An Open Label Trial of Growth Hormone in Children and Adolescents With Phelan-McDermid Syndrome Targeting Social Withdrawal
Phase: PHASE2
Conditions: Phelan McDermid Syndrome
Sponsor: Swathi Sethuram

An Open Label Trial of Growth Hormone in Children and Adolescents With Phelan-McDermid 
Syndrome Targeting Social Withdrawal   
PI: Swathi Sethuram, MD 
NCT04003207 
Document Date: 3-3-2019

Icahn School of Medicine at Mount Sinai
Mount Sinai Beth Israel
Mount Sinai Brooklyn
The Mount Sinai Hospital
Mount Sinai Queens
New York Eye and Ear Infirmary
of Mount Sinai
Mount Sinai St. Luke's
Mount Sinai West
Program for the Protection
of Human Subjects
Institutional Review Boards
Mount Sinai Health System
One Gustave L. Levy Place, Box
 1081
New York, NY 10029-6574
T 212-824-8200
F 212-876-6789
irb@mssm.edu
icahn mssm.edu/pphs
Initial Application
IRB-18-01272
Swathi Sethuram
Table of Contents
1. Summary - Title.....................................................................................................................................................................1
2. Summary - Setup..................................................................................................................................................................2
3. Summary - Background......................................................................................................................................................4
4. Research Personnel.............................................................................................................................................................6
5. Sites.......................................................................................................................................................................................... 7
6. Subjects - Enrollment.......................................................................................................................................................... 8
7. Subjects - Setting and Resources...................................................................................................................................9
8. Subjects - Populations......................................................................................................................................................10
9. Subjects - Participation.....................................................................................................................................................12
10. Subjects - Risk and Benefits........................................................................................................................................14
11. Subjects - Children..........................................................................................................................................................17
12. Procedures - Narrative...................................................................................................................................................18
13. Procedures - Genetic Testing......................................................................................................................................22
14. Procedures - Details....................................................................................................................................................... 23
15. Procedures - Compensation.........................................................................................................................................24
16. Consent - Obtaining Consent.......................................................................................................................................25
17. Consent - Parental Permission....................................................................................................................................26
18. Consent - Documents.....................................................................................................................................................27
19. Data - Collection...............................................................................................................................................................28
20. Data - HIPAA.................................................................................................................................................................... 29
21. Data - Storage.................................................................................................................................................................. 30
22. Data - Safety Monitoring................................................................................................................................................31
23. Funding................................................................................................................................................................................33
24. Radiation Safety............................................................................................................................................................... 34
25. Drugs / Biologics..............................................................................................................................................................36
26. Financial Administration................................................................................................................................................. 39
27. Attachments....................................................................................................................................................................... 40

IRB-18-01272
Initial Application
Swathi Sethuram
1. Summary - Title
Protocol Title
An Open Label Trial of Growth Hormone in Children and Adolescents with Phelan-McDermid Syndrome Targeting
 Social Withdrawal
Principal Investigator
Swathi Sethuram
Primary Department
Pediatrics
Application Initiated By
Swathi Sethuram
Lay Summary
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.
 Our 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: We hypothesize that rise in IGF-1 stimulated by growth hormone (GH) administration should produce
 the same improvement in behavior in children and adolescents with Phelan McDermid Syndrome as previously
 demonstrated  with use of IGF-1. 
RESEARCH PLAN: We seek to recruit 20 patients with Phelan McDermid Syndrome and administer growth hormone
 as once daily subcutaneous injections for 12 weeks at standard doses. We will monitor baseline anthropometric
 measures, laboratory parameters for growth, IGF-1 levels, 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 of their social withdrawal shall be made using standardized
 and validated behavioral scales. VEPs will be used as biomarkers of visual sensory reactivity. Each patient will have
 thorough history and physical evaluations prior to, during and following the trial. 
SIGNIFICANCE: Autism is a severe lifelong neuro-developmental disorder. Our pilot trial of IGF-1 in patients with
 Phelan McDermid Syndrome demonstrated the improvement in their behavioral skills. Growth hormone is an easily
 accessible medication that has been studied for decades in children with short stature. Its safety profile is well known
 and administration in children is easier with once daily injections compared to twice daily injections with IGF-1. Also,
 hypoglycemia which is a serious adverse effect of IGF-1 therapy is not associated with growth hormone therapy.
 We expect growth hormone to produce similar effects to IGF-1 in these patients considering GH acts via the IGF-1
 pathway. This project could perhaps make a breakthrough for treating children with all forms of autism in the future
 and must be explored.
IF Number
IF2355548
Page 1 of 40

IRB-18-01272
Initial Application
Swathi Sethuram
2. Summary - Setup
Funding Has Been Requested /
 Obtained
Yes
Application Type
Request to Rely on Mount Sinai IRB
Research Involves
Prospective Study ONLY
Consenting Participants
Yes
Requesting Waiver or Alteration
 of Informed Consent for Any
 Procedures
No
Humanitarian Use Device (HUD)
 Used Exclusively in the Course of
 Medical Practice
No
Use of an Investigational Device to
 Evaluate Its Safety or Effectiveness
No
Banking Specimens for Future
 Research
No
Cancer Related Research that
 Requires Approval from the
 Protocol Review and Monitoring
 Committee (PRMC).
No
   Is this Cancer Related Research?  Cancer Related Research is defined as research that
 has cancer endpoints or has a cancer population as part of or all of its targeted population.
 This includes protocols studying patients with cancer or those at risk for cancer.
  
Clinical Trial
Yes
   
   * A prospective biomedical or behavioral research study of human subjects that is
 designed to answer specific questions about biomedical or behavioral interventions
 (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices). 
   *  Used to determine whether new biomedical or behavioral interventions are safe,
 efficacious, and effective.    
  
Drugs / Biologics 
Yes
   
   * Drugs / Biologics That Are Not a Part of Standard Practice 
   * Controlled Substances 
   * Drugs / Biologics Supplied by the Research Sponsor or Purchased with Study Funds 
  
   Ionizing Radiation for imaging or therapy, including X-Ray, Fluoroscopy, CT, Nuclear
 Medicine, PET andor Radiation Therapy:
  
* Purely for standard of care:
Yes
* In frequency or intensity that
 exceeds what is necessary for
 standard of care:
Yes
Hazardous Materials
No
   * Recombinant DNA 

   * Viral Vectors 
   * Plasmids 
   * Bacterial Artificial Chromosomes 
   * Toxic Chemicals, Potentially Toxic Medications, Carcinogens 
   * Autologous Cell Lines 
  
Request Use of Clinical Research
 Unit Resources
No
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IRB-18-01272
Initial Application
Swathi Sethuram
3. Summary - Background
Objectives
1. To evaluate if growth hormone will adequately elevate IGF-1 levels within 12 weeks of therapy.
Hypothesis: Growth hormone will cause a rise in IGF-1 levels within 12 weeks of therapy.
2. To evaluate efficacy of growth hormone induced elevation in IGF1 on social withdrawal as the primary outcome
 measure using the ABC – Social Withdrawal subscale (Aman et al., 1985). 
Hypothesis: Growth hormone will produce the same effects in improvement in social withdrawal as compared to
 IGF-1. 
3. To evaluate efficacy of Growth hormone induced elevation in IGF1 on repetitive behaviors using the Repetitive
 Behavior Scale-Revised (Bodfish), sensory reactivity using the Short Sensory Profile (Dunn) and the Sensory
 Assessment for Neurodevelopmental Disorders (Siper et al., 2017), and hyperactivity using the ABC-Hyperactivity
 subscale.
Hypothesis: Growth hormone will be associated with improvement across all outcomes comparable with the use of
 IGF-1.
4. To evaluate the effect of growth hormone therapy on visual evoked potentials and auditory event related potentials
 in children with Phelan McDermid Syndrome. 
Hypothesis: Growth hormone will be associated with similar changes in visual evoked potentials and auditory event
 related potentials following 12 weeks trial as compared to IGF-1. 
Background
In recent years there have been major changes in the understanding of the etiology of autism spectrum disorders
 (ASD) and many genes associated with ASD have been identified. This has led to a profound shift in thinking, such
 that ASD can now be conceived of as having multiple independent causes, which in many cases can be largely
 attributed to a specific etiological genetic event. One such example is the 22q13 deletion syndrome, also called
 Phelan-McDermid syndrome (PMS), characterized by global developmental delay, hypotonia, delayed or absent
 speech, and ASD features, for which convincing evidence implicates SHANK3 as the critical gene (Bonaglia et
 al, 2006). SHANK3 codes for a master scaffolding protein which forms the framework in glutamatergic synapses
 (Boeckers et al, 2006) and makes up the core of the postsynaptic density (PSD). Recent studies exploring the rate
 of 22q13 deletions/SHANK3 mutations suggest that haploinsufficiency of SHANK3 can cause a monogenic form of
 ASD and intellectual disability with a frequency of up to 2% of ASD cases (Durand et al, 2007; Moessner et al, 2007;
 Gauthier et al, 2008; LeBlond et al., 2015). Although SHANK3 mutations and deletions account for a relatively small
 proportion of ASD cases, recent evidence suggests that this variant may be treatable, and therefore important to
 identify. 
Work on PMS at our Center began with Shank3-deficient mice showing a reduction in basal neurotransmission
 reflecting decreased glutamate (i.e., AMPA receptor-mediated) transmission. Long-term potentiation was impaired
 with no significant change in long-term depression (Bozdagi et al., 2010), and intraperitoneal injection of IGF-1
 reversed the electrophysiological and motor deficits seen in the Shank3-deficient mice (Bozdagi et al., 2013). 
Our clinical group began prospectively evaluating patients with PMS using standard evaluation tools in 2010; 65
 affected individuals have been seen to date at our site and an additional 54 participants have been evaluated across
 our national PMS network and will be leveraged to meet recruitment goals for this project. We have published
 descriptive results from 32 patients thus far, 27 of whom (84%) met criteria for ASD using a priori definitions derived
 from expert consensus commonly used in ASD research (Soorya et al., 2013). Subsequently, we began a controlled
 trial of IGF-1 in PMS and provided evidence of improvement in core ASD symptoms (Kolevzon et al., 2014) using the
 Aberrant Behavior Checklist (ABC; Aman et al., 1985) and the Repetitive Behavior Scale-Revised (RBS-R; Bodfish
 et al., 2000). IGF-1 also reversed phenotypic and electrophysiological changes in human neuronal models of PMS
 (Shcheglovitov et al., 2013) and iASD (Marchetto et al., 2016), providing additional support for this intervention.
IGF-1 enters the brain from the circulation where it is released mainly by the liver upon growth hormone stimulation.
 Blood-borne IGF-1 is found in the CNS and promotes brain vessel growth (Lopez-Lopez et al., 2004), neurogenesis,
 and synaptogenesis (O'Kusky et al., 2000). Once IGF-1 binds to the IGF-1 receptor, activation of the PI3K/mTOR/
AKT1 and MAPK/ERK pathways induces its downstream effects (Costales & Kolevzon, 2016). A recent study in Rett
 syndrome provides evidence of IGF-1 brain penetrance: cerebrospinal fluid and serum analysis revealed significant
 increases in IGF-1 levels after treatment (Khwaja et al., 2014). 

