Guanfacine for Hyperactivity in Children With Down Syndrome (HYPEbeGONE_DS)
Phase: PHASE2
Conditions: Hyperactivity in Children With Down Syndrome, Impulsivity in Children With Down Syndrome
Sponsor: Rachel G. Greenberg, MD, MB, MHS

 
Guanfacine for Hyperactivity in Children with Down Syndrome 
(HYPEbeGONE_DS) 
NCT number 06042257 
Document Date 08/29/2023 
 

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Pediatric Trials Network: 
Best Pharmaceuticals for Children Act 
 
Guanfacine for Hyperactivity in Children with Down Syndrome 
(HYPEbeGONE_DS) 
 
NICHD-2020-HYP01 
 
Phase: 2 
 
Funding Sponsor: 
The Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD) 
 
Funding Mechanism: Task Order 
Protocol Date: 
29AUG2023 
Protocol Version: 
3.0  
IND Number: 
154035 
NCT Number: 
 
06042257  
 
Principal Investigator: 
 
Rachel G. Greenberg, MD, MHS 
Associate Professor of Pediatrics,  
Department of Pediatrics,  
Division of Neonatal-Perinatal Medicine 
Duke University School of Medicine 
Duke Clinical Research Institute 
DUMC 102509  
Durham, NC 27710  
Phone: 919.668.4725 
Fax: 919.681.2714 
E-mail: rachel.greenberg@duke.edu  
 
 
 

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STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, International Council for Harmonisation 
(ICH) E6(R2) guideline for Good Clinical Practice (GCP), and the applicable regulatory 
requirements from the United States Code of Federal Regulations (CFR), including 45 CFR 
46 (Human Subjects Protection); 21 CFR 312 (Investigational New Drug); 21 CFR 50 (Informed 
Consent), 21 CFR Part 54 (Financial Disclosure), and 21 CFR 56 (Institutional Review Board [IRB]); 
as well as international regulatory requirements, if applicable. 
All individuals who are responsible for the conduct, management, or oversight of this study have 
completed Human Subjects Protection and ICH GCP Training. 
 

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SITE PRINCIPAL INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and the investigator brochure or package 
insert/product label, and I agree that the protocol contains all necessary details for my staff and me 
to conduct this study as described. I will personally oversee the conduct of this study as outlined 
herein and will make a reasonable effort to complete the study within the time designated. I agree to 
make all reasonable efforts to adhere to the attached protocol. 
I will provide all study personnel under my supervision with copies of the protocol and access to all 
information provided by the sponsor or the sponsor’s representative. I will discuss this material with 
study personnel to ensure that they are fully informed about the efficacy and safety parameters and 
the conduct of the study in general. I am aware that, before beginning this study, the institutional 
review board (IRB), Research Ethics Board (REB) or Independent/ Institutional Ethic Committee 
(IEC) responsible for such matters must approve this protocol in the clinical facility where it will be 
conducted. 
I agree to either obtain informed consent from participants, or obtain a waiver of informed consent 
(applicable to minimal risk studies only), as required by the IRB/REB/IEC of record and according to 
government regulations and International Council for Harmonisation guidelines. I further agree to 
report to the sponsor or its representative any adverse events in accordance with the terms of this 
protocol and the U.S. Code of Federal Regulations, Title 21, part 312.64, ICH GCP 4.11, as well as 
international regulatory requirements, if applicable. I further agree to ensure the study is conducted 
in accordance with the provisions as stated and will comply with the prevailing local laws and 
customs. 
 
 
 
 
 
Site Principal Investigator Name (Print)  
 
 
 
 
 
 
Site Principal Investigator Signature 
 
Date 
 
 

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STUDY PRINCIPAL INVESTIGATOR AND IND SPONSOR 
SIGNATURES 
The signature below documents the review and approval of this protocol and the attachments (e.g., 
Manual of Procedures (MOP), package inserts), and provides the necessary assurances that this 
clinical study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality and according to local legal and regulatory requirements and to the 
principles outlined in applicable U.S. and international regulations and ICH guidelines. 
 
 
Pediatric Trials Network Study Principal 
Investigator Name (Print or Type) 
Pediatric Trials Network Study PI Signature 
Date 
IND Sponsor (if different from above) 
IND Sponsor’s Signature 
Date 
 
 

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TABLE OF CONTENTS 
 
STATEMENT OF COMPLIANCE ............................................................................................... ii 
SITE PRINCIPAL INVESTIGATOR STATEMENT .................................................................... iii 
STUDY PRINCIPAL INVESTIGATOR AND IND SPONSOR SIGNATURES ............................ iv 
TABLE OF CONTENTS ............................................................................................................. v 
LIST OF TABLES ...................................................................................................................... ix 
LIST OF ABBREVIATIONS ........................................................................................................ x 
PROTOCOL HISTORY OF CHANGES ................................................................................... xiii 
PROTOCOL SYNOPSIS .......................................................................................................... xv 
SCHEMATIC/DESCRIPTION OF STUDY DESIGN ............................................................... xviii 
1 
KEY ROLES ...................................................................................................................... 1 
2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .................................... 3 
 
Background Information .......................................................................................... 3 
 
Background of Attention-Deficit/Hyperactivity Disorder (ADHD) in Down 
Syndrome (DS) ........................................................................................... 3 
 
Pediatric Labeling of Guanfacine................................................................. 5 
 
