Brain and Gut Plasticity in Mild TBI or Post-acute COVID Syndrome Following Growth Hormone Therapy

COVID-19 Clinical Trial

Official title:

Brain and Gut Plasticity in Mild TBI or Post-acute COVID Syndrome Following Growth Hormone Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03554265
• Other study ID #: 17-0313
• Status: Completed
• Phase: Phase 3
• Start date: August 6, 2018
• Est. completion date: October 4, 2023

Study information

• Verified date: January 2024
• Source: The University of Texas Medical Branch, Galveston
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients with a history of mild traumatic brain injury (mTBI) or post acute sequelae of SARS-CoV-2 (PASC) and abnormal growth hormone secretion, as measured by glucagon stimulation test, will be treated with replacement growth hormone therapy for a period of 6 months (mTBI) or 9 months (PASC). Testing of cognition, exercise, fatigue, brain activation and morphology, body composition and measurements of quality of life will be performed before and after the treatment period. Fecal sampling for characterization of the GI microbiome will occur monthly over the treatment period. Control subjects will be enrolled and will provide fecal samples monthly for 6 months. GI microbiomes will be compared between mTBI patients, PASC patients and controls at baseline as well as over the treatment period.

Description:

The investigators will study subjects (aged 18-70 years) with a history of mild TBI (n=25), post-acute sequelae of SARS-CoV-2 (PASC) (n=25)and healthy controls (n=25). mTBI subjects will undergo a 6-month intervention of rhGH therapy. PASC subjects will undergo a 9-month intervention of rhGH therapy. Controls will be asked to participate in questionnaires, blood draws (amino acid analysis), and fecal sampling (GI microbiome analysis). Controls will not receive any growth hormone treatment.

mTBI group

All patients presenting with a prior mTBI will undergo a phone pre-screen including the Brief Fatigue Inventory (BFI) questions 1-3. If they score ≥ 3 on any BFI questions 1-3, and are interested in participating in the study, they will be scheduled for a formal consenting and medical screening at the UTMB Clinical Research Center (CRC). During the medical screening, eligibility will be confirmed and a glucagon stimulation test (GST) will be performed. A glucagon stimulation with a growth hormone peak of <10 ng/mL is required to qualify for enrollment.

PASC group

All patients presenting with PASC will undergo a phone pre-screen including the Brief Fatigue Inventory (BFI) questions 1-3. If they score ≥ 3 on any BFI questions 1-3, and are interested in participating in the study, they will be scheduled for a formal consenting and medical screening at the UTMB Clinical Research Center (CRC). During the medical screening, eligibility will be confirmed and a glucagon stimulation test (GST) will be performed. A glucagon stimulation with a growth hormone peak of <10 ng/mL is required to qualify for enrollment.

Control group

All controls will undergo a phone pre-screen and if interested in participating in the study, will be scheduled for a formal consenting and medical screening at the UTMB Clinical Research Center (CRC).

Experimental Protocol.

mTBI Group

Before and at completion (month 6) of the rhGH intervention, mTBI subjects will report to the UTMB Institute for Translational Sciences (ITS) Clinical Research Center (CRC) for testing, which will consist of cognitive function assessment (MoCA), determination of brain morphology and connectivity using fMRI, determination of lean mass and fat mass using DEXA, resting energy expenditure, functional testing including leg strength and 6 minute walk test, fatigue measurements, and questionnaires of mood and quality of life, gastrointestinal health, sleep, and food preferences. Blood sampling for measurement of amino acid levels, hormones, and metabolites will be drawn before and 90 minutes (+/- 10 minutes) after a standardized meal. In addition, fecal samples for analysis of the GI microbiome will be collected monthly for the duration of the study. Insulin Growth Factor 1 (IGF-1) levels will monitored at a month 1 safety visit for all mTBI subjects. The month 1 safety visit will occur +/- 5 days from the expected date based on the baseline study visit. The monthly fecal sampling will occur +/- 7 days from the expected date based on the baseline study visit. The month 6 post study will occur +/- 7 days from the expected date based on the baseline study visit. A member of the study team will contact the subject each month to coordinate fecal sample transport to UTMB, check for adverse events and overall well-being, and ensure compliance and ongoing consent.

