Anterior Pituitary Hormone Replacement in Traumatic Brain Injury

Study Overview
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Brief Summary
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Fifteen to twenty percent of adults who suffer a traumatic brain injury (TBI) that requires hospitalization and rehabilitation have been found to have growth hormone (GH) deficiency by GH stimulation testing. Moreover, abnormalities have also been established for the cortisol and thyroid axis. The hypothesis of this proposal is that hormone replacement in TBI patients with documented abnormalities in the GH, thyroid, or cortisol axis will improve muscle function, body composition, aerobic capacity (GH) and tests of neuropsychologic function (GH, thyroid, cortisol).

Detailed Description
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This protocol is designed to screen and detect evidence of pituitary hormone deficiency in adults following traumatic brain injury. Growth hormone deficiency will be replaced for a period of one year. Subject will not be screened until at least one year following brain injury to allow for natural recovery of hormone function.

Official Title
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Anterior Pituitary Hormone Replacement in Traumatic Brain Injury

Conditions
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Growth Hormone Deficiency, Traumatic Brain Injury

Intervention / Treatment
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* Drug: Recombinant human growth hormone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 21 and older. Documented moderate to severe traumatic brain injury at least one year post injury. Exclusion Criteria: The only absolute exclusionary medication will be an anticoagulant (Coumadin) because of the risk of bleeding during the possible muscle biopsy procedure and daily injections of rhGH in the GH arm of the study. Any subject with a history of hepatitis or a 3-fold elevation of liver function tests (Alk phos, alanine aminotransferase (ALT), aspartate aminotransferase (AST)). We are uncertain of the effects of hormone replacement such as rhGH on the liver, so we will exclude any subjects with hepatitis. This exclusion applies only to subjects who would be enrolled in the GH arm of the study. Subjects who are deficient in cortisol or thyroid at screening will be excluded until hormone abnormalities have been corrected. Subjects with chronic pain who are being managed with narcotics will be excluded as the effects of central nervous system depressants may interfere with study test results.

Ages Eligible for Study
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Minimum Age: 21 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Human Growth Hormone<br>recombinant human growth hormone (rhGH) self administered daily for one year | Drug: Recombinant human growth hormone<br>* 200 mcg daily for two months, followed by 400 mcg daily for two months followed by 600 mcg daily for term of treatment period (one year total)<br>* Other names: hGH;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Oxygen Uptake at Baseline. | Maximum Oxygen Uptake was measured during cardiorespiratory testing using a modified Balke protocol with expired gases collected and analyzed by an automated metabolic cart. | baseline | 
| Maximum Oxygen Uptake After One Year of Human Growth Hormone Replacement Therapy. | Maximum Oxygen Uptake was measured during cardiorespiratory testing using a modified Balke protocol with expired gases collected and analyzed by an automated metabolic cart. | one year | 
| Minute Ventilation at Baseline. | Minute ventilation was measured during cardiorespiratory testing using a modified Balke protocol with expired gases collected and analyzed by an automated metabolic cart. | baseline | 
| Minute Ventilation After One Year of Human Growth Hormone Replacement Therapy. | Minute ventilation was measured during cardiorespiratory testing using a modified Balke protocol with expired gases collected and analyzed by an automated metabolic cart. | one year | 
| Respiratory Exchange Ratio at Baseline. | Respiratory exchange ratio was measured during cardiorespiratory testing using a modified Balke protocol with expired gases collected and analyzed by an automated metabolic cart. | baseline | 
| Respiratory Exchange Ratio After One Year of Human Growth Hormone Replacement Therapy. | Respiratory exchange ratio was measured during cardiorespiratory testing using a modified Balke protocol with expired gases collected and analyzed by an automated metabolic cart. | one year | 
