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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT04003207
Other study ID # GCO 18-2549
Secondary ID
Status Completed
Phase Phase 2
First received
Last updated
Start date September 13, 2019
Est. completion date June 5, 2020

Study information

Verified date April 2024
Source Icahn School of Medicine at Mount Sinai
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


Description:

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.


Recruitment information / eligibility

Status Completed
Enrollment 6
Est. completion date June 5, 2020
Est. primary completion date June 5, 2020
Accepts healthy volunteers No
Gender All
Age group 2 Years to 12 Years
Eligibility Inclusion Criteria: - Known pathogenic deletions or mutations in SHANK3 gene diagnosed by array CGH and/or direct sequencing. - Children between 2 and 12 years of age. - Open epiphyses on bone age x ray 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); - history of extreme prematurity (<1000 grams) with associated early neo-natal complications, e.g. intra-cerebral - hemorrhage, prolonged hypoxia, prolonged hypoglycemia; - patients with comorbid conditions who are deemed too medically compromised to tolerate the risk of experimental treatment with growth hormone. - Patient with visual problems that preclude the use of VEP's

Study Design


Intervention

Drug:
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.

Locations

Country Name City State
United States Seaver Autism Center New York New York

Sponsors (1)

Lead Sponsor Collaborator
Swathi Sethuram

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: Mol Autism. 2015;6:31. — View Citation

Outcome

Type Measure Description Time frame Safety issue
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. After 12 weeks of growth hormone therapy
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)
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)
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. 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. 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. Baseline and 12 weeks of growth hormone therapy