Clinical Trial in 22q13 Deletion Syndrome(Phelan-McDermid Syndrome)

A Double-Blind Placebo-Controlled Crossover Trial of Insulin-Like Growth Factor-1 (IGF-1) in Children and Adolescents With 22q13 Deletion Syndrome(Phelan-McDermid Syndrome)

The purpose of this study is to pilot the use of Insulin-Like Growth Factor-1 (IGF-1) treatment in 22q13 Deletion Syndrome (Phelan-McDermid Syndrome) caused by SHANK3 gene deficiency in order to evaluate safety, tolerability, and efficacy. IGF-1 is an injection under the skin that contains human IGF-1. IGF-1 is approved by the FDA under the brand name Increlex for the treatment of children with short stature due to primary IGF-1 deficiency. It is being used off-label in the current study and is not FDA approved, nor has it yet been studied in humans for the treatment of SHANK3 deficiency.

Overall, there will be 1-3 screening visits, a baseline visit where study drug will first be administered, and then 10 follow-up visits. Follow-up visits will occur at week 2, week 4, week 8, and week 12 in each treatment phase (IGF-1 or placebo), and then again 4 weeks after study completion, Parents/guardians will be asked to administer the IGF-1/ placebo by injection at home and will also be responsible for monitoring glucose levels in the child. Parents/guardians will be trained in these methods, and will have scheduled phone calls and appointments where the dose and tolerability will be discussed. Assessments include the following: Physical and neurological examination Medical and psychiatric history X-ray of long bone (e.g., hand) to ensure your child's growth plates are not closed Electrocardiography Echocardiography Pregnancy test if applicable Lab safety measures (through blood draw) Autism Diagnostic Interview (ADI) Autism Diagnostic Observation Schedule (ADOS) The Mullen Scales of Early Learning or the Leiter International Performance Scale-Revised Vineland Adaptive Behavior Scale (VABS) Clinical Global Impressions (CGI) Rating Scales The Repetitive Behaviors Scale (RBS) Aberrant Behavior Checklist (ABC) The Caregiver Strain Questionnaire (CSI) Language Environment Analysis (LENA) The Macarthur-Bates Communication Inventory (MCDI) Unified Parkinson's Disease Rating Scale (UPDRS) Quick Neurological Screening Test 2nd Edition (QNST-2) Gait Analysis with motion capture video systems and interactive 3-dimensional modeling systems

IGF-1 and placebo will each be administered for 3 months with a four-week washout period in between. IGF-1 will be administered for 3 months subcutaneously.

16 items on ABC-SW subscale, Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem). Total score from 0 to 48 with higher score indicating poorer health outcomes.

16 items on ABC-SW subscale, Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem). Total score from 0 to 48 with higher score indicating poorer health outcomes..

Repetitive Behavior Scale (RBS) - Total Score 43 items, each item scored on 4-point scale: 0-Behavior does not occur, 1-Behavior occurs and is a mild problem, 2-Behavior occurs and is a moderate problem, 3-Behavior occurs and is a severe problem. with total score from 0 (mild) to 129 (severe). The subscales are stereotyped behaviors 6 items (subscale 0-18), self-injurious behaviors 8 items (subscale 0-24), Compulsive behaviors- 8 items (subscale 0-24), Ritualistic Behaviors 6 items (subscale from 0-18), Sameness 11 items (subscale 0-33), restricted behaviors 4 items (subscale 0-12). Total score is the sum of all items in the subscale with total score range from 0 to 129. Higher scores indicate greater symptom severity.

The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. The Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.

21 question tool, about caregiver strain, where each question uses a Likert scale where 1 is "Not at all" and 5 is "Very much." The full scale ranges from 21-105, where higher scores indicate more severe strain.

The SP is a standardized parent-completed questionnaire that assesses sensory processing and its impact on the functioning of children ages 3-10 yr. The 125 items represent behaviors that can be interpreted as responses to sensory experiences. The parent rates the observed frequency of these behaviors on a 5-point Likert scale (ranging from 1 always to 5 never). The tool consists of 14 sections, listed below, that refer to sensory processing, modulation, and behavioral and emotional responses. Subscale scores are listed below. Each section's raw score is compared with a threshold value to determine a category of performance: typical performance, probable difference (1 standard deviation below the mean), and definite difference (2 standard deviations below the mean). A lower raw score means a greater difference.

The Short Sensory Profile is a caregiver report measure consisting of 38 items, each scored on a 1-point (always) to 5-point (never) Likert scale. SSP Subscales Tactile Sensitivity (7 to 35) Taste/Smell Sensitivity (4 to 20), Movement Sensitivity (3 to 15), Under-Responsive/Seek Sensation (7 to 35) , Auditory Filtering (6 to 30), Low Energy/Weak (6 to 30), Visual/Auditory Sensitivity (5 to 25), with total scale from (38 to 190) Lower scores indicate more sensory alterations.

Inclusion Criteria: 5 to 12 years old pathogenic deletions or mutations of the SHANK3 gene stable medication regimens for at least three months prior to enrollment Exclusion Criteria: closed epiphyses active or suspected neoplasia intracranial hypertension hepatic insufficiency renal insufficiency cardiomegaly / valvulopathy history of allergy to IGF-1 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 deemed too medically compromised to tolerate the risk of experimental treatment with IGF-1

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.

Kolevzon A, Breen MS, Siper PM, Halpern D, Frank Y, Rieger H, Weismann J, Trelles MP, Lerman B, Rapaport R, Buxbaum JD. Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome. Mol Autism. 2022 Apr 8;13(1):17. doi: 10.1186/s13229-022-00493-7.