The proposed clinical trial seeks to collect pilot data on the role of exogenous growth hormone in children and
 adolescents with Phelan McDermid Syndrome to increase IGF-1 levels, which has been shown to have positive
 effects on social withdrawal, repetitive behaviors, sensory reactivity, and hyperactivity. There is currently no
 treatment available for PMS and the use of growth hormone may be practical and effective.
Growth hormone binds to its receptor and initiates a cascade of events which involves transcription of several genes
 resulting in rise of IGF-1. (Vottero et al., 2013, Hormone Resistance and Hypersensitivity; Ashpole et al., 2015,
 Experimental Gerontology). We hypothesize that increase in IGF-1 stimulated by growth hormone administration
 should produce the same improvement in behavior in children and adolescents with Phelan McDermid Syndrome as
 previously demonstrated with use of IGF-1 (Kolevzon et al., 2014). 
Growth hormone is an easily available drug whose safety profile has been studied since 1985 (Ranke et al.; 2018).
 The experience with growth hormone has shown that it is well tolerated by children with few adverse effects as
 compared to IGF-1. Hypoglycemia is not associated with growth hormone therapy while it is a serious adverse
 event with IGF-1 therapy, requiring serial monitoring. Growth hormone is also easy to administer as a once daily
 subcutaneous dose compared to the twice daily subcutaneous injections for IGF-1.
Hence, administration of growth hormone may be a viable option to increase IGF-1 levels and have an impact on the
 behavior of these children.  
Primary and Secondary Study Endpoints
1. Improvement in social withdrawal following growth hormone administration measured using the ABC - Social
 Withdrawal Subscale and repetitive behavior using the Repetitive Behavior Scale-Revised.
2.Improvement in other behavioral scales following growth hormone administration, such as the Short Sensory
 Profile, Sensory Assessment for Neurodevelopmental Disorders, and the ABC-Hyperactivity subscale as seen with
 the IGF-1 trial.
2. VEPs  will show improvement in amplitudes in children with Phelan McDermid Syndrome following 12 weeks of
 growth hormone therapy, similar to the changes seen following IGF-1 therapy. 
Protocol Was Already Approved
 by the Icahn School of Medicine at
 Mount Sinai (ISMMS) Institutional
 Review Board (IRB) Under a
 Different Principal Investigator
No
Protocol Was Previously Submitted
 to an External(non-ISMMS) IRB
No
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IRB-18-01272
Initial Application
Swathi Sethuram
4. Research Personnel
Name/Department
Role/Status
Contact
Access
Signature
 Authority
Phone
Email
Swathi Sethuram /
 Pediatrics
PI / 
Yes
EDIT
Robert Rapaport /
 Pediatrics
Co-Investigator / 
Yes
SIGNAUTH
212-241-8487
Alexander Kolevzon /
 Psychiatry
Co-Investigator / 
Yes
SIGNAUTH
212-659-9134
 
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IRB-18-01272
Initial Application
Swathi Sethuram
5. Sites
Site Name
Icahn School of Medicine at Mount Sinai
Other External Site Name
Contact Details
Approved
Approval Document
Funded By Mount Sinai
Other IRB
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IRB-18-01272
Initial Application
Swathi Sethuram
6. Subjects - Enrollment
Site Name
Icahn School of Medicine at Mount Sinai
Subjects To Be Enrolled
20
Total Number of Subjects to be
 Enrolled Across All Listed Sites
 Above (Auto Populated)
20
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IRB-18-01272
Initial Application
Swathi Sethuram
7. Subjects - Setting and Resources
Setting of Human Research
Other
Specify Other Setting of Human Research
Seaver Autism Center for Research and Treatment at Icahn School of Medicine at Mount Sinai 
Total Number of Subjects Needed
 To Complete Study
20
Feasibility of Meeting Recruitment Goals
Power is calculated for differences in baseline to week 12 change scores. Testing for treatment x time interactions
 and # at .05, we have 80% power to detect moderate to large effects. 
Based on data from our previous clinical trial of IGF-1 in patients with Phelan McDermid Syndrome, a 12 week study
 was feasible in 9 patients. 
We feel that 20 patients would provide adequate data to establish the utility of growth hormone in this population. The
 Seaver Autism Center has access to this population of children with Phelan Mcdermid Syndrome which should help
 facilitate recruitment. 
Facilities To Be Used for Conducting Research
Seaver Autism Center at Icahn School of Medicine
Pediatric Endocrinology & Diabetes Outpatient Clinic at Mount Sinai 
Multi-Center Study
No
Community-Based Participant
 Research Study
No
  PI must attest to the following. 
   * Process is adequately described to ensure that all persons assisting with the trial are
 adequately informed about the protocol, the investigational product(s), and their trial-
related duties and functions.
     
    
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IRB-18-01272
Initial Application
Swathi Sethuram
8. Subjects - Populations
Inclusion Criteria
Diagnosis: Pathogenic deletions or mutations of the SHANK3 gene confirmed by array CGH and/or direct
 sequencing. 
Age Range: Cases will be between 2 and 12 years old at the time the phenotypic measures were collected. 
Exclusion Criteria
Cases will be excluded if any of the following criteria are applicable: 
- 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 VEPs
Enrollment Restrictions Based
 Upon Gender, Pregnancy,
 Childbearing Potential, or Race
Yes
Justify Restriction(s)
We will only recruit children between 2 to 12yrs of age and pregnant women will be excluded from the study since this
 is a pilot clinical trial of GH in children with Phelan McDermid Syndrome. 
Age Range(s)
Newborn to 8 Years, 9 to 17 Years
Targeted Population(s)
Children
Individuals Under 18 Consenting for
 Themselves Under NYS Law?
No
        In most cases this does not apply. Typically subjects under 18 assent and a parent
 (or two) consents for the subject to be in research. This is only for very limited scenarios
 where the study is related to services/treatment (usually limited to reproductive health,
 substance abuse or mental health issues) that those under 18 can obtain without parental
 involvement in NYS and where there was no parental involvement for the related clinical
 services. See SOP-013 (point 3.2) for additional information.
        
    
Other Aspects that Could Increase Subjects Vulnerability
Informed consent shall be obtained from parents or legal guardians of patients with Phelan McDermid Syndrome who
 typically have global developmental delays and are cognitively impaired. 
Safeguards to protect Subjects rights and welfare
Participants suitable for the study will undergo comprehensive medical evaluation by the study psychiatrist. Medical
 history, family history, physical and neurological examination (including anthropometric measurements, fundoscopic
 exams), routine hematology and blood chemistry (including liver profile) and X-ray will be performed at baseline.
  Patients will be monitored for tolerability every 4 weeks throughout the study using physical and neurological
 examination (including anthropometric measurements and fundoscopic  exams). Patients will be monitored at
 weeks 4, 8, and 12 and then again 4-weeks after study termination with the following safety measures: physical and
 neurological examination (including anthropometric measurements and fundoscopic exams), routine hematology and
 blood chemistry.