Scientific Rationale ................................................................................................. 5 
 
Potential Benefits .................................................................................................... 6 
 
Known Potential Risks ............................................................................................ 6 
 
Risks of Blood Drawing ............................................................................... 6 
 
Risks of Guanfacine Hydrochloride ............................................................. 6 
 
Potential Risk of Loss of Confidentiality....................................................... 6 
 
Unforeseen Risks ........................................................................................ 6 
3 
OBJECTIVES AND OUTCOME MEASURES .................................................................... 7 
4 
STUDY DESIGN ................................................................................................................ 8 
 
Overall Design ........................................................................................................ 8 
 
Study Design .......................................................................................................... 8 
 
Randomization ............................................................................................ 8 
 
Masking/Unmasking .................................................................................... 8 
 
Study Intervention ................................................................................................... 8 
 
Duration of Participant Participation ........................................................................ 8 
 
Biological Specimen Collection ............................................................................... 9 
 
Biological Specimen Retention Plan ....................................................................... 9 
 
Safety ..................................................................................................................... 9 
 
Scientific Rationale for Study Design ...................................................................... 9 
 
Rationale for Dose Selection .................................................................................. 9 
 
Study Definition of Enrollment into Active Study ................................................... 10 

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Study Definition of Completion .............................................................................. 10 
5 
STUDY POPULATION..................................................................................................... 11 
 
Selection of the Study Population ......................................................................... 11 
 
Inclusion/Exclusion Criteria ................................................................................... 11 
 
Screen Failures .................................................................................................... 13 
 
Treatment Assignment Procedures....................................................................... 13 
 
Randomization Procedures ....................................................................... 13 
 
Participant Discontinuation/Withdrawal ................................................................. 13 
 
Participant/Parent/Legal Guardian Decides to Withdraw Consent ............. 13 
 
Participant/Parent/Legal Guardian Decides to Withdraw from Study Product13 
 
Study Investigator/Sponsor Decides to Withdraw Participant .................... 13 
 
Handling of Withdrawals ....................................................................................... 14 
 
Early Withdrawal/Discontinuation Assessments ........................................ 14 
 
Replacements ........................................................................................... 14 
6 
STUDY PROCEDURES ................................................................................................... 15 
 
Summary of Procedures ....................................................................................... 15 
 
Screening (Day -29 to 0) ....................................................................................... 16 
 
Study Intervention (Day 1 to 56 ± 3 days) ............................................................. 16 
 
GIR Taper/Bridge (Up to 6 days post last study product administration) ............... 18 
 
Telephone Safety Follow-up (5 + 2 days after final study product administration) . 18 
 
Early Withdrawal / Termination Visit ..................................................................... 18 
 
Laboratory Evaluations ......................................................................................... 19 
 
Pharmacokinetic Specimens ..................................................................... 19 
 
Clinical Laboratory Determinations ............................................................ 19 
 
Dose Escalation Assessments .............................................................................. 20 
 
Clinical Outcome Assessments ............................................................................ 20 
 
Aberrant Behavioral Checklist (ABC) ........................................................ 21 
 
Sleep Assessments................................................................................... 21 
 
CGI-Severity for Eligibility and CGI-Improvement for Improvement ........... 21 
6.10 
Ask Suicide-Screening Questions (asQ) Tool ....................................................... 21 
 
Specimen Preparation, Handling, Storage, and Shipping ..................................... 22 
 
Study Product Description .................................................................................... 22 
6.13 
Dosage and Study Drug Information ..................................................................... 22 
 Dose Timing .............................................................................................. 22 
 Dose Discontinuation /Taper ..................................................................... 23 
 Formulation, Packaging, and Labeling ...................................................... 23 
 Product Storage and Stability .................................................................... 24 
 
Preparation and Administration of Study Product .................................................. 24 
 
Modification of Study Product for a Participant ..................................................... 24 
 
Accountability Procedures for the Study Product(s) .............................................. 24 
 Replacement Kits ...................................................................................... 24 
 Disposition of Study Products Upon Study Completion or Expiration ........ 24 

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Concomitant Medications of Interest/Treatments .................................................. 24 
7 
ASSESSMENT OF SAFETY............................................................................................ 25 
 
Adverse Events .................................................................................................... 25 
 
Unexpected Adverse Event ....................................................................... 25 
 
Safety Events of Special Interest (ESIs) .................................................... 25 
 
Guidelines for Determining Seriousness ............................................................... 26 
 
Guidelines for Assessing Intensity ........................................................................ 26 
 
Guidelines for Assessing Causality ....................................................................... 26 
 
Collection Period and Reporting Procedures ........................................................ 26 
 
Safety Event Follow up and Sponsor Reporting .................................................... 27 
 
Pregnancy ................................................................................................. 27 
 
Regulatory Reporting ............................................................................................ 28 
 
Data & Safety Oversight (Medical Monitor/Data Safety Monitoring Board) ............ 28 
8 
STUDY HALTING/TERMINATION................................................................................... 30 
 
Study or Site Halting Criteria/Termination Criteria ................................................. 30 
 
Halting Rules ........................................................................................................ 30 
9 
CLINICAL MONITORING ................................................................................................ 31 
10 
STATISTICAL CONSIDERATIONS ................................................................................. 32 
 
Study Hypotheses ................................................................................................ 32 
 