PASC Group

Before and at month 6 of the rhGH intervention, PASC subjects will report to the UTMB Institute for Translational Sciences (ITS) Clinical Research Center (CRC) for testing, which will consist of cognitive function assessment (MoCA), determination of lean mass and fat mass using DEXA, resting energy expenditure, functional testing including leg strength and 6 minute walk test, fatigue measurements, and questionnaires of mood and quality of life, gastrointestinal health, sleep, and food preferences. Blood sampling for measurement of amino acid levels, hormones, and metabolites will be drawn before and 90 minutes (+/- 10 minutes) after a standardized meal. In addition, fecal samples for analysis of the GI microbiome will be collected monthly for the duration of the study. Insulin Growth Factor 1 (IGF-1) levels will monitored at a month 1 safety visit for all mTBI subjects. The month 1 safety visit will occur +/- 5 days from the expected date based on the baseline study visit. The monthly fecal sampling will occur +/- 7 days from the expected date based on the baseline study visit. The month 6 post study will occur +/- 7 days from the expected date based on the baseline study visit. PASC subjects will continue on rhGH treatment for an additional 3 months. GI microbiome sampling and questionnaires will occur at month 9 and month 12. PASC subjects will have an repeat glucagon stimulation test (GST) to determine growth hormone status at month

12. A member of the study team will contact the subject each month to coordinate fecal sample transport to UTMB, check for adverse events and overall well-being, and ensure compliance and ongoing consent.

Control group

Before and at month 6, controls will report to the UTMB Institute for Translational Sciences (ITS) Clinical Research Center (CRC) for testing, which will consist of questionnaires of food preferences and gastrointestinal health and blood sampling for measurement of amino acid levels, hormones, and metabolites which will be drawn before and 90 minutes (+/ 10 minutes) after a standardized meal. In addition, fecal samples for the analysis of the GI microbiome will be collected monthly for the duration of the study, as well as questionnaire assessing gastrointestinal health. The monthly fecal sampling will occur +/- 7 days from the expected date based on the baseline study visit. The post study (month 6) will occur +/- 7 days from the expected date based on the baseline study visit. A member of the study team will contact the subject each month to coordinate fecal sample transport to UTMB, check for adverse events and overall well-being, and ensure compliance and ongoing consent.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 83
• Est. completion date: October 4, 2023
• Est. primary completion date: October 4, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

mTBI Inclusion criteria

1. Male or female with a diagnosis of mild TBI.

2. At least 6-month post-injury.

3. Ages 18 to 70 years.

4. Participant is willing and able to give informed consent for participation in the study.

mTBI Exclusion criteria

1. Unable to walk unassisted.

2. Significant heart, liver, kidney, blood or respiratory disease.

3. History of chest pain or coronary heart disease.

4. Uncontrolled Diabetes mellitus.

5. Any history of a recently (12 months) diagnosed cancer other than a skin cancer (excluding melanoma).

6. Recent (within 6 months) treatment with anabolic steroids or corticosteroids.

7. Current alcohol or drug abuse.

8. Premorbid history of psychiatric disorder.

9. Premorbid history of head trauma.

10. Pregnancy or become pregnant during the trial.

11. Coumadin because of the risk of bleeding with daily injections of rhGH.

12. Subjects who are deficient in cortisol or thyroid at screening will be excluded until hormone abnormalities have been corrected.

13. 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.