| Oxygen Pulse at Baseline. | Oxygen Pulse was measured during cardiorespiratory testing using a modified Balke protocol with expired gases collected and analyzed by an automated metabolic cart. Oxygen pulse is calculated by dividing VO2 consumed (mL/min) by heart rate (beats/min) yielding mL/beat. This provides an estimate of cardiac stroke volume. | baseline | 
| Oxygen Pulse After One Year of Human Growth Hormone Replacement Therapy. | Oxygen Pulse was measured during cardiorespiratory testing using a modified Balke protocol with expired gases collected and analyzed by an automated metabolic cart. Oxygen pulse is calculated by dividing VO2 consumed (mL/min) by heart rate (beats/min) yielding mL/beat. This provides an estimate of cardiac stroke volume. | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropsychological Function as Measured by California Verbal Learning Test-II With Total Recall at Baseline. | The California Verbal Learning Test II (CVLT-II) is a comprehensive assessment of verbal learning and memory. Subjects are read a list of 16 words. Total recall is a sum of all word list items correctly recalled immediately on learning trials 1 through 5. Data is reported as raw scores. Score range is 0 (lowest) to 80 (highest). A higher score indicates a better outcome. | baseline | 
| Neuropsychological Function as Measured by California Verbal Learning Test-II With Total Recall After 1 Year of Human Growth Hormone Replacement Therapy. | The California Verbal Learning Test II (CVLT-II) is a comprehensive assessment of verbal learning and memory. Subjects are read a list of 16 words. Total recall is a sum of all word list items correctly recalled immediately on learning trials 1 through 5. Data is reported as raw scores. Score range is 0 (lowest) to 80 (highest). A higher score indicates a better outcome. | One year | 
| Neuropsychological Function as Measured by California Verbal Learning Test-II With Delayed Recall at Baseline. | The California Verbal Learning Test II (CVLT-II) is a comprehensive assessment of verbal learning and memory. Subjects are read a list of 16 words. Delayed recall is a sum of all word list items correctly recalled after a 25 minute delay on learning trials 1 through 5. Data is reported as raw scores. Score range is 0 (lowest) to 80 (highest). A higher score indicates a better outcome. | baseline | 
| Neuropsychological Function as Measured by California Verbal Learning Test-II With Delayed Recall After 1 Year of Human Growth Hormone Replacement Therapy. | The California Verbal Learning Test II (CVLT-II) is a comprehensive assessment of verbal learning and memory. Subjects are read a list of 16 words. Delayed recall is a sum of all word list items correctly recalled after a 25 minute delay on learning trials 1 through 5. Data is reported as raw scores. Score range is 0 (lowest) to 80 (highest). A higher score indicates a better outcome. | One year | 
| Neuropsychological Function as Measured by Brief Visuospatial Memory Test-R With Total Recall at Baseline | The Brief Visuospatial Memory Test is measure of visual memory. The subject views a stimulus page with 6 shapes on it for 10 seconds. The subjects are then asked to draw as many figures as they remember in the correct locations as possible. Total recall is a measure of the subjects memory immediately after viewing the stimulus page. Data is reported as raw scores. Scores range from 0 (lowest) to 36 (highest). A higher score indicates a better outcome. | baseline | 
| Neuropsychological Function as Measured by Brief Visuospatial Memory Test-R With Total Recall After 1 Year of Human Growth Hormone Replacement Therapy. | The Brief Visuospatial Memory Test is measure of visual memory. The subject views a stimulus page with 6 shapes on it for 10 seconds. The subjects are then asked to draw as many figures as they remember in the correct locations as possible. Total recall is a measure of the subjects memory immediately after viewing the stimulus page. Data is reported as raw scores. Scores range from 0 (lowest) to 36 (highest). A higher score indicates a better outcome. | one year | 
| Neuropsychological Function as Measured by Brief Visuospatial Memory Test-R With Delayed Recall at Baseline | The Brief Visuospatial Memory Test is measure of visual memory. The subject views a stimulus page with 6 shapes on it for 10 seconds. The subjects are then asked to draw as many figures as they remember in the correct locations as possible. The delayed recall is a measure of the subjects memory after a 25 minutes delay. The participants are asked to freely recall and again draw the six figures.Data is reported as raw scores. Scores range from 0 (lowest) to 36 (highest). A higher score indicates a better outcome. | baseline | 