Study Endpoints ................................................................................................... 32 
 Primary Endpoint ...................................................................................... 32 
 Secondary Endpoints ................................................................................ 32 
 Exploratory Endpoints ............................................................................... 32 
 
Analysis Population .............................................................................................. 33 
 Intention-to-Treat (ITT) Population ............................................................ 33 
 Per-Protocol Population ............................................................................ 33 
 PK Population ........................................................................................... 33 
 Safety Population ...................................................................................... 33 
 Efficacy Population ................................................................................... 33 
 
Analysis Plan ........................................................................................................ 33 
 Primary Analysis ....................................................................................... 33 
 Secondary Analysis................................................................................... 34 
 Exploratory Analysis .................................................................................. 34 
 
Demographics and Baseline Characteristics ......................................................... 35 
 
Sample Size Considerations ................................................................................. 36 
11 
FUTURE USE OF STUDY RECORDS AND BIOLOGICAL SPECIMENS ....................... 37 
12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................. 38 
13 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 39 
14 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS ..................................................... 40 
 
Informed Consent Process ................................................................................... 40 

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 Permission from Parents, Legal Guardians, or Legally Authorized 
Representatives ........................................................................................ 40 
 Pediatric Assent ........................................................................................ 41 
 
Assent Process..................................................................................................... 41 
 
Documentation of Permission, Assent, and Consent ............................................ 41 
 
Confidentiality and Privacy ................................................................................... 42 
15 
DATA HANDLING AND RECORD KEEPING ................................................................. 44 
 
Data Handling ....................................................................................................... 44 
 
Data Management Responsibilities....................................................................... 44 
 
Data Capture Methods .......................................................................................... 44 
 
Types of Data ....................................................................................................... 44 
 
Timing/Reports ..................................................................................................... 45 
 
Study Records Retention ...................................................................................... 45 
 
Protocol Deviations ............................................................................................... 45 
16 
PUBLICATION POLICY .................................................................................................. 46 
17 
LITERATURE REFERENCES ......................................................................................... 47 
 
 

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LIST OF TABLES 
Table 1. Schedule of Study Procedures and Assessments .............................................................15 
Table 2. Frequency of measures and who completes each measure. .............................................21 
Table 3. Dose Escalation Plan* .......................................................................................................23 
Table 4. Distribution of CGI-I for Secondary Efficacy Outcome Measure ........................................34 
Table 5. Distribution of Scales for Exploratory Outcome Sleep Quality Measures (CSHQ and ESS-
CHAD) ............................................................................................................................................35 
 
 
 

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LIST OF ABBREVIATIONS 
ABC 
Aberrant Behavior Checklist 
ABC-H 
Aberrant Behavior Checklist Hyperactivity Subscale 
ADHD 
Attention-Deficit/Hyperactivity Disorder 
AE 
Adverse Event 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, Accurate, Complete 
ALT 
Alanine Transaminase 
AR 
Aortic Regurgitation  
ASD 
Autism Spectrum Disorder 
asQ 
Ask Suicide-Screening Questions 
AST 
Aspartate Transaminase 
AUC 
Area Under the Concentration Time Curve 
AUCss/F 
Apparent AUC Versus Time Curve at Steady State 
BID 
Twice Daily 
BMI 
Body Mass Index 
BMP 
Basic Metabolic Panel 
BP 
Blood Pressure 
BPCA 
Best Pharmaceuticals for Children Act 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression Improvement 
CGI-S 
Clinical Global Impression Severity 
CLss/F 
Apparent Clearance 
Cmax,ss 
Steady State Peak Drug Concentration 
Cmin,ss 
Minimum Concentration  
CMSU 
Clinical Materials Services Unit 
CNS 
Central Nervous System 
CoC 
Certificate of Confidentiality 
CPAP 
Continuous Positive Airway Pressure 
CSHQ 
Child’s Sleep Habits Questionnaire 
DASH 
NICHD’s Data and Specimen Hub 
DCC 
Data Coordinating Center 
DCRI 
Duke Clinical Research Institute 
DSMB 
Data Safety Monitoring Board 
DS 
Down Syndrome 
DUHS 
Duke University Health System 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram  
EDC 
Electronic Data Capture e.g., Emmes Advantage eClinical® 
ePRO 
Electronic Participant Reported Outcomes 
ER 
Exposure-Response 
ESI 
Event of Special Interest 
ESS-CHAD 
Epworth Sleepiness Scale for Children and Adolescents 
FDA 
Food and Drug Administration 
FWA 
Federal-Wide Assurance 

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GCP 
Good Clinical Practice 
GER 
Guanfacine Extended Release 
GIR 
Guanfacine Immediate Release 
GMP 
Good Manufacturing Practice 
HCl 
Hydrochloride 
HDPE 
High Density Polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart rate  
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identification  
IDD 
Intellectual or Developmental Disability 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
Kg 
Kilogram 
LAR 
Legally Authorized Representative  
LFT 
Liver Function Tests 
MedDRA  
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mL 
Milliliter 
MM 
Medical Monitor 
MOP 
Manual of Procedures 
NIH 
National Institutes of Health 
NICHD 
National Institute of Child Health and Human Development 
OAHI 
Obstructive Apnea Hypopnea Index 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PO# 
Masked Packaging Code 
PP 
Polypropylene  
PTN 
Pediatric Trials Network 
q.h.s 
Every night at bedtime 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
Standard of Care 
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction 
Tmax,ss 
Time at Peak Concentration 
TORO 
Transfer of Regulatory Obligations 
TSH 
Thyroid Stimulating Hormone 
t1/2 
Half-life 
UIP 
University of Iowa Pharmaceuticals 

