Growth Hormone Deficiency in Mild Traumatic Brain Injury

Study Overview
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Brief Summary
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The goal of this randomized control trial is to test if growth hormone therapy is a safe and effective treatment for patients suffering from growth hormone deficiency and persistent post-concussion symptoms. The main questions it aims to answer are: Is growth hormone therapy effective at mitigating persisting post-concussion symptoms in patients with growth hormone deficiency? Is it feasible to conduct a larger trial to examine efficacy of growth hormone therapy in patients with persistent post-concussion symptoms and growth hormone deficiency? Participants will be asked to complete an initial assessment for study inclusion and to complete clinical outcome questionnaires. If a participant meets study criteria they will be randomized to receive either growth hormone therapy (provided by Pfizer) or a placebo (provided by Pfizer). Participants will be instructed on how to self-administer their assigned drug daily for three months. Monthly follow-up visits will include a blood draw to measure a biomarker and clinical outcome questionnaires. At the final follow-up visit after three months, participants will learn what group they were assigned and given the option to complete the growth hormone therapy if they were originally assigned to the placebo group. Researchers will compare the growth hormone therapy group to the placebo group to identify any potential differences in outcomes.

Detailed Description
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Annually, over 250,000 Canadians and over 40 million individuals worldwide will suffer an uncomplicated concussion (head injury with no intracranial abnormalities seen on imaging). Most individuals will recover within weeks of injury but over 30% will have persistent profound symptoms (PPCS) that impedes daily function, work and social activities. To date, there are few evidence-based treatments available for patients suffering PPCS leaving patients and clinicians grasping for answers to improve health. The culminative numbers of Canadians that are living with PPCS following a concussion are staggering and symptoms impact individual's ability to work and actively contribute to society, increasing demands on health care resources, draining public supports and diminishing contribution to the national workforce. To date, there are no recommended evidence-based treatments available to improve PPCS. Current PPCS treatments are extrapolated from other conditions and often include trial and error. Hypopituitarism has been studied extensively in patients with more severe traumatic brain injuries (TBI), with growth hormone deficiency (GHD) being the most common hormone abnormality. Previous studies have examined GHD in patients with TBI due to complicated mild (evidence of intercranial abnormalities on imaging), moderate and severe TBI, but never uncomplicated mTBI (no intercranial abnormality on imaging) or concussion (terms used interchangeably in this document). These studies have shown GH therapy can significantly improve symptoms and function in patients with TBI often allowing them to return to previous work and social activities. Recent retrospective studies completed by CTD and collaborators found approximately 35-41% of patients with concussion referred for GH testing were GHD and 78% had a significant improvement in symptoms at 3 months post-treatment1. Treatment with GH provided significant improvement in symptoms, often allowing them to return to productive jobs, caregiver activities, leisure activities and greatly improving overall quality of life. This research project is incredibly important and novel as it will be the first study to prospectively follow patients with persistent symptoms following concussion to determine prevalence of growth hormone deficiency (GHD) and implement a randomized double blinded placebo controlled cross-over trial to explore the response to GH therapy. A randomized double-blinded placebo control cross-over trial will be completed to determine efficacy of GH treatment in this population as well as feasibility of a larger trial. We will recruit 20 individuals for this pilot study. Inclusion criteria will include 1) persistent symptoms 6-months following concussion and 2) Peak GH of < 3 mcg/L following glucagon stimulation test (GST). We will exclude patients with other untreated pituitary hormone deficits (gonadotrophin, TSH, ACTH, diabetes insipidus). We will perform a pilot trial in order to (1) determine GH therapy efficacy in patients with concussion and GHD and (2) assess the feasibility of a larger prospective study of this nature. We will collect demographic information, injury characteristics, symptom questionnaires, and results from GST and other endocrine testing. Primary outcome will include improvement on the QoL-AGHDA questionnaire (a quality of life questionnaire that has been validated in individuals with GHD) from baseline to 3 months following therapy. Secondary assessments will include cognition (RBANS - repeatable battery for the assessment of neuropsychological status), depression (PHQ9), anxiety (GAD7) and rivermead post-concussion symptom questionnaire (RPQ) pre-treatment and 3 months post-treatment. A Clinical follow-up and IGF-1 levels will be performed at 1 month intervals. Unblinding will occur at 3 months, and patients in the placebo group will have the opportunity to cross-over to the treatment group if they choose. Patients that cross over will complete an additional QoL-AGHDA questionnaire after three months of therapy.

