A Controlled Trial of Growth Hormone in Phelan-McDermid Syndrome and Idiopathic Autism

Study Overview
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Brief Summary
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This clinical trial will use growth hormone as a novel treatment for Phelan-McDermid syndrome (PMS) and idiopathic autism. A double-blind, placebo-controlled crossover trial design will be used in 30 children with idiopathic autism and 15 children with PMS to evaluate the the effects of growth hormone on visual evoked potentials (VEPs), socialization, language, and repetitive behaviors. The researchers expect to provide evidence for the feasibility of using VEPs in PMS, and to show support for growth hormone in ameliorating clinical symptoms of ASD.

Detailed Description
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This study will show that select electrophysiological markers in PMS are relevant to iASD and predictive of treatment response with growth hormone. The long-term goal is to optimize treatment selection in iASD by establishing biological signature(s) derived from PMS. The expected outcome is to establish the feasibility of electrophysiological biomarkers for use in clinical trials in PMS and iASD, demonstrate efficacy of growth hormone in PMS and iASD, and to define a biological profile that will mark a subset of patients with iASD likely to show clinical response to growth hormone. The study will enroll 45 children (15 PMS; 30 iASD; age 2-12 years) and administer growth hormone/placebo as once daily subcutaneous injection for 12 weeks at standard doses. The study team will monitor baseline anthropometric measures, laboratory parameters for growth, IGF-1 levels, and bone age throughout the study. Evaluations will include validated behavioral scales. Visual evoked potentials (VEPs) will be used as biomarkers of visual sensory reactivity. Growth Hormone is approved by the FDA for the treatment of children with short stature due to primary growth hormone deficiency, among several other indications. It is being used off-label in the current study and is not FDA approved for use in PMS or ASD.

Official Title
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Electrophysiological Markers for Interventions in Phelan-McDermid Syndrome and Idiopathic Autism

Conditions
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Phelan-McDermid Syndrome, Autism Spectrum Disorder (ASD)

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children between 2 and 12 years of age Open epiphyses on bone age x ray Must be on stable medication and psychosocial treatment regimens for at least three months prior to enrollment, assuming the concomitant medication is safe for use with Growth Hormone No prior use of Growth Hormone or IGF-1 ASD group: Meet DSM-5 criteria for Autism Spectrum Disorder confirmed by the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2); absence of known pathogenic copy number variants PMS group: Known pathogenic deletions or mutations in SHANK3 gene diagnosed by array CGH and/or direct sequencing Exclusion Criteria: Closed epiphyses Active or suspected neoplasia Intracranial hypertension Hepatic insufficiency Renal insufficiency Cardiomegaly/valvulopathy History of allergy to growth hormone or any component of the formulation (mecasermin) Patients with comorbid conditions who are deemed too medically compromised to tolerate the risk of experimental treatment with growth hormone (including severe obesity, sleep apnea, and various acute health conditions) Visual problems that preclude the use of VEP

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 12 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: Crossover Assignment
Interventional Model Description: A randomized, double-blind, placebo-controlled, crossover design, with 12 weeks in each treatment phase (rhGH and placebo) and a four week wash-out period between phases. During each phase, participants will be monitored at Baseline, Week 2, Week 4, Week 8, and Week 12.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Growth Hormone then Saline<br>12 weeks in each treatment phase (rhGH then placebo) and a four week wash-out period between phases. | Drug: Growth Hormone<br>* Growth hormone will be administered subcutaneously once daily. A starting dose of 0.15 mg/kg/week divided daily for 2 weeks to ensure safety and tolerance. The dose will then be increased to 0.3 mg/kg/week for 10 weeks. Doses will be titrated based on IGF-1 levels and monitored every four weeks up to a maximum dose of 0.45 mg/kg/week based on the package insert.<br>* Other names: rhGH;|
| Placebo Comparator: Placebo (saline) then Growth Hormone<br>12 weeks in each treatment phase (placebo then rhGH) and a four week wash-out period between phases. | Drug: Saline<br>* Placebo (saline) will be administered subcutaneously once daily.<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Evoked Potentials (VEP) | A noninvasive technique to evaluate the functional integrity of visual pathways in the brain from the retina to the visual cortex via the optic nerve/optic radiations. The VEP is recorded from the head's surface, over the visual cortex, and is extracted from ongoing EEG through signal averaging. VEPs reflect the sum of excitatory and inhibitory postsynaptic potentials occurring on apical dendrites which modulate excitatory and inhibitory signals received by the pyramidal cells. | After 12 weeks of growth hormone therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aberrant Behavior Checklist (ABC) Social Withdrawal Subscale | A caregiver report symptom checklist. 58-item instrument into 5 subscales: Irritability (score 0-45); Lethargy/Social Withdrawal (score 0-48); Stereotypic Behavior (score 0-21); Hyperactivity (score 0-48); Inappropriate Speech (score 0-12). Total scale 0-174, with higher score indicating more aberrant behavior. | After 12 weeks of growth hormone therapy | 
| Repetitive Behavior Scale-Revised (RBS-R) | A 43 item instrument with total score from 0-129, with higher score indicating more restricted, repetitive and stereotyped behaviors. | After 12 weeks of growth hormone therapy | 
| Sensory Profile | The Sensory Profile has 125 items. Parents use a Likert scale to rate how frequently their child demonstrates a particular behavior (ranging from 1 = always to 5 = never). Total scale from 125-625, with a lower score indicates greater deviation from typically developing children and indicates more sensory reactivity symptoms. | After 12 weeks of growth hormone therapy | 
| Sensory Assessment for Neurodevelopmental Disorders (SAND) | A clinician-administered assessment and corresponding caregiver interview that is not dependent on verbal or cognitive ability and is therefore appropriate for severely affected or nonverbal individuals with PMS. Responses are rated by a trained examiner on an algorithm. Scores are dichotomous, 0 (not present) or 1 (present) and are based on a summary of observed sensory behaviors throughout the duration of the observation. A total SAND score ranging from 0 to 90. Higher scores represent a higher level of sensory reactivity symptoms. | After 12 weeks of growth hormone therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autism Spectrum Disorder, Phelan-McDermid Syndrome, 22q13 deletion Syndrome, Growth Hormone, Insulin-Like Growth Factor-1, Electrophysiology