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ULN 
Upper Limit of Normal 
USP/NF 
United States Pharmacopeia and National Formulary 
V/F 
Volume of Distribution 
WBC 
White Blood Cell 
WGS 
Whole Genome Sequencing 
 
 

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PROTOCOL HISTORY OF CHANGES 
Version 
Date 
Summary of Changes 
v1.0 
27FEB2023 
N/A Original protocol 
v2.0 
23MAY2023 
HR and BP assessment were added prior to each 
dose escalation.  
Updated study design to indicate that participants will 
be given a FDA cleared device for parent/legal 
guardian to measure HR and BP remotely. 
Added definition of HR and BP criteria that would 
prevent dose escalation. 
Decreased HR and decreased BP were added as 
risks of Guanfacine Hydrochloride. 
HR and BP criteria were initially listed as ESIs to 
only be assessed at in-persion visits (Week 4 and 
Week 8). They have now been moved to the general 
list of Safety ESIs. 
References and Table of Contents (TOC) were 
updated accordingly. 
v3.0 
29AUG2023 
Added IND Number  
Updated number of sites to approximately 17 sites.  
Updated Exclusion Criteria to include any changes to 
another medication used to treat symptoms of 
hyperactivity, inattention and impulsivity within 
2 weeks.  
Updated to indicate that the HR/BP device would be 
distributed at Day 1 (randomization) instead of at 
Screening. 
Added clarification that parents would need to 
complete the Study Diary during the bridge/taper 
period for those who are in the GIR arm. 

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Updated definition of asQ from 
Ask-Suicidal-Screening Questions to Ask 
Suicide-Screening Questions. 
Updated to indicate contraception is allowed but not 
required.  
Specific references to pharmacy or pharmacist were 
removed and kept vague as site or clarified as 
pharmacist (or designee).  
Changed concomitant medications to concomitant 
medications of interest. 
Changed Study Product Diary to Study Diary since 
HR/BP was added to it. 
Updated the definition of the efficacy population. 
References and TOC were updated accordingly. 
 
 

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PROTOCOL SYNOPSIS 
Protocol Title: 
Guanfacine for Hyperactivity in Children with Down Syndrome 
(HYPEbeGONE_DS) 
NCT #: 
06042257 
Phase: 
Phase 2 
Study Product(s) or 
Intervention: 
Guanfacine hydrochloride, Immediate Release  
Objectives: 
Primary: 
1. Determine efficacy of guanfacine immediate release (GIR) for 
the treatment of hyperactivity/impulsivity and inattention in 
children with Down syndrome (DS) after 8 weeks of treatment. 
Secondary: 
1. Characterize the safety profile of GIR in children with DS. 
Exploratory: 
1. Characterize GIR exposure in children with DS. 
2. Characterize the exposure-response relationship of GIR for 
the treatment of hyperactivity/impulsivity, inattention, and 
sleep quality in children with DS. 
Study Design: 
Prospective, multi-center, randomized, double-masked, 
placebo-controlled, flexibly-dosed trial  
Study Population: 
Children ages 6-12 years old with DS 
Inclusion Criteria: 
1. Parent/Legal Guardian can understand the consent process 
and is willing to provide informed consent/HIPAA authorization 
prior to the conduct of any study related procedures. When 
applicable, the minor participant is willing to provide assent. 
2. Participant has clinical diagnosis of non-mosaic DS. 
3. Participant is between 6 and 12 years of age (inclusive) at 
time of consent. 
4. Participant weight is ≥ 25 kg. 
5. Participant has clinically significant symptoms of hyperactivity, 
inattention and impulsivity manifested as minimum scores on 
both of the following rating scales within 30 days of 
randomization: 
a. A minimum score of 18 on the parent-reported Aberrant 
Behavior Checklist - Hyperactivity (ABC-H) subscale, AND 
b. A minimum score of moderate or greater (≥ 4) on the 
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(CGI-S) score specific to hyperactivity, inattention, and 
impulsivity behaviors. 
6. Participant has co-morbid medical screening and clearance to 
proceed with a non-stimulant medication trial with GIR within 
30 days of randomization. 
7. Participant is willing and able to comply with study 
procedures, including adherence to medication dosing 
schedule.  
Exclusion Criteria: 
1. Participant has received guanfacine (any formulation) within 
30 days of randomization. 
2. Participant has received any of the following concomitant 
medication classes within 30 days of randomization:  
a. Strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, and voriconazole) 
b. Strong CYP3A4 inducers (e.g., avasimibe, 
carbamazepine, phenytoin, rifampin, and St. John’s wort)  
3. Participant has a psychiatric comorbidity, such as major 
depressive disorder, bipolar disorder, obsessive-compulsive 
disorder, or a psychotic disorder, that requires a 
pharmacological treatment other than guanfacine. 
4. For participants ≥ 8 years old at the time of consent, 
participant has a history of suicidality or positive screen on 
Ask Suicide-Screening Questions (asQ) Tool. 
5. Participant is currently in or plans to participate in another 
interventional study. 
6. Participant has a known hypersensitivity to guanfacine. 
7. Participant has had a previous guanfacine treatment failure, 
as determined by their primary treating physician. 
8. Participant has had a change in another medication intended 
to treat symptoms of hyperactivity, inattention, and impulsivity 
within the last 2 weeks. 
9. Participant has had a seizure within the last 6 months. 
10. Participant has had a change in their anti-convulsant dose 
within the last 4 weeks. 
11. Participant has a cardiac-related condition including: 
a. Significant symptomatic bradycardia;  
b. 2nd degree or 3rd degree (complete) heart block; 