14. Subjects with a history of inflammatory bowel disease, Celiac disease or active diverticular disease.

15. Other medical condition or medication administration deemed exclusionary by the study investigators.

Control Inclusion criteria

1. Ages 18 to 70 years.

2. Participant is willing and able to give informed consent for participation in the study.

Control Exclusion criteria

1. Significant heart, liver, kidney, blood or respiratory disease.

2. Uncontrolled Diabetes mellitus.

3. Any history of a recently (12 months) diagnosed cancer other than a skin cancer (excluding melanoma).

4. Recent (within 6 months) treatment with anabolic steroids or corticosteroids.

5. Current alcohol or drug abuse.

6. Premorbid history of psychiatric disorder.

7. Premorbid history of head trauma.

8. Pregnancy or become pregnant during the trial.

9. Subjects who are deficient in thyroid at screening will be excluded until thyroid hormone is replaced.

10. Subjects with a history of inflammatory bowel disease, Celiac disease or active diverticular disease.

11. Other medical condition or medication administration deemed exclusionary by the study investigators.

PASC Inclusion criteria

1. Male or female with a history of COVID with diagnosis confirmed by PCR test.

2. Minimum of 6 months since diagnosis of COVID by PCR test.

3. Ages 18 to 70 years.

4. Score of 3 or higher on any question 1-3 of the Brief Fatigue Inventory (BFI) questionnaire.

5. Participant is willing and able to give informed consent for participation in the study.

PASC Exclusion criteria

1. Current COVID infection.

2. Unable to walk unassisted.

3. Significant heart, liver, kidney, blood or respiratory disease as determined by Principal Investigator.

4. Uncontrolled diabetes mellitus.

5. Any history of a recently (12 months) diagnosed cancer other than a skin cancer (excluding melanoma).

6. Current alcohol or drug abuse.

7. History of psychosis.

8. Pregnancy or become pregnant during the trial.

9. Subjects who are being managed with narcotics will be excluded as the effects of central nervous system depressants may interfere with study test results.

10. Other medical condition or medication administration deemed exclusionary by the study investigators.

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Cognitive Dysfunction
• Cognitive Impairment
• COVID-19
• Fatigue
• Traumatic Brain Injury

Intervention

Drug:
• Somatropin
Genotropin given by injection

Locations

Country	Name	City	State
United States	University of Texas Medical Branch	Galveston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
The University of Texas Medical Branch, Galveston