Official Title
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Growth Hormone Deficiency in Patients With Persistent Symptoms Following Concussion

Conditions
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Growth Hormone Treatment, Growth Hormone Deficiency, Concussion, Mild, Concussion Post Syndrome

Intervention / Treatment
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* Drug: Growth Hormone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sustained a concussion according to the American Congress of Rehabilitation Medicine criteria with persistent symptoms 6-months following concussion Peak growth hormone of < 3 mcg/L following glucagon stimulation test Exclusion Criteria: Untreated pituitary dysfunction Moderate/severe TBI Intracranial abnormalities Chronic neurologic conditions

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Treatment group and placebo group. Participants assigned placebo group will be given the option to complete...
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Growth Hormone<br>Participants will perform daily at-home subcutaneous GH injections after receiving thorough at-home education training provided by a pharmaceutical nurse before and research personnel. The GH will be provided be Pfizer. Starting doses will be 0.2 ug/L and 0.3 ug/L for women taking exogenous oral estrogen. | Drug: Growth Hormone<br>* Pfizer provided GH therapy<br>* Other names: Growth Hormone Therapy;|
| Placebo Comparator: Placebo<br>Participants will perform daily at-home subcutaneous placebo injections after receiving thorough at-home education training provided by a pharmaceutical nurse before and research personnel. Starting doses will be 0.2 ug/L and 0.3 ug/L for women taking exogenous oral estrogen. | Drug: Placebo<br>* Pfizer provided placebo<br>* Other names: Placebo (no active therapy);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline QoL-AGHDA | Adult Growth Hormone Deficiency Assessment Quality of Life Questionnaire. A high score indicates a lower quality of life. | Minimum 6-months following injury (no maximum) | 
| 3-months QoL-AGHDA | Adult Growth Hormone Deficiency Assessment Quality of Life Questionnaire. A high score indicates a lower quality of life. | 3-months after baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline RBANS | Repeatable Battery for the Assessment of Neuropsychological Status. A higher score indicates better outcomes. | Minimum 6-months following injury (no maximum) | 
| 3-months RBANS | Repeatable Battery for the Assessment of Neuropsychological Status. A higher score indicates better outcomes. | 3-months after baseline | 
| Baseline GAD-7 | General Anxiety Disorder 7. A higher score indicates worse outcomes. | Minimum 6-months following injury (no maximum) | 
| 3-months GAD-7 | General Anxiety Disorder 7. A higher score indicates worse outcomes. | 3-months after baseline | 
| Baseline PHQ-9 | Personal Health Questionnaire 9. A higher score indicates worse outcomes. | Minimum 6-months following injury (no maximum) | 
| 3-months PHQ-9 | Personal Health Questionnaire 9. A higher score indicates worse outcomes. | 3-months after baseline | 
| Baseline RPQ | Rivermead Post-Concussion Symptom Questionnaire. A higher score indicates worse outcomes. | Minimum 6-months following injury (no maximum) | 
| 3-months RPQ | Rivermead Post-Concussion Symptom Questionnaire. A higher score indicates worse outcomes. | 3-months after baseline | 
| Baseline QoLIBRI | Quality of Life after Brain Injury. A higher score indicates better outcomes. | Minimum 6-months following injury (no maximum) | 
| 3-months QoLIBRI | Quality of Life after Brain Injury. A higher score indicates better outcomes. | 3-months after baseline | 
| Baseline Sleep and Concussion Questionnaire | Sleep and Concussion Questionnaire. A higher score indicates worse outcomes. | Minimum 6-months following injury (no maximum) | 
| 3-months Sleep and Concussion Questionnaire | Sleep and Concussion Questionnaire. A higher score indicates worse outcomes. | 3-months after baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Growth Hormone Deficiency, Persistent Post-concussion Symptoms, Growth Hormone Therapy, Clinical Trial