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c. Baseline heart rate (HR) or systolic blood pressure (BP) > 
2 standard deviations (SD) below mean for age as 
determined by medical examination; 
d. History of aborted sudden cardiac death, unexplained 
syncope or near syncope, or historical use of a pacemaker 
as determined by medical history will require clearance by 
cardiology prior to enrollment; 
e. Known history of congenital heart disease which requires 
ongoing care for monitoring or management will require 
clearance by cardiology prior to enrollment.  
12. Participant has a history of untreated severe obstructive sleep 
apnea defined as obstructive apnea hypopnea index (OAHI) ≥ 
10 events per hour or aortic regurgitation (AR). Participants 
with an OAHI index >10/hr are eligible if managed with 
continuous positive airway pressure (CPAP). 
13. Participant has untreated thyroid disease. 
14. Participant has a known hepatic impairment defined as 
aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >2x the upper limit of normal (ULN) 
for age. 
15. Participant has known impending or renal failure defined as:  
a. Anuria diagnosed within 12 hours prior to enrollment; 
b. Requiring renal replacement therapy. 
16. Participant is pregnant. 
17. Participant has any condition which would make the 
participant, in the opinion of the investigator, unsuitable for the 
study. 
Number of 
Participants: 
Approximately 60 participants, randomized 2:1 to GIR or placebo 
Number of Sites: 
Approximately 17 sites 
Duration of 
Participant 
Participation: 
A screening period of up to 29 days, followed by up to approximately 
10 weeks of active study drug or placebo including follow-up 
Dose Schedule: 
Initiate dose at 0.5 mg at bedtime. Dose escalation of daily dose by 
0.5 mg increments, on a BID schedule, as tolerated based on safety, 
HR, and BP assessments, no sooner than every 5 days up to a 
maximum dose of 3 mg/day (divided BID). 
Estimated Time to 
Complete 
Enrollment: 
Approximately 24 months 

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1 KEY ROLES 
For questions regarding this protocol, contact: 
 
IND Sponsor and Study Principal 
Investigator: 
 
Rachel G. Greenberg, MD, MHS 
Associate Professor of Pediatrics, 
Department of Pediatrics, 
Division of Neonatal-Perinatal Medicine 
Duke University School of Medicine 
Duke Clinical Research Institute 
DUMC 102509 
Durham, NC 27710 
Phone: 919-668-4725 
Fax: 919-681-2714 
E-mail:  rachel.greenberg@duke.edu  
 
Protocol Chair: 
 
Joan Jasien, MD 
Associate Professor Pediatrics 
Division of Pediatric Neurology 
Duke University School of Medicine 
3000 Erwin Road 
Durham, NC 27705-4599  
Phone: +1-919-668-0477 
Email:  joan.jasien@duke.edu 
 
 
BPCA Data Coordinating Center (DCC): 
 
The Emmes Company, LLC 
401 N Washington Street, Suite 700 
Rockville, MD 20850 
Phone: +1-301-251-1161 
Fax: +1-301-251-1355 
Study Email:  HYP01@emmes.com 
 
PI: 
 
Ravinder Anand, PhD 
Phone: +1-301-315-6143 
Email:  ranand@emmes.com 
 
Project Leader: 
 
Gina Simone 
Phone: +1-301-284-9067 
Afterhours Hotline: +1-301-641-3935 
Email:  gsimone@emmes.com 
 
Associate Project Leader:  
 
Kathleen O’Connor 
Phone: +1-403-863-5505 
Email:  koconnor@emmes.com 
 
Medical Monitor:  
 
Radhika Kondapaka, MBBS, RAC  
The Emmes Company, LLC 
401 N. Washington St # 700 
Rockville, MD 20850 
Phone: +1-301-284-9292 
Email:  bpcasafety@emmes.com 
 

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NICHD Contract Officer Technical 
Representative (COTR): 
 
Perdita Taylor-Zapata, MD 
National Institutes of Health 
Eunice Kennedy Shriver National Institute for 
Child Health & Human Development 
6710B Rockledge Drive MSC 7002 
Bethesda, MD 20892 
Phone: +1-301-496-9584 
Email:  taylorpe@mail.nih.gov 
 
NICHD Contract Officer Technical 
Representative (COTR): 
 
Katie M. Vance, Ph.D. 
Obstetric and Pediatric Pharmacology and 
Therapeutics Branch 
National Institutes of Health 
Eunice Kennedy Shriver National Institute for 
Child Health & Human Development 
Phone: +301-435-6640 
Email:  Katie.Vance@nih.gov 
 
Duke Clinical Research Institute 
(DCRI)- Clinical Coordinating Center 
HYP01 Study  
 
Study Email:  HYP01@dm.duke.edu 
 
 