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cognitive Function as measured by Montreal Cognitive Assessment at baseline	The Montreal Cognitive Assessment (MoCA) will be used to assess cognition at baseline in mTBI and PASC subjects only.; The Montreal Cognitive Assessment (MoCA) is a rapid assessment of cognition. The MoCA consists of 9 questions with the following subcategories: visuospatial/executive, naming, memory, language, abstraction, delayed recall and orientation. The MoCA has been used extensively to detect cognitive impairment in many conditions, including head trauma. Version 7.1 will be used at the Month 0 testing and Version 7.2 will be used at the Month 6 testing. Scores range from 0 to 30, higher score being a better outcome.	baseline
Other	Cognitive Function as measured by Montreal Cognitive Assessment at 6 months	The Montreal Cognitive Assessment (MoCA) will be used to assess cognition after 6 months of growth hormone treatment in mTBI and PASC subjects only.; The Montreal Cognitive Assessment (MoCA) is a rapid assessment of cognition. The MoCA consists of 9 questions with the following subcategories: visuospatial/executive, naming, memory, language, abstraction, delayed recall and orientation. The MoCA has been used extensively to detect cognitive impairment in many conditions, including head trauma. Version 7.1 will be used at the Month 0 testing and Version 7.2 will be used at the Month 6 testing. Scores range from 0 to 30, higher score being a better outcome.	6 months
Other	Global Fatigue Score as Measured by Brief Fatigue Inventory (BFI) at baseline	The Brief Fatigue Inventory is a 9 item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life), with "0" being no fatigue and "10" being as bad as you can imagine. The Global Fatigue score is calculated by averaging the answers of all the questions. Brief Fatigue Inventory is measured in mTBI and PASC subjects at baseline.	baseline
Other	Global Fatigue Score as Measured by Brief Fatigue Inventory (BFI) at 6 months	The Brief Fatigue Inventory is a 9 item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life), with "0" being no fatigue and "10" being as bad as you can imagine. The Global Fatigue score is calculated by averaging the answers of all the questions. Brief Fatigue Inventory is measured in mTBI and PASC subjects after 6 months of growth hormone treatment.	6 months
Other	Global Fatigue Score as Measured by Brief Fatigue Inventory (BFI) at 9 months	The Brief Fatigue Inventory is a 9 item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life), with "0" being no fatigue and "10" being as bad as you can imagine. The Global Fatigue score is calculated by averaging the answers of all the questions. Brief Fatigue Inventory is measured in PASC subjects after 9 months of growth hormone treatment.	9 months
Other	Global Fatigue Score as Measured by Brief Fatigue Inventory (BFI) at 12 months	The Brief Fatigue Inventory is a 9 item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life), with "0" being no fatigue and "10" being as bad as you can imagine. The Global Fatigue score is calculated by averaging the answers of all the questions. Brief Fatigue Inventory is measured in PASC subjects after 9 months of growth hormone treatment and 3 months off treatment (total time: 12 months).	12 months
Other	Personal Perception of Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form at Baseline	Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF) from the Moffitt Cancer Center, University of South Florida The MFSI-SF is a 30 question assessment designed to assess the principal manifestations of fatigue.; There 5 subscales used to calculate a total score. The subscales are: General Fatigue, Physical Fatigue, Emotional Fatigue, Mental Fatigue, and Vigor (an estimate of the patient's energy level). The total score is calculated with the equation: (general + physical + emotional + mental) - vigor = total score.; The range of the total score is -24 to 96, with the higher the number meaning more fatigue.; The MFSI is measured at baseline.	baseline
Other	Personal Perception of Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form at 6 months	Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF) from the Moffitt Cancer Center, University of South Florida The MFSI-SF is a 30 question assessment designed to assess the principal manifestations of fatigue.; There 5 subscales used to calculate a total score. The subscales are: General Fatigue, Physical Fatigue, Emotional Fatigue, Mental Fatigue, and Vigor (an estimate of the patient's energy level). The total score is calculated with the equation: (general + physical + emotional + mental) - vigor = total score.; The range of the total score is -24 to 96, with the higher the number meaning more fatigue.; The MFSI is measured after 6 months of growth hormone treatment.	6 months
