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Phelan McDermid syndrome (PMS) is a rare genetic form of autism spectrum disorder (ASD) due to deletions or mutations in the SHANK3 gene. This is a pilot open labeled trial of growth hormone therapy in children with PMS targeting social withdrawal and repetitive behavior. This research study will include children with PMS between 2-12 years of age who will receive growth hormone daily for 12 weeks, if found to be eligible. The aim of this study is to evaluate the effect of growth hormone on behavioral outcomes such as the aberrant behavior checklist social withdrawal subscale (ABC-SW) and repetitive behavior scale- revised (RBS-R). The effects of growth hormone on visual evoked potentials will also be assessed. Growth hormone increases insulin like growth factor 1 (IGF-1) levels and a previous trial of IGF-1 therapy in PMS children showed improvement in these behavioral scales. Growth hormone has been studied for decades with an excellent safety profile and fewer adverse effects compared to IGF-1 therapy in other conditions. Hence, this may be a viable therapeutic option. There is no treatment currently available for PMS and this trial is therefore extremely important.
BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic form of autism spectrum disorder (ASD) associated with developmental delay and hypotonia. IGF-1 promotes brain vessel growth, neurogenesis, and synaptogenesis.
The research team previous clinical trial of IGF-1 in patients with Phelan McDermid Syndrome has shown improvement in core ASD symptoms using the Aberrant Behavior Checklist (ABC) and the Repetitive Behavior Scale-Revised (RBS-R). Growth hormone (GH) binds to its receptor and initiates a cascade of events which directly increases synthesis and release of IGF-1 levels. HYPOTHESIS: The study team hypothesize that rise in IGF-1 stimulated by growth hormone (GH) administration should produce improvement in behavior in children and adolescents with PMS as previously demonstrated with use of IGF-1.
RESEARCH PLAN: The study team seek to recruit 10 patients with PMS and administer growth hormone as once daily subcutaneous injections for 12 weeks at standard doses. The study team will monitor baseline anthropometric measures, laboratory parameters for growth, IGF-1 levels, and bone age prior to therapy and continue to monitor safety laboratory parameters during and after therapy. The goal of therapy would be to maintain IGF-1 levels between 1-2SD above the mean for age and puberty. Evaluations will include validated behavioral scales. Visual evoked potentials (VEPs) will be used as biomarkers of visual sensory reactivity.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phelan-McDermid syndrome | Experimental | Patients with Phelan-McDermid syndrome receive 12 weeks of growth hormone therapy |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Recombinant human Growth hormone | Drug | Subcutaneous growth hormone injections given once daily at a dose between 0.15mg/kg/week to 0.47 mg/kg/week titrated based on IGF-1 levels in serum for a duration of 12 weeks. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. Subscales Stereotyped Behavior (0-27) Self-injurious Behavior (0-24) Compulsive Behavior (0-18) Ritualistic Behavior (0-36) Sameness Behavior (0-33) Restricted Behavior (0-12) | After 12 weeks of growth hormone therapy |
| The Sensory Profile | The full Sensory Profile has 125 items and the short version contains 38 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 for the Short Sensory Profile 38-190, with a lower score indicates greater deviation from typically developing children and indicates more sensory reactivity symptoms. Subscales Tactile (7-35) Taste / Smell (4-20) Movement (3-15) Sensation (7-35) Auditory (6-30) Low Energy / Weak (6-30) Visual / Auditory (5-25) | After 12 weeks of growth hormone therapy |
| The 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. |
| 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 (Zemon et al., 1986) which modulate excitatory and inhibitory signals received by the pyramidal cells. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Swathi Sethuram, MD | Icahn School of Medicine at Mount Sinai | Principal Investigator |