Potential adverse events from Growth Hormone (GH) will be explained to participant's families and also be monitored
 for during their serial evaluations. 
Informed consent shall be obtained from parents or legal guardians after a thorough explanation of the study
 protocol. 
The study will be conducted according to Good Clinical Practice (GCP), the 1996 Declaration of Helsinki (Protocol
 Appendix A), (US 21 CFR Part 50—Protection of Human Subjects, and Park 56—Institutional Review Boards) and
 local rules and regulations of the country. 
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IRB-18-01272
Initial Application
Swathi Sethuram
9. Subjects - Participation
Duration of an Individual Subjects Participation in the Study
Approximately 6 months or lesser
Duration Anticipated to Enroll All Study Subjects
15 months
Estimated Date for the Investigators
 to Complete This Study
Within two years
Procedures for Subjects to Request Withdrawal
Indications to halt active participation of the subject in the GH study
1. Withdrawal of Consent : Patient families may withdraw consent at any time during the course of the study. 
To avoid bias, all analyses will include all subjects, including those withdrawn from the study, regardless
 of adherence to study protocol.  If there is doubt concerning a subject's safety, the default mode must be
 withdrawal from treatment or active study participation, followed by close observation (safety follow up visits) and
 recommendation of standard treatment.
Return of a subject to active study participation will not be permitted, except if a transient clinical or laboratory
 abnormality unrelated to study treatment has occurred and subsequent permission to return the patient to active
 study has been provided.
If a subject is withdrawn from active study during Growth Hormone treatment, they will be returned to the referring
 physician and standard care will be recommended; in addition, we will request the subject's participation in an end-
of-study visit.
Procedures for Investigator to Withdraw Subjects
Indications to halt active participation of the subject in the GH study
1. PI or any regulatory authority (IRB, or FDA) believe withdrawal is necessary for the subject's health, well-being, or
 best interests.
2. PI or any regulatory authority believe that withdrawal is necessary for the subject's health, well-being, or best
 interests 
3. Laboratory: any abnormality on any test with adverse event (AE, Common Terminology Criteria for Adverse
 Events, National Cancer Institute, scales) # 3 or greater at any time in the study
4. Any AE of any sort (clinical, laboratory) # 4 will result in halting for the individual and also for the study as a whole.
Participants Will Be Recruited
Yes
Recruitment Method(s)
Clinical Practice, Other Website
How Participants Will Be Identified
All participants must be diagnosed with Phelan McDermid Syndrome.
Phenotype definition will be conducted using a comprehensive assessment battery, including: (1) psychiatric
 evaluation; (2) clinical genetics evaluation; (3) neurological examination; (4) Vineland Adaptive Behavior Scales.  
All patients must also have pathogenic deletions or mutations of the SHANK3 gene confirmed by array CGH and/or
 direct sequencing on record. 
Who Will Initially Approach
 Potential Participants
Study Personnel, Member of Primary Care
 Team, Treating Physician, Clinic Personnel
How Research Will Be Introduced to Participants
Potential participants in the Seaver Autism Center outpatient clinic as well as families of patients with Phelan
 McDermid Syndrome will be informed about this study directly or via websites (such as Phelan McDermid Syndrome
 Foundation)
How Participants Will Be Screened
Participants will be screened based on the inclusion criteria and a diagnosis of Phelan McDermid Syndrome and with
 open epiphyses as evidenced by a bone age x ray. 

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IRB-18-01272
Initial Application
Swathi Sethuram
10. Subjects - Risk and Benefits
Risks to Subjects
Growth hormone will be administered as subcutaneous injections once daily by parent or guardian at home. 
Blood draws will be done every 4 weeks during study and 4 weeks following study. 
Potential adverse events from Growth Hormone(GH) are described in the package insert. Some adverse effects
 include headaches, myalgia, fluid retention, benign intracranial hypertension, slipped capital femoral epiphyses,
 insulin resistance and hypothyroidism. Local reactions include erythema or pain at injection site and lipoatrophy with
 long term use. 
Patients will require to be seen by a physician at our center every 4 weeks for evaluations and monitoring safety. 
Description of Procedures Taken to Lessen the Probability or Magnitude of Risks 
Participants suitable for the study will undergo comprehensive medical evaluation by the study psychiatrist. Medical
 history, family history, physical and neurological examination (including anthropometric measurements, fundoscopic
 exams), routine hematology and blood chemistry and X-ray will be performed at baseline.  All families will be
 educated on appropriate growth hormone administration. Patients will be monitored for tolerability every 4 weeks
 throughout the study using physical and neurological and psychological evaluations (including anthropometric
 measurements, fundoscopic exams). This monitoring will occur at weeks 4, 8, and 12 and then again 4-weeks after
 study termination. 
All testing will be scheduled at the same time as the four weekly visit in order to avoid inconveniencing patient. 
Provisions for Research Related Harm / Injury
Serial evaluations by physician every 4 weeks during study and also safety parameters monitored by blood draws will
 reduce research related harm/injury. 
An adverse event (AE) will be defined as any untoward medical occurrence in a study subject, temporally associated
 with the use of the experimental medication, whether or not considered related to the medication. An adverse event
 can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or
 disease (new or exacerbated) temporally associated with the use of the experimental medication. A serious adverse
 event (SAE) will be defined as an AE that meets any of the following criteria:
results in death; 
is life threatening; 
requires inpatient hospitalization; 
results in a persistent or significant disability/incapacity; 
any other adverse event that, based upon appropriate medical judgment, may jeopardize the subject's health and
 may require medical or surgical intervention to prevent one of the outcomes listed above. 
Adverse Events Reporting 
The Principal Investigator (PI) will be responsible for the detection and documentation of events meeting the criteria
 and definition of an adverse event or serious adverse event, as provided in this protocol. During the study, when
 there is a safety evaluation, the investigator or team member will be responsible for reporting adverse events and
 serious adverse events. Each subject's parents/guardians will be instructed to contact the investigator immediately
 should the subject manifest any signs or symptoms they perceive as serious. 
Clinical laboratory parameters and other abnormal assessments qualifying as adverse events and serious adverse
 events:
Abnormal laboratory findings or other abnormal assessments that are judged by the investigator to be clinically
 significant will be recorded as AEs or SAEs if they meet the definition of an AE. Clinically significant abnormal
 laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and
 significantly worsen following the start of the study will be reported as AEs or SAEs. The investigator will exercise
 his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal
 assessment is clinically significant. 
Medically attended visits 
For each AE the subject experiences, the subject's parents/guardians will be asked if they received medical attention
 defined as hospitalization, an emergency room visit or a visit to or from medical personnel (medical doctor/doctor of
 osteopathy or nurse practitioner) for any reason. This information will be recorded in the CRF (case report form). 

Lack of Efficacy 
Lack of efficacy per se will not be reported as an AE. The signs and symptoms or clinical sequelae resulting from lack
 of efficacy will be reported if they fulfill the AE or SAE definition (including clarifications). 
Time Period, Frequency, and Method of Detecting AEs:
All AEs occurring from the initiation of therapy until 4 weeks following its completion will be recorded on the Adverse
 Event form in the subject's CRF, irrespective of severity or whether or not they are considered medication-related.
 Onset of chronic illness (e.g. autoimmune disorders, asthma, type 1 diabetes and allergies) and conditions prompting
 emergency room (ER) visits or physician office visits that are not related to well-child care, injury, or common acute
 illnesses (e.g., upper respiratory tract infection, otitis media, pharyngitis, and gastroenteritis) will be reported during
 the entire study period. The investigator will inquire about the occurrence of AEs at every visit/contact during the
 study and throughout the follow-up phase as appropriate. All AEs either observed by the investigator or a clinical
 collaborator or reported by the subject's parent/guardian spontaneously or in response to a direct question will be
 evaluated by the investigator. AEs not previously documented in the study will be recorded in the Adverse Event
 form within the subject's CRF. The nature of each event, date and time (where appropriate) of onset, outcome,
 intensity and relationship to drug administration should be established. Details of any corrective treatment should be
 recorded on the appropriate page of the CRF. 
When an AE/SAE occurs, it will be the responsibility of the investigator to review all documentation (e.g., hospital
 progress notes, laboratory, and diagnostic reports) relative to the event. The investigator will then record all relevant
 information regarding an AE/SAE on the eCRF or SAE Report Form as applicable. The investigator will attempt to
 establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. 
Safety: To evaluate safety, participants will be assessed every 4 weeks by the study psychiatrist. There are a number
 of tertiary outcomes designed to monitor the safety of GH. 
Monitoring for AEs will be conducted during scheduled and unscheduled visits per clinical and laboratory
 assessments.  General AEs will be graded by the National Cancer Institute (NCI) CTCAE scales (note: please see
 discussion immediately following for AEs with neurological signs and symptoms).  Examples of possible AE grades
 for parameters which will be measured during treatment (shown in Table 3 Research Protocol PDF).  Also, any AE
 that the PI deems serious, although not easily categorized in the National Cancer Institute grading system, will be
 considered # grade 3.
If a subject develops significant (CTCAE AE # 3 grade) neurological signs and symptoms (e.g.  cerebrovascular
 event or peripheral neuropathy), they will be seen immediately for a comprehensive evaluation, appropriate
 treatment, and removal from active participation in the study. We will also apply NCI-CTCAE criteria for attribution of
 AE by means of the following descriptors and codes, following the NCI guidelines for their application.
unrelated to treatment   1
unlikely related to treatment  2
possibly related to treatment  3
probably related to treatment  4
definitely related to treatment  5
The following are the potential adverse events associated with GH and how we intend to monitor and prevent these
 occurrences.
 