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2 BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
Background Information 
Section 409I of the Public Health Service Act, also known as The Best Pharmaceuticals for 
Children Act (BPCA) mandates the National Institutes of Health (NIH) to prioritize therapeutic 
areas in critical need for pediatric labeling; to sponsor pediatric clinical trials; and to submit 
these data to the Food and Drug Administration (FDA) for consideration for labeling changes. 
This study will be conducted in accordance with Section 409I of the Public Health Service Act; 
as such, the results from this research may be submitted to the FDA for review and use in 
negotiated labeling changes. This research study is contractually supported by the Eunice 
Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The 
NICHD awarded a contract to Duke University (Durham, NC), which established a Pediatric 
Trials Network (PTN) through its Duke Clinical Research Institute (DCRI) to facilitate trial design 
for studies supported by the NIH. The NICHD awarded a separate contract to The Emmes 
Company, LLC (Rockville, MD) to serve as the Data Coordinating Center (DCC). 
See ICH E6 (R2) GCP, Section 6.2 
(https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf) 
 Background of Attention-Deficit/Hyperactivity Disorder (ADHD) in Down 
Syndrome (DS) 
Clinical significance of ADHD in patients with Down syndrome: Down syndrome (DS), 
caused by full or partial trisomy of chromosome 21, is the most frequent genetic cause of 
intellectual disability, occurring at an estimated prevalence of 12.9 per 10,000 individuals in the 
United States.1,2 Children with DS are at risk for many comorbid conditions that require chronic 
medication therapies, and very little is known about drug disposition and effect in this population 
specifically. 
Psychiatric and behavioral disorders are common in children with DS, with estimates of 
psychiatric comorbidity up to 38%.3 Behavioral challenges, including hyperactivity and 
impulsivity, emerge as early as age 3, and it is estimated that between 10-45% of individuals 
with DS may be diagnosed with co-occurring ADHD4,5 putting this population at high risk for 
other disruptive behaviors and comorbidities.3,6-8 Hyperactivity and impulsivity place children 
with DS with baseline cognitive deficits at especially high risk for accidental injury and becoming 
lost or running away; and this becomes increasingly difficult to manage as they age into 
adulthood and other psychiatric comorbidities emerge.3 Furthermore, there is a growing body of 
evidence suggesting that the diagnosis of DS itself confers a specific risk for ADHD compared 
to the general population, even more than other conditions associated with intellectual 
disability.7,9 
Outcome measures for ADHD in DS: Identifying measures to evaluate cognition and behavior 
in children with intellectual or developmental disability (IDD) and DS specifically, within clinical 
trials has traditionally been challenging.10 Leading clinician and scientific experts were 
assembled by the NIH to review existing measures and identify those that are appropriate for 
clinical trials in individuals with IDD and specifically DS.11 The Aberrant Behavior Checklist 
(ABC) is a rating scale that measures the severity of a range of problem behaviors commonly 
observed in individuals with IDD.12 It is an empirically developed scale designed to measure 
psychiatric symptoms and behavioral disturbance exhibited by individuals with IDD across 
5 domains: Irritability, Agitation, & Crying; Lethargy/Social Withdrawal; Stereotypic Behavior; 

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Hyperactivity/Noncompliance; and Inappropriate Speech, and it has been used extensively in 
pediatric and adult behavioral and psychiatric studies due to its high reliability and 
validity.11,13 The ABC-hyperactivity (ABC-H) subscale has been the primary outcome measure in 
the only trial of Guanfacine Immediate Release (GIR) for ADHD and disruptive behaviors in 
children with DS, as well as in several trials of ADHD with and without Autism Spectrum 
Disorder (ASD) in children.14-17 In addition to the ABC, the Clinical Global Impression (CGI) 
Scale will be utilized. The CGI was developed for use in National Institute of Mental 
Health-sponsored clinical trials to provide a brief, stand-alone clinician-determined summary 
measure prior to and after initiating a study medication that takes into account all available 
information, including a knowledge of the patient's history, psychosocial circumstances, 
symptoms, behavior, and the impact of the symptoms on the patient's ability to function.18 The 
CGI has two components − the CGI-Severity (CGI-S), which rates illness severity, and the 
CGI-Improvement (CGI-I), which rates change from the initiation (baseline) of treatment. The 
CGI is a widely used tool deemed appropriate for use in DS as identified by expert review. 
Previous studies have shown good concordance between parent/legal guardian and teacher 
ratings in neurotypical children19 and children with ASD,20 which supports the utility of this 
measure as a behavior outcome measurement in children with DS. 
Therapeutic options for treatment of ADHD in DS: Recommended management of ADHD in 
neurotypically developing children, depending on age, includes a combination of medications 
and behavioral therapy in young children and medications alone in school age children and 
older. Medications approved by the FDA to treat ADHD in children include stimulants and 
non-stimulant classes of medications.21 While stimulant medications (ex, methylphenidate, 
dexmethylphenidate, amphetamines) are very effective in the treatment of ADHD in 
neurotypically developing children, and are in fact considered the preferred first line therapy, 
studies in neurodevelopmental disorders, such as ASD, suggest that individuals with 
neurodevelopmental disorders respond differently to stimulant medications. Not only have they 
been shown to be less effective, but also have decreased tolerability and an unacceptable side 
effect profile specifically upon appetite and growth.16,21 Furthermore, individuals with DS have an 
increased risk of congenital heart disease, which further limits the use of stimulant medications 
in this population.  
Non-stimulant medications used for the treatment of ADHD include atomoxetine, clonidine, and 
guanfacine. Both clonidine and guanfacine are central alpha 2A-adrenergic receptor agonists 
thought to exert their actions through presynaptic stimulation and likely involve facilitation of 
both dopamine and noradrenaline neurotransmission, important in the pathophysiology of 
ADHD.22 Although the effect size is reportedly slightly less than the stimulant medications, 
non-stimulant medications are well accepted and may be preferred when stimulant medications 
are ineffective or the side effects intolerable, which has been reported in up to 30-50% of 
children and adults.23-25 Many thought leaders prefer guanfacine to clonidine in clinical practice 
because guanfacine has less sedation side effects than clonidine. Guanfacine IR (immediate 
release), or GIR, and Guanfacine Extended Release (GER) have been shown to be safe and 
effective in children with ASD and IDD,14,15,17 and one study has shown that GIR is effective and 
well tolerated in children with DS.6 However, only the extended release formulation, GER, is 
currently FDA approved for the treatment of ADHD as monotherapy and as adjunctive therapy 
to stimulant medications in children based on two clinical trials conducted in patients aged 
6–17 years who met DSM-IV® criteria for ADHD.26-28  
Prescribing guidelines report differences in pharmacokinetics and exposure between GIR and 
GER, and note that a dose substitution on a milligram for milligram basis will result in 
differences in exposure (INTUNIV® label);26 GIR is 80% bioavailable and the relative 
bioavailability of GER tablets to GIR tablets is 58%. Compared to GIR, the Area Under the 