Other	Personal Perception of Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form at 9 months	Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF) from the Moffitt Cancer Center, University of South Florida The MFSI-SF is a 30 question assessment designed to assess the principal manifestations of fatigue.; There 5 subscales used to calculate a total score. The subscales are: General Fatigue, Physical Fatigue, Emotional Fatigue, Mental Fatigue, and Vigor (an estimate of the patient's energy level). The total score is calculated with the equation: (general + physical + emotional + mental) - vigor = total score.; The range of the total score is -24 to 96, with the higher the number meaning more fatigue.; The MFSI is measured after 9 months of growth hormone treatment in PASC subjects only.	9 months
Other	Personal Perception of Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form at 12 months	Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF) from the Moffitt Cancer Center, University of South Florida The MFSI-SF is a 30 question assessment designed to assess the principal manifestations of fatigue.; There 5 subscales used to calculate a total score. The subscales are: General Fatigue, Physical Fatigue, Emotional Fatigue, Mental Fatigue, and Vigor (an estimate of the patient's energy level). The total score is calculated with the equation: (general + physical + emotional + mental) - vigor = total score.; The range of the total score is -24 to 96, with the higher the number meaning more fatigue.; The MFSI is measured after 9 months of growth hormone treatment and then 3 months without treatment (total 12 months) in PASC subjects only.	12 months
Other	Gastrointestinal Health as measured by the gastrointestinal symptom rating scale at baseline	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome). GSRS will be measured monthly at baseline mTBI, PASC and control subjects.	baseline
Other	Gastrointestinal Health as measured by the gastrointestinal symptom rating scale at 1 month	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome). GSRS will be measured monthly in all subjects.	1 month
Other	Gastrointestinal Health as measured by the gastrointestinal symptom rating scale at 2 months	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome). GSRS will be measured monthly in all subjects.	2 months
Other	Gastrointestinal Health as measured by the gastrointestinal symptom rating scale at 3 months	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome). GSRS will be measured monthly in all subjects.	3 months
Other	Gastrointestinal Health as measured by the gastrointestinal symptom rating scale at 4 months	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome). GSRS will be measured monthly all subjects.	4 months
Other	Gastrointestinal Health measured by the gastrointestinal symptom rating scale at 5 months	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome). GSRS will be measured monthly in all subjects.	5 months
Other	Gastrointestinal Health measured by the gastrointestinal symptom rating scale at 6 months	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome). GSRS will be measured monthly in all subjects.	6 months
Other	Gastrointestinal Health measured by the gastrointestinal symptom rating scale at 9 months	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome). GSRS will be measured in month 9 in PASC subjects only.	9 months
Other	Gastrointestinal Health measured by the gastrointestinal symptom rating scale at 12 months	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome). GSRS will be measured in month 12 in PASC subjects only.	12 months
Other	Mood Measured by Profile of Mood States at Baseline	Profile of Mood States (POMS) is a questionnaire by MultiHealth Systems, that measures mood. In this 65 item questionnaire, subjects are asked to rate their feelings toward a statement from 0-4, with 0 being "not at all' and 4 being "extremely". There are 6 subscales which include, tension-anxiety, depression, anger-hostility, vigor, fatigue, and confusion. To calculate the total mood disturbance, which is what is reported here, the subscales tension-anxiety, depression, anger-hostility, fatigue and confusion are summed and vigor is subtracted. The scale range for total mood disturbance is 200 (worst) to -32 (best). POMS will be measured at baseline in mTBI and PASC subjects only.	baseline
Other	Mood Measured by Profile of Mood States at 6 months	Profile of Mood States (POMS) is a questionnaire by MultiHealth Systems, that measures mood. In this 65 item questionnaire, subjects are asked to rate their feelings toward a statement from 0-4, with 0 being "not at all' and 4 being "extremely". There are 6 subscales which include, tension-anxiety, depression, anger-hostility, vigor, fatigue, and confusion. To calculate the total mood disturbance, which is what is reported here, the subscales tension-anxiety, depression, anger-hostility, fatigue and confusion are summed and vigor is subtracted. The scale range for total mood disturbance is 200 (worst) to -32 (best). POMS will be measured after 6 months of treatment with Growth hormone in mTBI and PASC subjects only.	6 months
