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.

Study Overview

• Status: Completed
• Conditions: Phelan-McDermid Syndrome; 22q13 Deletion Syndrome
• Intervention / Treatment: Drug: Insulin-Like Growth Factor-1 (IGF-1); Drug: Normal saline

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Seaver Austin Center, Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Insulin-Like Growth Factor-1 (IGF-1); Injection	Drug: Insulin-Like Growth Factor-1 (IGF-1); 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.; Other Names: Mecasermin; Increlex
Placebo Comparator: Normal saline; Injection	Drug: Normal saline; Saline solution will be administered for three months subcutaneously.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Aberrant Behavior Checklist - Social Withdrawal (ABC-SW) Subscale - Study 1	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.	Baseline and Week 12
Change in Aberrant Behavior Checklist - Social Withdrawal (ABC-SW) Subscale Study 2	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..	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Repetitive Behavior Scale - Study 2	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.	Baseline and Week 12
Change in CGI-Improvement and Severity Scales; - Study 2	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.	Baseline and Week 12
Change in Caregiver Strain Questionnaire	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.	Baseline and Week 12
Change in Sensory Profile (SP) - Study 2	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.	Baseline and Week 12
Change in Short Sensory Profile (SSP) - Study 2	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.	Baseline and 12 weeks

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: National Institute of Mental Health (NIMH)

Publications and helpful links

General Publications

• 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.

Helpful Links

• Seaver Autism Center
• SHANK3 gene
• Phelan-McDermid Syndrome Foundation

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): August 23, 2016
• Study Completion (Actual): August 23, 2016

Study Registration Dates

• First Submitted: February 1, 2012
• First Submitted That Met QC Criteria: February 1, 2012
• First Posted (Estimate): February 3, 2012

Study Record Updates

• Last Update Posted (Actual): May 12, 2022
• Last Update Submitted That Met QC Criteria: April 18, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Autism; IGF-1; SHANK3
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Chromosome Aberrations; Aneuploidy; Monosomy; Syndrome; Chromosome Disorders; Chromosome Deletion; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Mitosis Modulators; Growth Substances; Mitogens; Mecasermin
• Other Study ID Numbers: GCO 12-0929; IF# 1358648; 1R34MH100276-01 (U.S. NIH Grant/Contract); GCO 11-1555 (Other Identifier: Icahn School of Medicine at Mount Sinai); R34MH100276 (U.S. NIH Grant/Contract)