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Curve (AUC) and maximum serum concentration (Cmax) of GER tablets are 43% and 60% 
lower, respectively. Peak plasma concentrations occur 1 to 4 (average 2.6) hours after a single 
oral dose of GIR in adults and adolescents with hypertension and 5 hours after oral 
administration of extended-release tablets to children and adolescents with ADHD. However, 
studies have found that similar pharmacokinetics can be achieved between formulations. For 
example, plasma trough concentrations were similar in adults treated for smoking cessation with 
3 mg/day administered BID of GIR and 4 mg/day of GER (3 mg/day GIR: M=3.40 ng/mL, 
standard error (SE) 0.34 vs. 4 mg/day GER: M=3.46 ng/mL, SE=0.67) with similar safety 
profiles between formulations.29  
The GER formulation is a practical challenge to prescribe in children with DS because the pill 
cannot be crushed and must be swallowed whole, and children with DS are at a high risk for 
comorbid dysphagia and swallowing dysfunction that puts them at significant risk for 
aspiration.30 Safely swallowing tablets is a challenge. Children with DS have also been shown to 
have high risk for sleep apnea and baseline diminished blood pressure profiles compared to 
age-matched controls,31 thus this elevates the safety concerns for sedation and hypotension as 
known side effects that could be prolonged with an extended release formulation. As such, 
providers are using GIR to treat ADHD in children with DS in clinical practice with dosing 
strategies guided by the monitoring of side effects as doses are escalated. No formal dosing 
guidance exists for this population. 
 Pediatric Labeling of Guanfacine 
Adult: Guanfacine immediate release (GIR) is FDA approved for the management of 
hypertension. It may be given alone or in combination with other antihypertensive agents, 
especially thiazide-type diuretics. 
Pediatric: Included on the GIR label: Safety and effectiveness in children under 12 years of age 
have not been demonstrated. There is no specific information included regarding the use for 
ADHD/hyperactivity, inattention, or impulsivity. Adverse reactions noted with guanfacine 
hydrochloride are similar to those of other drugs of the central α2-adrenoreceptor agonist class: 
dry mouth, sedation (somnolence), weakness (asthenia), dizziness, constipation, and 
impotence. While the reactions are common, most are mild and tend to disappear on continued 
dosing. Adverse events (AEs) reported in post marketing at an incidence greater than 1% 
included dry mouth, dizziness, somnolence, fatigue, headache, and nausea.32  
There have been spontaneous post-marketing reports of mania and aggressive behavioral 
changes in pediatric patients with ADHD receiving GIR tablets. The reported cases were from a 
single center. All patients had medical or family risk factors for bipolar disorder. All patients 
recovered upon discontinuation of guanfacine tablets. Hallucinations have been reported in 
pediatric patients receiving guanfacine tablets for treatment of ADHD. 
Included in the label for GER: INTUNIV® is indicated for the treatment of ADHD as 
monotherapy and as adjunctive therapy to stimulant medications. INTUNIV® was studied for the 
treatment of ADHD in three controlled monotherapy clinical trials (up to 8 weeks in duration) and 
one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and 
adolescents ages 6-17 who met DSM-IV® criteria for ADHD. The effectiveness of INTUNIV® for 
longer-term use (more than 8 weeks) has not been systematically evaluated in controlled trials. 
 
Scientific Rationale  
As mentioned in Section 2.1.1, one study has shown that guanfacine is effective and tolerated in 
children with DS.6 While the aforementioned study demonstrated preliminary data, it was limited 
by the fact that it was open-label, did not include a randomized placebo group, and did not 

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include scheduled dose increases or follow-ups. To date, there are no randomized, masked, 
placebo-controlled studies of any ADHD medication in children with DS. This is a significant gap 
in care for these individuals for a number of reasons: 1) This is a high-risk population for ADHD, 
with 2) inherent challenges using FDA-approved formulations, and 3) specific comorbidities that 
make them a uniquely vulnerable population for both the diagnosis and treatment of 
ADHD.33 Trials to evaluate drug efficacy and safety coupled with drug exposure data are 
desperately needed to ensure safe and effective dosing in children with DS.  
 