Slipped capital femoral epiphyses (SCFE)
SCFE is a potential adverse effect of growth hormone therapy. We will monitor for this by parental reporting of hip
 pain (unilateral or bilateral), limping or difficulty bearing weight. Children suspected of SCFE will undergo bilateral hip
 x-ray in a frog leg position for diagnosis. 
Alterations in glucose homeostasis
Glucose homeostasis will be measured using hemoglobin A1C levels as well as glucose and insulin levels prior to
 and during therapy. 
Increased intracranial pressure
In order to monitor for increased intracranial pressure, children will undergo fundoscopic examination. 
Expected Direct Benefit to Subjects
Autism is a severe lifelong neuro-developmental disorder characterized by impairments in reciprocal social
 interaction, communication deficits and repetitive and restricted patterns of behavior and interests with onset in the
 first three years of life.

Our pilot study on use of IGF-1 in patients with Phelan McDermid syndrome showed improvement in the standardized
 Aberrant Behavior Checklist (ABC) and the Repetitive Behavior SubScale-Revised (RBS-R) after 12 weeks of
 therapy (Kolevzon, 2014). 
Considering growth hormone acts via the IGF-1 pathway, this medication that is easily accessible and administered
 once daily (in comparison to twice daily IGF-1) should improve social withdrawal in this population. Growth hormone
 will also not produce hypoglycemia in patients that has been known to occur with IGF-1 use. 
Benefit to Society
Growth hormone is a commercially available drug that has a good safety profile following decades of study. Growth
 hormone administration has been shown to improve mental and motor development in children with Prader Willi
 Syndrome owing to its impact on IGF-1 (Donze et al, 2018). 
The success of this clinical trial could have implications on other genetic forms of autism spectrum disorder in the
 future. It will also provide more information to the healthcare community in this field. 
Provisions to Protect the Privacy Interests of Subjects
Members of the research team may also provide clinical care to this population in the Seaver Autism Center; thus, it
 is acceptable and appropriate for the team to present the research to patients in the clinic. Patients recruited outside
 of the Seaver Autism Center will approach study personnel after viewing our ads and only if the family is willing will
 our research personnel discuss the study with family. We may conduct initial telephone conversations with these
 families to inform them regarding the study. Prospective subjects and their parents will be informed of and consented
 for the study in the privacy of an investigator's office during a clinic visit.  Follow-up visits and phone calls made to
 subjects will be carried out in the context of clinical care.
It will be explained to the subject's parents that all questions asked and procedures performed will be part of the
 study, and they will be informed that they do not need to answer all of the questions or they can decline a procedure
 if they feel uncomfortable.
Economic Impact on Subjects
None
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IRB-18-01272
Initial Application
Swathi Sethuram
11. Subjects - Children
  Select Which of the Following Best Describes the Risk Presented to Children 
  * No greater than minimal risk to children is presented. 
  * Greater than minimal risk to children and the research presents the prospect of direct
 benefit to the individual subjects. 
  * Greater than minimal risk to children presented by an intervention or procedure
 that does not hold out the prospect of direct benefit for the individual subject, or by a
 monitoring procedure which is not likely to contribute to the well-being of the subject. 
  * None of the above but the research presents a reasonable opportunity to further the
 understanding, prevention, or alleviation of a serious problem affecting the health or
 welfare of children. 
     
 
Risk Presented to Children
Greater Than Minimal Risk With Direct
 Benefit
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IRB-18-01272
Initial Application
Swathi Sethuram
12. Procedures - Narrative
Description of the Study Design
The proposed pilot will seek to recruit 20 children aged 2 to 12 years old with SHANK3 deletions or mutations and
 with radiographic evidence of open epiphyses. Phenotype definition will be conducted using a comprehensive
 assessment battery, including: (1) psychiatric evaluation; (2) clinical genetics evaluation; (3) neurological
 examination; (4) Vineland Adaptive Behavior Scales.  The study will include newly recruited children in addition to
 those who have been previously recruited for the purposes of genetic studies by the Seaver Autism Center. 
Patients recruited will have screening prior to trial and will then follow up at 4 weeks, 8 weeks and 12 weeks of
 therapy with growth hormone daily injections. A 4 week post therapy follow up will also be arranged. 
Inclusion criteria: 
Diagnosis: Pathogenic deletions or mutations of the SHANK3 gene confirmed by array CGH and/or direct
 sequencing. 
Age Range: Cases will be between 2 and 12 years old at the time the phenotypic measures were collected. 
Exclusion criteria: 
Cases will be excluded if any of the following criteria are applicable: 
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 VEPs
Drug
Growth hormone is secreted by the somatotrophs of the anterior pituitary gland in a pulsatile manner. It binds to its
 receptor, signaling a cascade of intracellular events which directly stimulated the synthesis and release of IGF-1.
 (Ashpole et al; 2014, Grimberg et al; 2016).
 
Growth hormone is FDA approved for use in children with growth hormone deficiency (including idiopathic [of
 unknown cause] growth hormone deficiency), Turner syndrome, Noonan syndrome, Prader-Willi syndrome, short
 stature homeobox-containing gene (SHOX) deficiency, chronic renal insufficiency, idiopathic short stature and
 children small for gestational age. (https://www.fda.gov/Drugs/DrugSafety/ucm237839.htm)
 
It is available in the form of several commercial preparations. This is typically available as a 10 mg vial to be
 reconstituted with in-package syringe of 1 mL of bacteriostatic water (preserved with 0.33% metacresol), and a 25G
 reconstitution needle.
Drug Administration
Growth hormone will be administered subcutaneously once daily using a 12-week single group design. No placebo
 will be used. The 12-week duration was selected because of our previous trial with IGF-1 showing effects in
 standardized behavior scales in that duration, hence establishing proof of concept. 
The dose of daily growth hormone varies with the indication for therapy. Approved doses of growth hormone range
 from 0.16-0.25mg/kg/week for growth hormone deficient patients (Grimberg et al.; 2016) and up to 0.47 mg/kg/week
 for patients born small for gestational age. 
In our proposed trial, we expect a majority of our patients to be growth hormone sufficient and therefore similar to
 the population of children with idiopathic short stature treated with growth hormone. We will recommend a dose of
 0.15mg/kg/week divided daily for 2 weeks as a starting dose to ensure safety and tolerance. The dose will then be
 increased to 0.3mg/kg/week for 10 weeks, an average growth hormone dose in children with idiopathic short stature.