Other	Mood Measured by Profile of Mood States at 9 months	Profile of Mood States (POMS) is a questionnaire by MultiHealth Systems, that measures mood. In this 65 item questionnaire, subjects are asked to rate their feelings toward a statement from 0-4, with 0 being "not at all' and 4 being "extremely". There are 6 subscales which include, tension-anxiety, depression, anger-hostility, vigor, fatigue, and confusion. To calculate the total mood disturbance, which is what is reported here, the subscales tension-anxiety, depression, anger-hostility, fatigue and confusion are summed and vigor is subtracted. The scale range for total mood disturbance is 200 (worst) to -32 (best). POMS will be measured after 9 months of treatment with Growth hormone in PASC subjects only.	9 months
Other	Mood Measured by Profile of Mood States at 12 months	Profile of Mood States (POMS) is a questionnaire by MultiHealth Systems, that measures mood. In this 65 item questionnaire, subjects are asked to rate their feelings toward a statement from 0-4, with 0 being "not at all' and 4 being "extremely". There are 6 subscales which include, tension-anxiety, depression, anger-hostility, vigor, fatigue, and confusion. To calculate the total mood disturbance, which is what is reported here, the subscales tension-anxiety, depression, anger-hostility, fatigue and confusion are summed and vigor is subtracted. The scale range for total mood disturbance is 200 (worst) to -32 (best). POMS will be measured after 9 months of treatment with Growth hormone treatment and 3 months without treatment (total 12 months) in PASC subjects only.	12 months
Other	Sleep Quality measured by Pittsburgh Sleep Quality Index at baseline	Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1 month-time interval. Minimum Score = 0 (better); Maximum Score = 21 (worse). Interpretation: Total < 5 associated with good sleep quality. Total > 5 associated with poor sleep quality. PSQI will be measured at baseline in mTBI and PASC subjects only.	baseline
Other	Sleep Quality measured by Pittsburgh Sleep Quality Index at 6 months	Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1 month-time interval. Minimum Score = 0 (better); Maximum Score = 21 (worse). Interpretation: Total < 5 associated with good sleep quality. Total > 5 associated with poor sleep quality. PSQI will be measured after 6 months of treatment with growth hormone in mTBI and PASC subjects only.	6 months
Other	Sleep Quality measured by Pittsburgh Sleep Quality Index at 9 months	Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1 month-time interval. Minimum Score = 0 (better); Maximum Score = 21 (worse). Interpretation: Total < 5 associated with good sleep quality. Total > 5 associated with poor sleep quality. PSQI will be measured after 9 months of treatment with growth hormone in PASC subjects only.	9 months
Other	Sleep Quality measured by Pittsburgh Sleep Quality Index at 12 months	Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1 month-time interval. Minimum Score = 0 (better); Maximum Score = 21 (worse). Interpretation: Total < 5 associated with good sleep quality. Total > 5 associated with poor sleep quality. PSQI will be measured after 9 months of treatment with growth hormone and 3 months without treatment (total 12 months) in PASC subjects only.	12 months
Other	Symptoms of Growth Hormone Deficiency measured by the questionnaire Quality of Life - Assessment of Growth Hormone Defiency in Adults at baseline	Symptoms of growth hormone deficiency will be measured in mTBI and PASC subjects using the Quality of Life - Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). This 25-item questionnaire measures specific symptoms associated with growth hormone deficiency, with a score range of 0 to 25, with a higher score indicating worse symptoms. The QoL-ADGHA will be measured at baseline in mTBI and PASC subjects only.	baseline
Other	Symptoms of Growth Hormone Deficiency measured by the questionnaire Quality of Life - Assessment of Growth Hormone Deficiency in Adults at 6 months	Symptoms of growth hormone deficiency will be measured in mTBI and PASC subjects using the Quality of Life - Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). This 25-item questionnaire measures specific symptoms associated with growth hormone deficiency, with a score range of 0 to 25, with a higher score indicating worse symptoms. The QoL-ADGHA will be measured after 6 months of growth hormone treatment in mTBI and PASC subjects only.	6 months
Other	Symptoms of Growth Hormone Deficiency measured by the questionnaire Quality of Life - Assessment of Growth Hormone Deficiency in Adults at 9 months	Symptoms of growth hormone deficiency will be measured in PASC subjects using the Quality of Life - Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). This 25-item questionnaire measures specific symptoms associated with growth hormone deficiency, with a score range of 0 to 25, with a higher score indicating worse symptoms. The QoL-ADGHA will be measured after 9 months of growth hormone treatment in PASC subjects only.	9 months