| Alexander Kolevzon, MD | Icahn School of Medicine at Mount Sinai | Study Director |
| Robert Rapaport, MD | Icahn School of Medicine at Mount Sinai | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Seaver Autism Center | New York | New York | 10029 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25685306 | Background | Kolevzon A, Bush L, Wang AT, Halpern D, Frank Y, Grodberg D, Rapaport R, Tavassoli T, Chaplin W, Soorya L, Buxbaum JD. A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. Mol Autism. 2014 Dec 12;5(1):54. doi: 10.1186/2040-2392-5-54. eCollection 2014. | |
| 29719671 | Background |
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| ID | Title | Description |
|---|---|---|
| FG000 | Phelan-McDermid Syndrome | Patients with Phelan-McDermid syndrome receive 12 weeks of growth hormone therapy Recombinant human Growth hormone: Subcutaneous growth hormone injections given once daily at a dose between 0.15mg/kg/week to 0.47 mg/kg/week titrated based on IGF-1 levels in serum for a duration of 12 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Phelan-McDermid Syndrome | Patients with Phelan-McDermid syndrome receive 12 weeks of growth hormone therapy Recombinant human Growth hormone: Subcutaneous growth hormone injections given once daily at a dose between 0.15mg/kg/week to 0.47 mg/kg/week titrated based on IGF-1 levels in serum for a duration of 12 weeks. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | score on a scale | After 12 weeks of growth hormone therapy |
|
12 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Phelan-McDermid Syndrome | Patients with Phelan-McDermid syndrome receive 12 weeks of growth hormone therapy Recombinant human Growth hormone: Subcutaneous growth hormone injections given once daily at a dose between 0.15mg/kg/week to 0.47 mg/kg/week titrated based on IGF-1 levels in serum for a duration of 12 weeks. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Increase in appetite | Gastrointestinal disorders | SLAES | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Alexander Kolevzon, MD | Icahn School of Medicine at Mount Sinai | (212) 659-9134 | alexander.kolevzon@mssm.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 3, 2019 | Oct 29, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| C536801 | Telomeric 22q13 Monosomy Syndrome |
| D001321 | Autistic Disorder |
| ID | Term |
|---|---|
| D000067877 | Autism Spectrum Disorder |
| D002659 | Child Development Disorders, Pervasive |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D013006 | Growth Hormone |
| ID | Term |
|---|---|
| D010908 | Pituitary Hormones, Anterior |
| D010907 | Pituitary Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
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| After 12 weeks of growth hormone therapy |
| After 12 weeks of growth hormone therapy |
| Change in Auditory Event Related Potentials (AERP) | AERP is useful for characterizing early processing of auditory tones and habituation to rapidly repeated stimuli as in speech processing. AERP amplitudes are measured at 12 weeks and compared to baseline. | Baseline and 12 weeks of growth hormone therapy |
| De Rubeis S, Siper PM, Durkin A, Weissman J, Muratet F, Halpern D, Trelles MDP, Frank Y, Lozano R, Wang AT, Holder JL Jr, Betancur C, Buxbaum JD, Kolevzon A. Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations. Mol Autism. 2018 Apr 27;9:31. doi: 10.1186/s13229-018-0205-9. eCollection 2018. |
| 26780584 | Background | Costales J, Kolevzon A. The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders. Neurosci Biobehav Rev. 2016 Apr;63:207-22. doi: 10.1016/j.neubiorev.2016.01.001. Epub 2016 Jan 15. |
| 27884013 | Background | Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB, Rossi WC, Feudtner C, Murad MH; Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society. Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency. Horm Res Paediatr. 2016;86(6):361-397. doi: 10.1159/000452150. Epub 2016 Nov 25. |
| 24837495 | Background | Aramburo C, Alba-Betancourt C, Luna M, Harvey S. Expression and function of growth hormone in the nervous system: a brief review. Gen Comp Endocrinol. 2014 Jul 1;203:35-42. doi: 10.1016/j.ygcen.2014.04.035. Epub 2014 May 13. |