 The growth hormone dose will be titrated based on IGF-1 levels monitored serially up to a maximum dose of 0.45mg/
kg/week.(http://www.ferringusa.com/wp-content/uploads/2018/07/ZOMACTON-PI-7-18.pdf )
Drug dose is calculated on a mg/kg/week basis. Using Center for Disease Control average Weight-for-age statistics
 in typically developing children ages 2 to 12 years (www.cdc.gov/growthcharts/cdc_charts.htm), the overall average
 weight across a representative sample of males and females in this age range is 24.65kg. 
Average growth hormone dose for weeks 1-2: 0.15mg * 24.65kg per week = 3.7 mg per week
Average growth hormone dose for weeks 3-10: 0.3mg * 24.65kg per week = 7.4 mg per week
With a recruitment target of 20 patients, we anticipate the need for a total of 1628 mg of growth hormone with
 each person requiring about 81 mg of growth hormone in 12 weeks. We anticipate the need for 17 vials of growth
 hormone (10 mg per vial). 
Description of Procedures Being Performed
Description of Phenotypic Measures (See Table 3): 
The phenotypic measures include standardized measures such as history and physical, neurologic exam, treatment
 history, prenatal-perinatal questionnaire as well as the measures listed below. 
Vineland Adaptive Behavior Scale (VABS): The VABS is a semi-structured interview designed to measure personal
 and social sufficiency in individuals from birth to adulthood. It provides a general assessment of adaptive behavior
 within the sub-domains of Communication, Daily Living Skills, Socialization, and Motor Skills. Administration takes
 between 20-60 minutes.  
Description of Outcome Measures:
Parent-Rated Measures 
The Aberrant Behavior Checklist (Aman et al., 1985) is a caregiver report symptom checklist validated and widely
 used for assessing problem behaviors in children and adults with intellectual disability. Fifty-eight specific items are
 rated and a manual provides comprehensive descriptions for each assessed behavior. The 58 items resolve into five
 subscales: Irritability; Lethargy/Social Withdrawal; Stereotypic Behavior; Hyperactivity; Inappropriate Speech. 
The Repetitive Behavior Scale-Revised (Lam and Aman, 2007) is a validated tool that captures the breadth of
 restricted and repetitive behaviors in ASD. The RBS-R has 43 items that resolve into five factors and a total
 score: Ritualistic/Sameness; Stereotypies; Self Injury; Compulsive Behavior; Restricted Interests. The RBS-R is
 a continuous measure of the presence and severity of repetitive behaviors. A total score is generated, with higher
 scores indicating more restricted, repetitive and stereotyped behaviors but each subscale independently shows
 adequate psychometric properties and acceptable reliability and validity.  
The Sensory Profile (Dunn, 1999) is a caregiver questionnaire which measures responses to sensory experiences
 in everyday life. There are 125 items in the full Sensory Profile, and there is a short version which contains 38 items
 commonly used in research settings. Sensory processing subscales on the Short Sensory Profile (SSP) include
 tactile sensitivity, taste/smell sensitivity, visual/ auditory sensitivity, movement sensitivity, low energy/ weak, and
 under-responsivity/seeks sensation. Tactile, smell/taste and visual/auditory sensitivity scores represent a child's
 ability to respond to respective sensory stimuli in the environment. Parents use a Likert scale to rate how frequently
 their child demonstrates a particular behavior (ranging from 1 = always to 5 = never). A lower score indicates greater
 deviation from typically developing children and indicates more sensory reactivity symptoms. 
The Caregiver Top Three Concerns is a Visual Analog Scale rating of severity of the top three causes for concern for
 the caregivers. Caregivers are instructed to identify causes for concern that are related to the individual's PMS.
Clinician-Rated Measures
The PMS Domain Specific Concerns is a Visual Analog Scales that assesses domain specific individualized items
 that are identified as key areas of impairment by caregivers. The domains that are assessed are: Social Withdrawal,
 Repetitive Behaviors, Speech and Language, Anxiety, Motor Performance, Sensory Reactivity, and Cognition. The
 identified concerns should be related to the subject's PMS.
The Clinical Global Impression – Severity of Illness (CGI-S) and Clinical Global Impression – Improvement of Illness
 (CGI-I; Guy, 1976) are brief, easy to administer, clinician-rated measures. The CGI-S asks the clinician to rate the
 patient's current severity of illness based on the clinician's clinical experience with the relevant population. The CGI-
S is rated on a 7-point scale, with a range of responses from 1 (normal, not at all ill) through 7 (amongst the most
 extremely ill patients). The CGI-I asks the clinician to rate the patients' total improvement since baseline, whether
 or not the improvement is judged to be due entirely to the experimental treatment. The CGI-I is rated on a 7-point

 scale, with a range of responses from 1 (very much improved) to 7 (very much worse). For both the CGI-S and the
 CGI-I, the clinician is allowed to use all available information at the time of the rating. The CGI-I has emerged as a
 convention for bifurcating clinical trial subjects into "responders" (i.e. a CGI-I of 1 or 2) and "non-responders" (i.e. a
 CGI-I of 3 to 7) (Busner et al., 2009). In this application, the CGI-I can be a useful tool for gaining a general overview
 of the therapeutic potential of an experimental treatment. We will improve the sensitivity of the CGI-S and –I by using
 anchor points that are specific to the signs and symptoms of FXS and train all sites in the application.
Peabody Picture Vocabulary Test (PPVT): This is a wide-range measure of receptive language for standard English
 that is administered by a clinician to children in the 2-6 age range. It takes 10-15 minutes to administer. 
Objective Measures 
Visual Evoked Potentials (VEPs) provide 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. The major positive and negative
 peaks and troughs in VEP waveforms reflect different cellular events. The contrast-reversing checkerboard stimulus
 used in this study produces a positive peak at approximately 60 ms (P0 or P60), reflecting activation of the primary
 visual cortex from the lateral geniculate nucleus. A negative peak at approximately 75 ms (N0 or N75) reflecting
 depolarization and glutamatergic postsynaptic activity spreading to the superficial layers of primary visual cortex, and
 a positive peak at approximately 100 ms (P1 or P100) reflecting superficial hyperpolarization and GABAergic activity
 (Zemon et al., 1980). VEPs have been used in clinical trials; for example, an antiepileptic drug (gabapentin; Conte
 et al., 2009) and an infant formula (O'Connor et al., 2001); both received FDA approval based in part on positive
 findings from VEP studies. Data from ongoing clinical trials at Mount Sinai provide support for use of VEPs as a
 measure of treatment response. 
Auditory Event Related Potentials (AERPs) are useful for characterizing early processing of auditory tones and
 habituation to rapidly repeated stimuli as in speech processing. Tones are presented in rapid succession (e.g., up
 to every 500 ms) and ERP components to both initial stimulus presentations and their habituation to subsequent
 stimuli (i.e., reduction in amplitude) are examined. Auditory gating waveforms have been well characterized across
 development (Milner at l., 2014; Tremblay et al., 2014; Magnee et al., 2011) and are comprised of a fronto-central
 peak 100 ms after the onset of the auditory stimulus (N1) and a subsequent positive peak (P2) reflecting activity
 in auditory cortex, mesencephalitic reticular activating system, planum temporale, and auditory association cortex
 (Crowley et al., 2004; Godey et al., 2001). The N1-P2 complex reflects two distinct components: initial stimulus
 processing (N1) and subsequent attention to and processing of stimulus information (P2). P2 also has been
 implicated in speech processing (Knowland et al., 2014; Klucharev et al., 2003) suggesting that its analysis may
 be important for understanding neurophysiological mechanisms associated with broader cognitive and language
 developmental dysfunctions in FXS. Recent AERP studies suggest that measures of auditory gating may provide
 a sensitive and selective probe of sensory physiology in FXS (Hall et al., 2009). Individuals with FXS, for example,
 show auditory hypersensitivities consistent with Fmr1KO mouse models of local-circuit hyper-excitability involving
 prolonged "UP" states in the gamma frequency range, decreased glutamatergic drive on fast-spiking GABAergic
 inhibitory neurons in sensory cortex, and heightened neurophysiological response to auditory stimuli (Rotschafer et
 al., 2013). 
The Sensory Assessment for Neurodevelopmental Disorders (SAND) is 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 FXS. The algorithm measures sensory discrete hyperreactivity,
 hyporeactivity, and seeking behaviors across visual, tactile, and auditory domains. The SAND has also been
 validated in ASD with significant correlation to the previously validated Sensory Profile. Results from our preliminary
 data suggest the SAND can identify sensory reactivity subtypes that differentiate FXS and other forms of ASD.
Eye tracking will utilize three tasks to measure attention in general and social attention specifically. (1) The Visual
 Paired Comparison task presents two identical stimuli (faces or patterns) side by side for familiarization. The familiar
 stimulus and a new stimulus are then paired on test and recognition is inferred from preferential looking to the new
 target. (2) The Gap-Overlap task measures the latencies of gaze shifts from a central fixation point to a peripheral
 target are under 2 conditions. During gap trials, the fixation cross disappears prior to the onset of the peripheral cue,
 whereas in the overlap condition, the fixation cross remains on the screen throughout the trial. Saccadic latencies
 are typically greater for overlap than for gap trials since the former requires disengagement of attention in addition to
 orienting to a target (gap effect). (3) Flicker measures the temporal resolution of attention. Four squares that flicker
 from black to white are presented against a grey background. The target square flickers 180 degrees out-of-phase
 from the three distractors. Flickering occurs at 1 of 4 frequencies: 0.2, 0.5, 1, or 2 Hz. A preference for the target
 square indicates phase individuation, which is easier at slower frequencies. Participants are required to look at a
 screen for approximately 10 minutes while images of human faces will be presented and automated assessments of
 time spent looking at socially salient features of test images are recorded.