| Neuropsychological Function as Measured by Brief Visuospatial Memory Test-R With Delayed Recall After 1 Year of Human Growth Hormone Replacement Therapy | The Brief Visuospatial Memory Test is measure of visual memory. The subject views a stimulus page with 6 shapes on it for 10 seconds. The subjects are then asked to draw as many figures as they remember in the correct locations as possible. The delayed recall is a measure of the subjects memory after a 25 minutes delay. The participants are asked to freely recall and again draw the six figures.Data is reported as raw scores. Scores range from 0 (lowest) to 36 (highest). A higher score indicates a better outcome. | one year | 
| Neuropsychological Function as Measured by Digit Span Total at Baseline | Digit Span; Wechsler Memory Scale III (WMS III). Digits Forward is a test of digit span (range = 3 to 9 digits) consisting of seven items (each with 2 trials). Digits Backward is a test of digit span (range = 3 to 9 digits); however the participant must provide the presented sequence in reverse order. The test consists of seven items (each with 2 trials). Total score is calculated by adding the scores from forward and backward. Data is reported as raw scores. Score ranges are 0 (lowest) to 32 (highest). A higher score indicates a better outcome. | baseline | 
| Neuropsychological Function as Measured by Digit Span Total After One Year of Human Growth Hormone Replacement Therapy. | Digit Span; Wechsler Memory Scale III (WMS III). Digits Forward is a test of digit span (range = 3 to 9 digits) consisting of seven items (each with 2 trials). Digits Backward is a test of digit span (range = 3 to 9 digits); however the participant must provide the presented sequence in reverse order. The test consists of seven items (each with 2 trials). Total score is calculated by adding the scores from forward and backward. Data is reported as raw scores. Score ranges are 0 (lowest) to 32 (highest). A higher score indicates a better outcome. | one year | 
| Neuropsychological Function as Measured by Processing Speed Index at Baseline | Processing Speed Index is a subcategory of the Wechsler Adult Intelligence Scale III (WAIS-III). Processing speed refers to the speed of cognitive processes and response output. This index is comprised of performances on two separate tests of visuomotor speed of information processing ability. On one test (Coding) participants refer to a key on top of a page to translate non-verbal symbols to an alpha-numeric digit. The participants then fill in boxes with the correct symbol assigned to a particular number. On the other test (Symbol Search) participants are asked to visually scan and mark items that are identical to one of two targets. If neither target is shown in the array the participant must mark out the work NO. Total correct responses for both task within 120 seconds are recorded. Ranges are 0 (lowest) to 150 (highest) with 100 being the normal average. A higher score indicates a better outcome. | baseline | 
| Neuropsychological Function as Measured by Processing Speed Index After One Year of Human Growth Hormone Replacement Therapy. | Processing Speed Index is a subcategory of the Wechsler Adult Intelligence Scale III (WAIS-III). Processing speed refers to the speed of cognitive processes and response output. This index is comprised of performances on two separate tests of visuomotor speed of information processing ability. On one test (Coding) participants refer to a key on top of a page to translate non-verbal symbols to an alpha-numeric digit. The participants then fill in boxes with the correct symbol assigned to a particular number. On the other test (Symbol Search) participants are asked to visually scan and mark items that are identical to one of two targets. If neither target is shown in the array the participant must mark out the work NO. Total correct responses for both task within 120 seconds are recorded. Ranges are 0 (lowest) to 150 (highest) with 100 being the normal average. A higher score indicates a better outcome. | one year | 
| Neuropsychological Function as Measured by Letter Fluency at Baseline | Letter Fluency is a condition measured as part of the subcategory, Verbal Fluency, in the Delis-Kaplan Executive Function System (D-KEFS). Subjects are asked to name as many words as they can starting with a specified letter for 60 seconds. The words can not be names, places, numbers or grammatical variants of previous answers. Repeated answers are not scored as a correct response. There are 3 trials, with 3 different letters. The total number of correct responses is totaled for all 3 trials and a Letter Fluency Score is given. A higher score is considered better. There is no set range as the score depends on how many correct words the subject relays in the given time period. | baseline | 