| 35093163 | Derived | Sethuram S, Levy T, Foss-Feig J, Halpern D, Sandin S, Siper PM, Walker H, Buxbaum JD, Rapaport R, Kolevzon A. A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome. Mol Autism. 2022 Jan 29;13(1):6. doi: 10.1186/s13229-022-00485-7. |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Units | Counts |
|---|
| Participants |
|
|
| Primary | 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. Subscales Stereotyped Behavior (0-27) Self-injurious Behavior (0-24) Compulsive Behavior (0-18) Ritualistic Behavior (0-36) Sameness Behavior (0-33) Restricted Behavior (0-12) | Posted | Mean | Standard Deviation | score on a scale | After 12 weeks of growth hormone therapy |
|
|
|
| Primary | The Sensory Profile | The full Sensory Profile has 125 items and the short version contains 38 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 for the Short Sensory Profile 38-190, with a lower score indicates greater deviation from typically developing children and indicates more sensory reactivity symptoms. Subscales Tactile (7-35) Taste / Smell (4-20) Movement (3-15) Sensation (7-35) Auditory (6-30) Low Energy / Weak (6-30) Visual / Auditory (5-25) | Posted | Mean | Standard Deviation | score on a scale | After 12 weeks of growth hormone therapy |
|
|
|
| Primary | The 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. | Data not collected due to pandemic. | Posted | After 12 weeks of growth hormone therapy |
|
|
| Secondary | 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 (Zemon et al., 1986) which modulate excitatory and inhibitory signals received by the pyramidal cells. | Data not collected due to pandemic. | Posted | After 12 weeks of growth hormone therapy |
|
|
| Secondary | Change in Auditory Event Related Potentials (AERP) | AERP is useful for characterizing early processing of auditory tones and habituation to rapidly repeated stimuli as in speech processing. AERP amplitudes are measured at 12 weeks and compared to baseline. | Data not collected due to pandemic. | Posted | Baseline and 12 weeks of growth hormone therapy |
|
|
| 0 |
| 6 |
| 0 |
| 6 |
| 6 |
| 6 |
| Gastroenteritis | Gastrointestinal disorders | SLAES | Systematic Assessment |
|
| Polyuria/nocturia | Renal and urinary disorders | SLAES | Systematic Assessment |
|
| Crying spells | Psychiatric disorders | SLAES | Systematic Assessment |
|
| Runny nose/cough/sneezing | General disorders | SLAES | Systematic Assessment |
|
| Decrease in appetite | Gastrointestinal disorders | SLAES | Systematic Assessment |
|
| Fever | Infections and infestations | SLAES | Systematic Assessment |
|
| Worsening repetitive behavior | Psychiatric disorders | SLAES | Systematic Assessment |
|
| Eye/ear infection | Infections and infestations | SLAES | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | SLAES | Systematic Assessment |
|
| Worsening hyperactivity | General disorders | SLAES | Systematic Assessment |
|
| Sleep disturbance | Psychiatric disorders | SLAES | Systematic Assessment |
|
| Disruptive behavior | Psychiatric disorders | SLAES | Systematic Assessment |
|
| Bruising at injection site | Skin and subcutaneous tissue disorders | SLAES | Systematic Assessment |
|
| Sweating of hands/feet | General disorders | SLAES | Systematic Assessment |
|
| Limping/gait changes | Musculoskeletal and connective tissue disorders | SLAES | Systematic Assessment |
|
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| D006730 |
| Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
|
| Self-injurious Behavior at Week 12 |
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| Compulsive Behavior at baseline |
|
| Compulsive Behavior at Week 12 |
|
| Ritualistic Behavior at baseline |
|
| Ritualistic Behavior at Week 12 |
|
| Sameness Behavior at baseline |
|
| Sameness Behavior at Week 12 |
|
| Restricted Behavior at baseline |
|
| Restricted Behavior at Week 12 |
|
| Total at baseline |
|
| Total at Week 12 |
|
| Title | Measurements |
|---|---|
|
| Taste / Smell at Week 12 |
|
| Movement at Baseline |
|
| Movement at Week 12 |
|
| Sensation at Baseline |
|
| Sensation at Week 12 |
|
| Auditory at Baseline |
|
| Auditory at Week 12 |
|
| Low Energy / Weak at Baseline |
|
| Low Energy / Weak at Week 12 |
|
| Visual / Auditory at Baseline |
|
| Visual / Auditory at Week 12 |
|
| Total at Baseline |
|
| Total at Week 12 |
|