Description of the Source Records that Will Be Used to Collect Data About Subjects 
Data will be collected from patient's medical records including history and physical examinations, laboratory and
 radiological information and psychiatric evaluations. We use EPIC as electronic medical record system. Patient
 information from the past will also be available on EPIC such as past medical records. A confidential data set
 will be maintained electronically to store patient information with separate study ID's for patients to maintain their
 confidentiality. 
Description of Data that Will Be Collected Including Long-Term Follow-Up
These patients will be followed in the Seaver Autism Center four weeks post therapy and will continue to follow at this
 center if they are patients here. If not, they will return to their primary providers for standard care. 
Research Requires HIV Testing
No
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IRB-18-01272
Initial Application
Swathi Sethuram
13. Procedures - Genetic Testing
Genetic Testing Will Be Performed
No
Guidance and Policies > Future Use Data Sharing and Genetic Research
  
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IRB-18-01272
Initial Application
Swathi Sethuram
14. Procedures - Details
Surveys or Interviews
Yes
Type of Instruments Being Used
Standardized
Names of Standardized Instruments
Vineland Adaptive Behavior Scale (VABS)
Description of Outcome Measures:
Parent-Rated Measures 
The Aberrant Behavior Checklist 
The Repetitive Behavior Scale-Revised (RBS-R)
The Sensory Profile 
The Caregiver Top Three Concerns 
Clinician-Rated Measures
The PMS Domain Specific Concerns 
The Clinical Global Impression – Severity of Illness (CGI-S) and Clinical Global Impression – Improvement of Illness
 (CGI-I) 
Peabody Picture Vocabulary Test (PPVT)
Objective Measures 
Visual Evoked Potentials (VEPs) 
Auditory Event Related Potentials (AERPs) 
The Sensory Assessment for Neurodevelopmental Disorders (SAND) 
Eye tracking 
Audio / Photo / Video Recording
No
Deception
No
Results of the Study Will Be Shared
 with Subjects or Others
No
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IRB-18-01272
Initial Application
Swathi Sethuram
15. Procedures - Compensation
Compensation for Participation
No
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IRB-18-01272
Initial Application
Swathi Sethuram
16. Consent - Obtaining Consent
Consent Process
Parental Permission / Child Assent
Where and When Consent Will Be Obtained
The investigator will describe the protocol to potential subjects' parents/guardians in person, although general
 information and assessment for eligibility can be carried out by phone if necessary. The Informed Consent may be
 read to the subjects' parent/guardians, but, in any event, the investigator or designee shall give the subjects' parents/
guardians ample opportunity to inquire about details of the study and ask any questions before dating and signing the
 Informed Consent Form. The Informed Consent will be created with a level of language fully comprehensible to the
 prospective subjects' parents/guardians. Informed consent will be documented by the use of a written consent form
 approved by the IRB and signed and dated by the subjects' parents/guardians and by the person who conducted the
 informed consent discussion. The signature confirms the consent is based on information that has been understood.
 Each subject's signed informed consent form will be kept on file by the investigator for possible inspection by
 regulatory authorities. The parents/guardians will receive a copy of the signed and dated written informed consent
 form and any other written information provided to the subjects' parents/guardians, and will receive copies of any
 signed and dated consent form updates. Any amendments to the written information will be provided to subjects'
 parents/guardians. 
Waiting Period for Obtaining Consent
Two weeks
SOP HRP-090 Informed Consent
 Process for Research Is Being
 Used
Yes
PPHS Worksheets, Checklists and SOPs
  
Process to Document Consent in
 Writing
Will Use Standard Template
Non-English Speaking Participants
 Will Be Enrolled
No
Justification for Not Enrolling Non-English Speaking Participants
We will have our consenting forms only in English and do not want to enroll participants unable to understand English
 since it will not be fair for them to not have a complete understanding of the study. The various scales being used in
 the study are also available in English. Since this is only a pilot trial with 20 patients, we will enroll English speaking
 patients for this particular trial. 
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IRB-18-01272
Initial Application
Swathi Sethuram
17. Consent - Parental Permission
Permission To Be Obtained From
One Parent
Parental Permission Document
GH Consent version date 02-26-19.docx
Assent To Be Obtained From
None of the Children
Which of the Following Are True
 (Choose At Least One)
The capability of these children is so limited
 that they cannot reasonably be consulted.
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IRB-18-01272
Initial Application
Swathi Sethuram
18. Consent - Documents
Consent Documents
Type
Consent form
Name
Consent for GH PMS trial
Upload
GH Consent version date 02-26-19.docx
Consent Templates
  
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IRB-18-01272
Initial Application
Swathi Sethuram
19. Data - Collection
Health Related Information Will Be
 Viewed, Recorded, or Generated
Yes
Description of Health Information That Will Be Viewed, Recorded, or Generated
We will view, record and generate information on patient's age, clinical status based on physical examination findings,
 laboratory parameters monitored during trial and radiological findings. 
We will also generate and record information on psychological assessments of these patients and their VEP's results
 during the trial. 
Non-Health Related Information Will
 Be Viewed or Recorded
Yes
Description of Non-Health Information That Will Be Viewed or Recorded
Patient's name, demographic information including address, telephone number will be viewed and recorded. 
HIV / AIDS Related Information Will
 Be Viewed or Recorded
No
Data That Will Be Viewed,
 Recorded, or Generated Contains
 ANY of the Following Directly
 Identifiable Information
Yes
Will Be Viewed
Name, Medical Record Number, Address
 by street location, Telephone number,
 All Elements of Dates for Dates Directly
 Related to an Individual (i.e., Birth Date,
 Admission Date, Discharge Date), Email
 Address
Will Be Recorded
Name, Medical Record Number, Address
 by street location, Telephone number,
 All Elements of Dates for Dates Directly
 Related to an Individual (i.e., Birth Date,
 Admission Date, Discharge Date), Email
 Address
Data Collection Sheet
DATA COLLECTION SHEET edited.docx
        
        A Data Collection Sheet is required if you are either performing a retrospective review,
 or your study meets the category of exempt 4 research, or your study meets the category
 of expedited 5 research. Please upload it here.
        
    
Data Collection Source(s)
Participant, Medical Chart (Paper or
 Electronic), Clinical Database
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IRB-18-01272
Initial Application
Swathi Sethuram
20. Data - HIPAA
Obtaining HIPAA Authorization
Yes
How PHI Will Be Protected from Improper Use or Disclosure
Data will be stored in a secure data warehouse which will remain confidential. Only members of the study will have
 access to this information. Patients will be provided with a study ID which will maintain their confidentiality. 
PHI Will Be Destroyed at the
 Earliest Opportunity Consistent
 with the Research
No
Justification for Retaining PHI Indefinitely
This PHI may provide data to establish more long term studies in the field of growth hormone therapy in children with
 genetic forms of autism to look at its impact on their social withdrawal. 
PHI Will Be Shared
No
  PI must attest to the following.
  * I assure that the protected health information (PHI) will not be disclosed to any other
 person or entity not listed on this form except where required by law or for the authorized
 oversight of this research project. If at any time I want to reuse this PHI for other purposes
 or disclose it to other individuals or entities I will seek approval from the IRB. 
  