| Neuropsychological Function as Measured by Letter Fluency After One Year of Human Growth Hormone Replacement Therapy | Letter Fluency is a condition measured as part of the subcategory, Verbal Fluency, in the Delis-Kaplan Executive Function System (D-KEFS). Subjects are asked to name as many words as they can starting with a specified letter for 60 seconds. The words can not be names, places, numbers or grammatical variants of previous answers. Repeated answers are not scored as a correct response. There are 3 trials, with 3 different letters. The total number of correct responses is totaled for all 3 trials and a Letter Fluency Score is given. A higher score is considered better. There is no set range as the score depends on how many correct words the subject relays in the given time period. | one year | 
| Depression as Measured by the Beck Depression Inventory at Baseline. | Beck Depression Inventory (BDI-II) is used to measure the severity of depression symptoms. The BDI-II contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs are: 0-13: minimal depression; 14-19: mild; depression; 20-28: moderate depression; 29-63: severe depression. | baseline | 
| Depression as Measured by Beck Depression Inventory After One Year of Human Growth Hormone Replacement Therapy. | Beck Depression Inventory (BDI-II) is used to measure the severity of depression symptoms. The BDI-II contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs are: 0-13: minimal depression; 14-19: mild; depression; 20-28: moderate depression; 29-63: severe depression. | one year | 
| Fatigue as Measured Using Fatigue Severity Scale at Baseline. | Fatigue Severity Scale (FSS) is a measure of fatigue and how that fatigue interferes with life. It is a 9-item scale, with a range from 9 to 63, with a higher number indicating greater severity. | baseline | 
| Fatigue Measured Using the Fatigue Severity Scale After One Year of Human Growth Hormone Therapy. | Fatigue Severity Scale (FSS) is a measure of fatigue and how that fatigue interferes with life. It is a 9-item scale, with a range from 9 to 63, with a higher number indicating greater severity. | one year | 
| Muscle Function in Male Subjects Measured Using Maximum Isometric Leg Extension by Biodex Pro 4 at Baseline. | Maximum torque production during isometric contraction of the knee extensor muscles. | baseline | 
| Muscle Function in Male Subjects Measured Using Maximum Isometric Leg Extension by Biodex Pro 4 After One Year of Human Growth Hormone Replacement Therapy. | Maximum torque production during isometric contraction of the knee extensor muscles. | one year | 
| Muscle Function in Male Subjects Measured Using Maximum Isokinetic Leg Extension by Biodex Pro 4 at Baseline. | Maximum torque production during maximal isokinetic contractions at 90 degrees per second. | baseline | 
| Muscle Function in Male Subjects Measured Using Maximum Isokinetic Leg Extension by Biodex Pro 4 After One Year of Human Growth Hormone Replacement Therapy. | Maximum torque production during maximal isokinetic contractions at 90 degrees per second. | one year | 
| Muscle Fatigue as Measured by Biodex Pro 4 at Baseline. | Muscle fatigue is measured using repetitive isokinetic contractions of the knee extensors at 90 degrees per second. Each subject was asked to produce 40 contractions at full force. Data is presented as % of maximum torque at the 40th contraction in the fatigue protocol. | baseline | 
| Muscle Fatigue as Measured by Biodex Pro 4 After One Year of Human Growth Hormone Replacement Therapy. | Muscle fatigue is measured using repetitive isokinetic contractions of the knee extensors at 90 degrees per second. Each subject was asked to produce 40 contractions at full force. Data is presented as % of maximum torque at the 40th contraction in the fatigue protocol. | one year | 
| Body Mass in Male Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) at Baseline. | Body mass was calculated from whole body scan taken using a GE Lunar iDEXA. | baseline | 
| Body Mass in Male Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) After One Year of Human Growth Hormone Replacement Therapy. | Body mass was calculated from whole body scan taken using a GE Lunar iDEXA | one year | 
| Lean Body Mass in Male Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) at Baseline | Lean Body mass was calculated from whole body scan taken using a GE Lunar iDEXA | baseline | 
| Lean Body Mass in Male Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) After One Year of Human Growth Hormone Replacement Therapy. | Lean Body mass was calculated from whole body scan taken using a GE Lunar iDEXA | one year | 