Other	Symptoms of Growth Hormone Deficiency measured by the questionnaire Quality of Life - Assessment of Growth Hormone Deficiency in Adults at 12 months	Symptoms of growth hormone deficiency will be measured in PASC subjects using the Quality of Life - Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). This 25-item questionnaire measures specific symptoms associated with growth hormone deficiency, with a score range of 0 to 25, with a higher score indicating worse symptoms. The QoL-ADGHA will be measured after 9 months of growth hormone treatment and then 3 months without treatment (total 12 months) in PASC subjects only.	12 months
Other	Depression measured by the Beck Depression Inventory-II at baseline	The Beck Depression Inventory- II assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of "3" indicating a severe symptoms and a score of "0" indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: =13 = minimal; 14-19 = mild; 20-28 = moderate; = 29 = severe. The BDI will be measured at baseline in mTBI and PASC subjects only.	baseline
Other	Depression measured by the Beck Depression Inventory-II at 6 months	The Beck Depression Inventory- II assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of "3" indicating a severe symptoms and a score of "0" indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: =13 = minimal; 14-19 = mild; 20-28 = moderate; = 29 = severe. The BDI will be measured after 6 months of growth hormone treatment in mTBI and PASC subjects only.	6 months
Other	Depression measured by the Beck Depression Inventory-II at 9 months	The Beck Depression Inventory- II assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of "3" indicating a severe symptoms and a score of "0" indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: =13 = minimal; 14-19 = mild; 20-28 = moderate; = 29 = severe. The BDI will be measured after 9 months of growth hormone treatment in PASC subjects only.	9 months
Other	Depression measured by the Beck Depression Inventory-II at 12 months	The Beck Depression Inventory- II assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of "3" indicating a severe symptoms and a score of "0" indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: =13 = minimal; 14-19 = mild; 20-28 = moderate; = 29 = severe. The BDI will be measured after 9 months of growth hormone treatment and 3 months without treatment (total 12 months) in PASC subjects only.	12 months
Other	Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 at Baseline	Peak isometric strength is measured on a Biodex System 4 Pro. This test is isolated to the quadricep muscle of one leg. Isometric test is performed at 90 degrees with 15 seconds of force production for each contraction and 15 seconds of rest. 1 set of 3 contractions at 100% force performed. Isometric strength will be measured at baseline. Measured in mTBI and PASC subjects only.	baseline
Other	Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 at 6 months	Peak isometric strength is measured on a Biodex System 4 Pro. This test is isolated to the quadricep muscle of one leg. Isometric test is performed at 90 degrees with 15 seconds of force production for each contraction and 15 seconds of rest. 1 set of 3 contractions at 100% force performed. Isometric strength will be measured after 6 months of growth hormone treatment. Measured in mTBI and PASC subjects only.	6 months
Other	Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 at baseline	Isokinetic strength (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 1 set of 3 contractions were performed at 100% force. Isokinetic strength will be measured at baseline. Measured in mTBI and PASC subjects only.	baseline
Other	Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 at 6 months	Isokinetic strength (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 1 set of 3 contractions were performed at 100% force. Isokinetic strength will be measured after 6 months of growth hormone treatment. Measured in mTBI and PASC subjects only.	6 months
Other	Walking Distance at 25% Perceptual Effort as measured by walking test at baseline	Walking performance will be assessed in mTBI and PASC patients during 6 minutes of walking in long corridor hallways. This is a standard test of walking performance that has been validated in similar studies. Here, the test will be slightly modified, with subjects asked to walk at a 25% perceived effort from minute 0 - 2, at a 50% perceived effort from minute 2 - 4, and at a 100% effort (as quickly as they can safely walk without running) from minute 4 -6. Distance traveled for each 2-minute category will be recorded. The 6-minute walking test will be completed at baseline. Measured in mTBI and PASC subjects only.	baseline