 
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IRB-18-01272
Initial Application
Swathi Sethuram
21. Data - Storage
Location Where Data Will Be Stored
Research data will be stored on a Microsoft Excel file on a secure server accessed via secure log-ins and passwords
 on hospital computers by the named personnel involved in the study.  Only members of the research team will have
 access to the data. The subject will be identified by study number, and the link between the subject's full name and
 the study number will be stored in a locked room on the 4th floor of the Annenberg building.
How will the data be stored?
With a Code That Can Be Linked to the
 Identity of the Participant
Research Personnel Responsible
 for:
Swathi Sethuram
Accessing Data
Yes
Receipt or Transmission of Data
Yes
Holding Code That Can Be Linked
 to Identity of Participants
Yes
Research Personnel Responsible
 for:
Robert Rapaport
Accessing Data
Yes
Receipt or Transmission of Data
Yes
Holding Code That Can Be Linked
 to Identity of Participants
Yes
Research Personnel Responsible
 for:
Alexander Kolevzon
Accessing Data
Yes
Receipt or Transmission of Data
Yes
Holding Code That Can Be Linked
 to Identity of Participants
Yes
Duration Data Will Be Stored
10 years
Steps That Will Be Taken to Secure the Data During Storage, Use, and Transmission
Data with PHI will only be stored on hospital computers. Data shared outside hospital networks will only have de-
identified information. All data will only be accessible to study personnel. 
Power Analysis/Data Analysis Plan (Including Any Statistical Procedures)
The model for this design is baseline to week 12 change scores. To examine whether electrophysiological markers
 track changes in clinical profiles, we will fit an additional GLMM with VEP values included as a time-varying rather
 than baseline covariate. If treatment effects become less significant it will suggest that GH is acting on clinical
 outcomes through the biomarker. Finally, we will directly correlate week-12 change scores for VEP and clinical
 measures. All tests will use a two-sided # of .05. 
Power Analysis
Power is calculated for differences in baseline to week 12 change scores. Testing for treatment x time interactions
 and # at .05, we have 80% power to detect moderate to large effects. 
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IRB-18-01272
Initial Application
Swathi Sethuram
22. Data - Safety Monitoring
More Than the Minimum Data
 Safety Monitoring Will Be Done
Yes
Principal Monitor
Swathi Sethuram
Additional Monitors
Name
Robert Rapaport
Title
Professor
Department
Pediatrics
Contact Details
Work1 Gustave L. Levy PlaceNew
 YorkNY10029
Type
Team Member
Name
Alexander Kolevzon
Title
Associate Professor of Psychiatry and
 Pediatrics
Department
Psychiatry
Contact Details
WorkOne Gustave L. Levy PlaceNew
 YorkNY10029
Type
Team Member
Specific Items That Will Be Monitored for Safety
Adverse effects from growth hormone administration, subject compliance, drop outs
Frequency of Data Review
Data will be reviewed every 4 weeks during trial and thereafter every 3-6 months. 
Rules for Alteration of Study Design
Not applicable
Selection Procedures to Minimize Toxicity
Growth hormone will be administered subcutaneously once daily using a 12-week single group design. No placebo
 will be used. The 12-week duration was selected because of our previous trial with IGF-1 showing effects in
 standardized behavior scales in that duration, hence establishing proof of concept. 
The dose of daily growth hormone varies with the indication for therapy. Approved doses of growth hormone range
 from 0.16-0.25mg/kg/week for growth hormone deficient patients (Grimberg et al.; 2016) and up to 0.47 mg/kg/week
 for patients born small for gestational age. 
In our proposed trial, we expect a majority of our patients to be growth hormone sufficient and therefore similar to
 the population of children with idiopathic short stature treated with growth hormone. We will recommend a dose of
 0.15mg/kg/week divided daily for 2 weeks as a starting dose to ensure safety and tolerance. The dose will then be
 increased to 0.3mg/kg/week for 10 weeks, an average growth hormone dose in children with idiopathic short stature.
 The growth hormone dose will be titrated based on IGF-1 levels monitored serially up to a maximum dose of 0.45mg/
kg/week.(http://www.ferringusa.com/wp-content/uploads/2018/07/ZOMACTON-PI-7-18.pdf )
Drug dose is calculated on a mg/kg/week basis. Using Center for Disease Control average Weight-for-age statistics
 in typically developing children ages 2 to 15 years (www.cdc.gov/growthcharts/cdc_charts.htm), the overall average
 weight across a representative sample of males and females in this age range is 30kg. 
Average growth hormone dose for weeks 1-2: 0.15mg * 30kg per week = 4.5mg per week = 0.6mg per day
Average growth hormone dose for weeks 3-10: 0.3mg * 30kg per week = 9mg per week = 1.3 mg per day
Grading System to Evaluate Adverse Events
 We will apply NCI-CTCAE criteria for attribution of AE by means of the following descriptors and codes, following the
 NCI guidelines for their application.

unrelated to treatment   1
unlikely related to treatment  2
possibly related to treatment  3
probably related to treatment  4
definitely related to treatment  5
Procedures to Assure Data Accuracy
Data will be stored only by study personnel and will be cross checked twice prior to saving data. 
Suspension Reported to
IRB and GCO
Anticipated Circumstances of Subject Withdrawal
The following criteria will be used to identify possible adverse treatment events, which will indicate the need to halt
 active participation of the subject in the GH study
Withdrawal of Consent PI or any regulatory authority (IRB, or FDA) believe withdrawal is necessary for the subject's
 health, well-being, or best interests.
PI or any regulatory authority believe that withdrawal is necessary for the subject's health, well-being, or best
 interests.
Laboratory: any abnormality on any test with adverse event (AE, Common Terminology Criteria for Adverse Events,
 National Cancer Institute, scales) # 3 or greater at any time in the study.
Any AE of any sort (clinical, laboratory) # 4 will result in halting for the individual and also for the study as a whole.
Primary or Secondary Safety Endpoints
The study will be halted* if two patients experience stopping conditions.  (Exceptions for this criterion: Patients who
 withdraw voluntarily for reasons not directly related to or intrinsic to the study, e.g. incidental considerations such as
 concerns about travel time to study visits, unexpected pregnancy in the family, etc.  Clearly, patients who experience
 adverse effects during growth hormone treatment would count towards this criterion for whole study stopping).
In addition, the study will be halted if one patient experiences a serious related adverse effect (grade # 4 AE).
All safety data will be reported to the IRB, and FDA every six months, or, in the case of any major safety concern or
 question, immediately.  If any study stopping condition occurs, this will be reported immediately and the study halted,
 pending review by  IRB, and FDA, and until the decision by regulatory authorities to resume, suspend or close the
 study has been made.
*Operationally, "halting" will ordinarily mean that no further screening of new subjects and no treatment initiation will
 occur until the safety issue has been investigated and resolved (i.e., a final decision has been made to resume,
 suspend or close the study has been made).  Enrolled study participants who have no new symptoms or adverse
 effects will ordinarily be allowed to continue study observation or treatment without interruption while the safety issue
 is being investigated, unless it is the contemporaneous judgment of the PI or subsequent judgment of the IRB, or
 FDA that it is unsafe to do so, in which case all observation or treatment interventions will be suspended forthwith.
Data Monitoring Committee
 Description
Data Monitoring Committee.docx
DMC Charter Available
No
Will the Research Include Data
 Coordinating Center Activities?
No
Page 32 of 40

IRB-18-01272
Initial Application
Swathi Sethuram
23. Funding
Funding Source Name
Seaver Foundation
Contact
Funding Category
Foundation
Meditrack (https://
contracts.tractmanager.com/
Contracts/Login.aspx)
Meditrack (https://contracts.tractmanager.com/Contracts/Login.aspx)
Grant or Contract Title
An Open Label Trial of Growth Hormone in Children and Adolescents with Phelan-
McDermid Syndrome Targeting Social Withdrawal and Repetitive Behavior
Grant or Contract 
 Number
Funding Status
Funded
Project Initiated By
Investigator
Grant / Contract Principal
 Investigator (PI)
Swathi Sethuram
Department
Pediatrics
Department
Pediatrics
Phone
Email
swathi.sethuram@mountsinai.org
Protocol and Funding
 Proposal Match
Yes
Identify Substantive
 Differences Between
 Protocol and Funding
 Proposal
Page 33 of 40

IRB-18-01272
Initial Application
Swathi Sethuram
24. Radiation Safety
Study protocol involves any of the
 following Radiological Procedures
 requiring use of Dosimetry Chart
Yes
          
         * Radiological procedures that are administered in addition to those that the
 participant would receive as part of standard care (radiation above and beyond standard of
 care) 
         * Radiological procedures that are administered solely for experimental or research
 purposes (would NOT be otherwise administered) 
         * Standard of care radiological procedures that are being altered or performed
 differently for research 
         * Use of radiological procedures that are the subject of the investigation (comparison
 studies) 
          
      
            Dosimetry Chart
            Please fill out the chart and attach it below.
        
Dosimetry Chart
DOSIMETRY.xlsx
Study protocol involves any of the
 following Radiological Procedures
No
          
         * Use of an investigational radiopharmaceutical, or use of an approved
 radiopharmaceutical for an investigational purpose 
            * Use of investigational radiotherapy, or use of approved radiotherapy for an
 investigational purpose 
            * Use of fluoroscopy 
            * Radiation exposure to children or pregnant women 
            * Radiation exposure to healthy subjects (ADULTS) 
            * Use of an investigational radiologic device (such as an experimental scanner), or
 use of an approved device for an investigational purpose 
          
      
Study protocol involves any of
 the following Standard of Care
 Radiological Procedures (including
 projects where discrete Standard
 of Care Imaging is acquired in
 addition to Research Imaging)
Yes
          
            * CT imaging 
         * Nuclear medicine 
         * Radiography 
         * Fluoroscopy 
         * Radiation-based therapy 
         * PET/CT 
          
      

