absorptiometry (DEXA). | Drug: Recombinant human growth hormone<br>* recombinant human growth hormone (rhGH)<br>* Other names: Somatropin;|
| Placebo Comparator: Placebo<br>Drug: Placebo After randomization patients will be started at a dose of 200-300 mcg/d of daily injections of GHRT. A biweekly titration period of 6 weeks will be performed in increments of 100 mcg/d as needed until IGF-1 levels are between +1 and +2 standard deviation score, up to a maximum dose of 2,000 mcg/d, provided the dose is well tolerated. Participants will be randomized in a 1:1 ratio to rhGH versus placebo for six months, stratified by participating site. Study participants and study team will be blinded to treatment assignment. Participants will complete in-clinic follow-up visits at Days 14, 40, 65, 90, and 180. The primary outcome will be the change in truncal fat mass percentage from baseline to six months measured by dual-energy x-ray absorptiometry (DEXA). | Drug: Placebo<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in truncal fat mass from baseline to six months | The primary outcome measure is the between-group mean difference of truncal fat mass percentage from baseline to six months. Truncal fat mass will be assessed at baseline, 3-months, and 6-months using calibrated dual energy x-ray absorptiometry (DEXA). A large mean difference corresponds with greater changes in truncal fat mass. Decreased truncal fat mass is associated with reduced risk of cardiovascular disease. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiometabolic Risk Factors | Change in cardiometabolic risk factors from baseline to 6 months measured by fasting low density lipoproteins (LDL) and highly sensitive C-reactive protein levels. A decrease in lipoprotein corresponds with increased lipoprotein metabolism, and lower C-reactive protein levels corresponds with less inflammation. A reduction in both suggests lower risk of cardiometabolic disease. | 6 months | 
| Lean body mass | The change in appendicular lean body mass between baseline and 6 months will be assessed using calibrated dual energy x-ray absorptiometry. The difference will capture changes in body composition (fat and muscle) with a higher difference corresponding with greater body composition changes. | 6 months | 
| Assessment of quality of life | Change in the quality of life from baseline to 6 months will be measured by the Quality of Life questionnaire for Adult Growth Hormone Deficiency. The score ranges from 0 to 25, with a score of 25 representing highest symptomatic burden and lower quality of life. A change in score is positively correlated with the patient's perception of treatment benefit, and a score change of 3.5 points is considered clinically meaningful. | 6 months | 
| Fatigue | Fatigue will be measured using the Fatigue Severity Scale. The questionnaire minimum score is a 9 and maximum score is 63. Higher scores represent greater fatigue severity. | 6 months | 
| Depression, Anxiety, and Stress | The Depression, Anxiety, and Stress Scale-21 (DASS-21), a 21-item questionnaire, will be used to assess depression, anxiety, and stress symptoms. The score range is 0 - 126 with a higher score representing greater severity or frequency of negative emotional symptoms. | 6 months | 
| Pain Intensity and Interference | Pain intensity and interference will be assessed using the Defense and Veterans Pain Rating Scale. The questionnaire contains two sections, one assessing current level of pain and the other evaluating the extent to which pain interferes with biopsychosocial factors such as daily activity, sleep, mood, and stress. The minimum score for each section is 0 and maximum score is 10 where higher scores correspond with more intense pain and greater interference. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recombinant human growth hormone, growth hormone replacement therapy