| Fat Free Mass in Male Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) at Baseline. | Fat free mass is calculated from whole body scan measured using a GE Lunar iDEXA. | baseline | 
| Fat Free Mass in Male Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) After One Year of Human Growth Hormone Replacement Therapy. | Fat free mass is calculated from whole body scan measured on a GE Lunar iDEXA. | one year | 
| Percent Body Fat as Measured by Dual Energy X-Ray Absorptiometry (DEXA) at Baseline. | Percent body fat is calculated from a whole body scan measured on a GE Lunar iDEXA. | baseline | 
| Percent Body Fat in Male Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) After One Year of Human Growth Hormone Replacement Therapy. | Percent body fat is calculated from a whole body scan measured on a GE Lunar iDEXA. | one year | 
| Muscle Function in Female Subjects Measured Using Maximum Isometric Leg Extension by Biodex Pro 4 at Baseline. | Maximum torque production during isometric contraction of the knee extensor muscles. | baseline | 
| Muscle Function in Female Subjects Measured Using Maximum Isometric Leg Extension by Biodex Pro 4 After One Year of Human Growth Hormone Replacement Therapy | Maximum torque production during isometric contraction of the knee extensor muscles. | one year | 
| Muscle Function in Female Subjects Measured Using Maximum Isokinetic Leg Extension by Biodex Pro 4 at Baseline | Maximum torque production during maximal isokinetic contractions at 90 degrees per second. | baseline | 
| Muscle Function in Female Subjects Measured Using Maximum Isokinetic Leg Extension by Biodex Pro 4 After One Year of Human Growth Hormone Replacement Therapy | Maximum torque production during maximal isokinetic contractions at 90 degrees per second. | one year | 
| Perceptual Fatigability as Measured by a Fatigue Rating Scale at Baseline. | Perceptual fatigue was measured before and directly after performing the muscle fatigue exercise protocol (40 continuous maximal force isokinetic knee extensions at 90 degress per second). Subjects were asked to rate their fatigue on a scale of 0-10 with 0 being no fatigue at all and 10 being extreme fatigue. Data is presented as change in fatigue rating induced by exercise testing. | baseline | 
| Perceptual Fatigability as Measured by a Fatigue Rating Scale After One Year of Human Growth Hormone Therapy. | Perceptual fatigue was measured before and directly after performing the muscle fatigue exercise protocol (40 continuous maximal force isokinetic knee extensions at 90 degress per second). Subjects were asked to rate their fatigue on a scale of 0-10 with 0 being no fatigue at all and 10 being extreme fatigue. Data is presented as change in fatigue rating induced by exercise testing. | one year | 
| Body Mass in Female Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) at Baseline. |  | baseline | 
| Body Mass in Female Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) After One Year of Human Growth Hormone Replacement Therapy | Body mass was calculated from whole body scan taken using a GE Lunar iDEXA | one year | 
| Lean Body Mass in Female Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) at Baseline | Lean Body mass was calculated from whole body scan taken using a GE Lunar iDEXA. | baseline | 
| Lean Body Mass in Female Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) After One Year of Human Growth Hormone Replacement Therapy. | Lean Body mass was calculated from whole body scan taken using a GE Lunar iDEXA | one year | 
| Fat Free Mass in Female Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) at Baseline. | Fat free mass is calculated from whole body scan measured using a GE Lunar iDEXA. | baseline | 
| Fat Free Mass in Female Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) After One Year of Human Growth Hormone Replacement Therapy | Fat free mass is calculated from whole body scan measured on a GE Lunar iDEXA. | one year | 
| Percent Body Fat in Female Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) at Baseline. | Percent body fat is calculated from a whole body scan measured on a GE Lunar iDEXA. | baseline | 
| Percent Body Fat in Female Subjects as Measured by Dual Energy X-Ray Absorptiometry (DEXA) After One Year of Human Growth Hormone Replacement Therapy. | Percent body fat is calculated from a whole body scan measured on a GE Lunar iDEXA. | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TBI, Traumatic Brain injury, Growth hormone deficiency, Anterior pituitary hormone, Recombinant human growth Hormone, Genotropin