Other	Walking Distance at 25% Perceptual Effort as measured by walking test at 6 months	Walking performance will be assessed in mTBI and PASC patients during 6 minutes of walking in long corridor hallways. This is a standard test of walking performance that has been validated in similar studies. Here, the test will be slightly modified, with subjects asked to walk at a 25% perceived effort from minute 0 - 2, at a 50% perceived effort from minute 2 - 4, and at a 100% effort (as quickly as they can safely walk without running) from minute 4 -6. Distance traveled for each 2-minute category will be recorded. The 6-minute walking test will be completed at month 6. Measured in mTBI and PASC subjects only.	6 months
Other	Walking Distance at 50% Perceptual Effort as measured by walking test at baseline	Walking performance will be assessed in mTBI and PASC patients during 6 minutes of walking in long corridor hallways. This is a standard test of walking performance that has been validated in similar studies. Here, the test will be slightly modified, with subjects asked to walk at a 25% perceived effort from minute 0 - 2, at a 50% perceived effort from minute 2 - 4, and at a 100% effort (as quickly as they can safely walk without running) from minute 4 -6. Distance traveled for each 2-minute category will be recorded. The 6-minute walking test will be completed at baseline. Measured in mTBI and PASC subjects only.	baseline
Other	Walking Distance at 50% Perceptual Effort as measured by walking test at 6 months	Walking performance will be assessed in mTBI and PASC patients during 6 minutes of walking in long corridor hallways. This is a standard test of walking performance that has been validated in similar studies. Here, the test will be slightly modified, with subjects asked to walk at a 25% perceived effort from minute 0 - 2, at a 50% perceived effort from minute 2 - 4, and at a 100% effort (as quickly as they can safely walk without running) from minute 4 -6. Distance traveled for each 2-minute category will be recorded. The 6-minute walking test will be completed at month 6. Measured in mTBI and PASC subjects only.	6 months
Other	Walking Distance at 100% Effort as measured by walking test at baseline	Walking performance will be assessed in mTBI and PASC patients during 6 minutes of walking in long corridor hallways. This is a standard test of walking performance that has been validated in similar studies. Here, the test will be slightly modified, with subjects asked to walk at a 25% perceived effort from minute 0 - 2, at a 50% perceived effort from minute 2 - 4, and at a 100% effort (as quickly as they can safely walk without running) from minute 4 -6. Distance traveled for each 2-minute category will be recorded. The 6-minute walking test will be completed at baseline. Measured in mTBI and PASC subjects only.	baseline
Other	Walking Distance at 100% Effort as measured by walking test at 6 months	Walking performance will be assessed in mTBI and PASC patients during 6 minutes of walking in long corridor hallways. This is a standard test of walking performance that has been validated in similar studies. Here, the test will be slightly modified, with subjects asked to walk at a 25% perceived effort from minute 0 - 2, at a 50% perceived effort from minute 2 - 4, and at a 100% effort (as quickly as they can safely walk without running) from minute 4 -6. Distance traveled for each 2-minute category will be recorded. The 6-minute walking test will be completed at month 6. Measured in mTBI and PASC subjects only.	6 months
Primary	Lean Body Mass as Measured by Dual Energy X-Ra Absorptiometry (DEXA) at Baseline	Lean body mass will be measured in mTBI and PASC subjects by GE Lunar iDEXA at baseline.	baseline
Primary	Lean Body Mass as Measured by Dual Energy X-Ra Absorptiometry (DEXA) at 6 months	Lean body mass will be measured in mTBI and PASC subjects by GE Lunar iDEXA after 6 months of growth hormone treatment.	6 months
Primary	Fat Mass as Measured by Dual Energy X-Ra Absorptiometry (DEXA) at Baseline	Fat mass will be measured in mTBI and PASC subjects by GE Lunar iDEXA at baseline.	baseline
Primary	Fat Mass as Measured by Dual Energy X-Ra Absorptiometry (DEXA) at 6 months	Fat mass will be measured in mTBI and PASC subjects by GE Lunar iDEXA after 6 months of growth hormone treatment.	6 months
Secondary	Basal Metabolic rate as measured by Resting Energy Expenditure at baseline	Resting Energy Expenditure will be measured by capturing the expired breath of mTBI and PASC subjects while at rest with a metabolic cart over a 30 minute time period. Data will be reported as kilocalories/day.	baseline
Secondary	Basal Metabolic rate as measured by Resting Energy Expenditure at 6 months	Resting Energy Expenditure will be measured by capturing the expired breath of mTBI and PASC subjects while at rest with a metabolic cart over a 30 minute time period. Data will be reported as kilocalories/day. This will be measured after 6 months of growth hormone treatment in mTBI and PASC subjects only.	6 months