Page 35 of 40

IRB-18-01272
Initial Application
Swathi Sethuram
25. Drugs / Biologics
Study Fund Account (or
 alternate departmental /
 fund account, if study is
 not yet established)
Generic Name
Recombinant Human Growth Hormone (Somatropin)
Brand Name
Uncertain at this point
Drug Has Valid IND
No
For each drug / biologic with an IND number, ensure that the application includes one
 of the following. * Sponsor protocol with the IND number. * Communication from the
 sponsor or the FDA with the IND number.
IND Number
Name of IND Holder
Type of IND Holder
Drug Meets One of the
 Following Categories for
 Exemption
Yes
Category 1: * The drug is lawfully marketed in the United States. * The research is
 not intended to be reported to the FDA as a well-controlled study in support of a new
 indication for use nor intended to be used to support any other significant change
 in the labeling for the drug. * The research is not intended to support a significant
 change in the advertising for the product. * The research does not involve a route
 of administration or dosage level or use in a patient population or other factor that
 significantly increases the risks (or decreases the acceptability of the risks) associated
 with the use of the drug. * The research is conducted in compliance with the marketing
 limitations described in 21 CFR §312.7. Category 2: * A clinical investigation for an
 in vitro diagnostic biological product that involves one or more of the following: (1)
 Blood grouping serum; (2) Reagent red blood cells; or (3) Anti-human globulin. * The
 diagnostic test is intended to be used in a diagnostic procedure that confirms the
 diagnosis made by another, medically established, diagnostic product or procedure.
 * The diagnostic test is shipped in compliance with 21 CFR §312.160. Category 3:
 * A clinical investigation involving use of a placebo when the investigation does not
 otherwise require submission of an IND.
Category for Exemption
Category 1
Justification for Meeting
 Criteria
Growth hormone is FDA approved for use in children with growth hormone deficiency
 (including idiopathic [of unknown cause] growth hormone deficiency), Turner syndrome,
 Noonan syndrome, Prader-Willi syndrome, short stature homeobox-containing gene
 (SHOX) deficiency, chronic renal insufficiency, idiopathic short stature and children
 small for gestational age. (https://www.fda.gov/Drugs/DrugSafety/ucm237839.htm) This
 research is intended as a pilot clinical trial to look at social withdrawal and repetitive
 behavior in children with PMS and not as a new indication for GH treatment. Our study
 population will not have growth hormone administered for any of the FDA approved
 indications. The results of this study may warrant further such studies in the future. The
 dose of daily growth hormone varies with the indication for therapy. Approved doses
 of growth hormone range from 0.16-0.25mg/kg/week for growth hormone deficient
 patients (Grimberg et al.; 2016) and up to 0.47 mg/kg/week for patients born small for
 gestational age. In our proposed trial, we expect a majority of our patients to be growth
 hormone sufficient and therefore similar to the population of children with idiopathic
 short stature treated with growth hormone. We will recommend a dose of 0.15mg/
kg/week divided daily for 2 weeks as a starting dose to ensure safety and tolerance.
 The dose will then be increased to 0.3mg/kg/week for 10 weeks, an average growth
 hormone dose in children with idiopathic short stature. We will obtain an exemption
 from the FDA IND for the use of growth hormone in this study. Neither the patients nor
 their insurances will be charged for growth hormone. The medication will be funded by
 the study and provided to families to administer daily at home.

To be a coordinating center, the Mount Sinai investigator is the Principal Investigator for
 multi-site participation in the trial. The Investigational Drug Service (IDS) may support
 trials as the coordinating center. IDS services include but are not limited to randomizing
 for other sites, storing and shipping drugs to participating sites, etc.
Icahn School of Medicine
 at Mount Sinai (ISMMS)
 Is the Coordinating
 Center
Yes
Role of the
 Investigational Drug
 Service (IDS)
Not applicable, single center study
Drug / Biologic
 Description
 (Manufacturer/Generic
 Name/Form/Strength)
Somatropin/recombinant Human Growth Hormone as a subcutaneous injection,
 typically sold commercially as 10mg/vial
Controlled Substance
No
Schedule
In order for the Icahn School of Medicine at Mount Sinai (ISMMS) to be compliant with
 the regulations regarding controlled substance research, a New York State Department
 of Health-issued Researcher license and DEA-issued Researcher Registration Number
 must be on file for each trial using controlled substances. The Investigational Drug
 Service maintains these licences and will make them available to our investigators to
 support our research. Refer to www.health.state.ny.us/professionals/narcotic and http://
firstclinical.com/journal/2011/1112_DEA.pdf for more information.
Using Investigational
 Drug Service (IDS)
 Research License
Use of this Drug /
 Biologic Is Considered
 Standard of Care
No
Requested Pharmacy
 Services
Dispensation, Storage, Label
Specify Other Requested
 Pharmacy Services
Drug / Biologic Will Be
 Supplied By
Commercially Available/Sourced by Hospital
Specify Other Drug /
 Biologic Supplier
Using Placebo
No
Placebo Will Be Supplied
 By
Compounding Required
 (Paid for by Study
 Funds)
Where Drug / Biologic
 Will Be Administered
Outpatient Clinic
Specify Location of
 Private Office
Storage Requirements of
 Drug / Biologic
Refrigerated (2-8°C)
Where Drug / Biologic
 Will Be Stored
Patients Own Supply
ALL of the Following
 Storage Criteria Are Met
* The storage area is well maintained, provides adequate lighting, ventilation, sanitation,
 space and security. * The temperature in the storage area is controlled and monitored
 using calibrated monitoring devices. * The temperature monitoring system has sensors

 for continuous monitoring and alarms set at the points representing the temperature
 extremes. * Records of temperatures and alarms are maintained and all excursions
 outside the labeled storage conditions are appropriately investigated and reported to
 the sponsor.
Justification Why Any
 of the Above Storage
 Criteria Cannot Be Met
ALL of the Following
 Distribution Criteria Are
 Met
* The investigator will not dispense the investigational agent to any person not
 authorized under the protocol to receive it. * The drug, agent, biologic may only be
 used in subjects under the investigators personal supervision or under the supervision
 of a physician who is directly responsible to the investigator. * The investigator will
 maintain adequate records for the receipt, storage, and disposition of the drug,
 including dates, quantity, and use by subjects. * The investigational agents will be
 stored in a secure area and in such a way to restrict access to authorized personnel
 only as defined in the protocol. Additionally, all associated records will be stored in a
 restricted area and/or locked.
Justification Why Any of
 the Above Distribution
 Criteria Cannot Be Met
Page 38 of 40

IRB-18-01272
Initial Application
Swathi Sethuram
26. Financial Administration
  This information will help the Financial Administration of Clinical Trials Services (FACTS)
 office determine whether a Medicare Coverage Analysis (MCA) is needed for the research
 study. If you have any questions while completing this form, please contact the FACTS
 office at (212) 731-7067 or FACTS@mssm.edu.
  
 
Clinical Research Study Category
Investigator Initiated
  Payment Options: 
  * Option 1:  No protocol-required services will be billed to patients or third-party payers.
 Does Not Need MCA 
  * Option 2:  Protocol-required services (i.e., routine care services) will be billed to patients
 or third-party payers. Must Have MCA 
  * Option 3:  Study is initiated and federally funded by a Government Sponsored
 Cooperative Group who will only pay for services that are solely conducted for research
 purposes and other protocol-required services (i.e., routine care services) will be billed to
 patients or third-party payers. Billing Grid Only Required, NO MCA 
  * Option 4:  Study involves only data collection and has no protocol-required clinical
 services. Does Not Need MCA 
  * Option 5:  Study is not described in any of the above options. Please describe the study
 and specify whether External Sponsor (i.e., industry, government, or philanthropic source)
 and/or patient/third party payer will pay for protocol required services. MCA MAY Be
 Required 
  
 
Payment Option
Option 1
  
  No MCA is needed per option selected above. 
  
 
  
  Payment Option 1: 
  * Option 1A:  Department/collaborating departments will act as internal sponsor paying for
 all protocol-required services and no protocol-required services will be billed to patients or
 third party payers. 
  * Option 1B:  Study involves protocol-required clinical services and an External Sponsor
 (i.e., industry, government, or philanthropic source) will pay for all protocol-required
 services. 
  
 
Payment Option 1
Option 1A
Page 39 of 40

IRB-18-01272
Initial Application
Swathi Sethuram
27. Attachments
Type
Name
Version Status
Filename
Uploaded
 Date
FDA - Package Insert
 for Approved Drug
Package Insert for
 Zomacton
1
New
ZOMACTON
 Somatropin Package
 insert.pdf
11/14/2018
FDA - Other
 Materials
Kolevzon IGF-1 trial
 performed at ISMMS
1
New
IGF-1 in PMS clinical
 trial.Kolevzon.pdf
11/14/2018
Consent Documents
GH consent.docx
1
New
GH Consent version
 date 02-26-19.docx
02/26/2019
Data Collection Sheet DATA COLLECTION
 SHEET edited.docx
1
New
DATA COLLECTION
 SHEET edited.docx
11/15/2018
Other - Other IRB
 Correspondance
Research Plan
 PDF.pdf
1
New
Research Plan PDF
 12.3.18.pdf
12/03/2018
Parental Permission
 Document
GH consent.docx
1
New
GH Consent version
 date 02-26-19.docx
02/27/2019
Data Monitoring
 Committee
 Description
Data Monitoring
 Committee.docx
1
New
Data Monitoring
 Committee.docx
11/15/2018
Package Insert
 Document (DRUG
 NAME)
ZOMACTON
 Somatropin Package
 insert.pdf
1
New
ZOMACTON
 Somatropin Package
 insert.pdf
11/15/2018
Advertisement -
 Website text/Screen
 shots/URLs
Ad for websites
1
New
Ad.docx
12/03/2018
Dosimetry Chart
DOSIMETRY.xlsx
1
New
DOSIMETRY.xlsx
01/17/2019
Other - Other IRB
 Correspondance
Correspondance
 regarding dosimetry
1
New
Radiation dosimetry
 correspondance.pdf
01/17/2019
FDA - FDA or
 Manufacturer Risk
 Determination
FDA IND exemption
1
New
FDA IND
 exemption.pdf
02/06/2019
 
Page 40 of 40