Potential Benefits 
The use of GIR in this population may result in improved hyperactivity measures, including 
irritability in participants who are randomized to study drug; however, it is unknown if there will 
be a benefit to the participant for being in this study. Nonetheless, by sharing the study data and 
specimens (via NICHD’s Data and Specimen Hub (DASH)), children in the future may benefit. 
 
Known Potential Risks 
 Risks of Blood Drawing 
It is possible that the participant will feel discomfort during the blood draw. It is also possible 
there will be bruising, swelling or bleeding where the needle enters the skin. The participant may 
also feel dizzy or a little light-headed when blood is drawn. Every effort should be made to avoid 
non-standard-of-care draw/sticks for this study and to time clinical blood draws with timed study 
specimens. 
 Risks of Guanfacine Hydrochloride 
Adverse reactions associated with guanfacine hydrochloride include: 
• 
Dry mouth 
• 
Sedation (somnolence) 
• 
Weakness (asthenia) 
• 
Dizziness 
• 
Constipation 
• 
Impotence 
• 
Decreased HR  
• 
Decreased BP  
Most reactions are mild and typically disappear after continued dosing. 
 Potential Risk of Loss of Confidentiality 
There is a potential risk of loss of confidentiality. Every effort will be made to protect the 
participant’s confidential medical information, but this cannot be guaranteed.  
 Unforeseen Risks 
There may be other risks to the participant from this research that are not known or foreseeable 
at this time.  

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3 OBJECTIVES AND OUTCOME MEASURES 
 
Objectives 
Outcome Measure(s) 
Endpoint(s) 
Primary 
Objective: 
Determine efficacy of 
GIR for the treatment of 
hyperactivity/impulsivity 
and inattention in 
children with DS after 
8 weeks of treatment. 
Primary Efficacy Outcome 
Measure: Parent-rated 
ABC-H subscale score  
 
Secondary Efficacy 
Outcome Measure: 
CGI-I specific to 
hyperactivity, inattention 
and impulsivity behaviors 
 
Primary Endpoint: Change from 
baseline to Week 8 of the ABC-H 
subscale score 
 
Secondary Efficacy Endpoints:  
Change from baseline to Week 4 of 
the ABC-H subscale score. 
Proportion of participants with a 
CGI-I score of 2 or better at Week 
4 and Week 8. 
Secondary 
Objective: 
Characterize the safety 
profile of GIR in children 
with DS. 
• Adverse Events (AEs) 
• Serious Adverse Events 
(SAEs) 
• Safety Events of 
Special Interest (ESIs) 
Incidence of AEs, SAEs, and safety 
ESIs through Week 8 
Exploratory 
Objective 1: 
Characterize GIR 
exposure in children with 
DS. 
Guanfacine HCl plasma 
concentration 
Guanfacine HCl exposure at Week 
4 and Week 8 as indicated by the 
following endpoints: 
• Steady state peak drug 
concentration (Cmax,ss)  
• Time at peak concentration 
(Tmax,ss)  
• Minimum concentration (Cmin,ss)  
• Apparent area under the 
concentration versus time curve 
at steady state (AUCss/F)  
• Apparent clearance (CL𝑠𝑠/F) 
• Volume of distribution (V/F) 
• Half-life (t1/2) 
Exploratory 
Objective 2: 
Characterize the 
exposure-response 
relationship of GIR for 
the treatment of 
hyperactivity/impulsivity, 
inattention, and sleep 
quality in children with 
DS. 
 
• Guanfacine HCl plasma 
concentrations (Cmax,ss 
and Cmin,ss)  
• Area under the 
concentration time 
curve (AUCss) 
• ABC-H subscale score 
• CGI-I 
• Epworth Sleepiness 
Scale for Children and 
Adolescents  
(ESS-CHAD) 
• Child’s Sleep Habits 
Questionnaire (CSHQ) 
Change in behavioral and sleep 
scales (ABC-H, CGI-I, ESS-CHAD, 
and CSHQ) relative to Guanfacine 
HCl plasma concentration (Cmax,ss 
and Cmin,ss) and AUCss at Week 
4 and Week 8 

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4 STUDY DESIGN 
 
Overall Design  
A prospective, multi-center, randomized, double-masked, placebo-controlled, flexibly-dosed 
trial. 
 
Study Design  
 Randomization 
Participants will be randomized 2:1 to GIR or placebo. 
 Masking/Unmasking 
A masked pharmacist or designee will dispense study product according to randomization 
treatment assignments. All other site staff as well as participants and parents/legal guardians 
will also be masked for up to 8 weeks while the study participant is receiving study product. 
Participants, parents/legal guardians, site staff, and study administrators will be unmasked at 
the 8 week study visit. Emergency unmasking may occur at any time throughout the study in the 
event that knowledge of the actual treatment is absolutely essential for further management of 
the participant. Refer to Section 4.4 below and to the Manual of Procedures (MOP) for details.  
Unmasking at the 8-week visit is necessary to maintain ethical practice as guanfacine is a 
commercially available product, and it would be unethical to wean a study participant off of 
guanfacine if they and their treating clinician determine that it is best for them to maintain 
treatment outside of the study. 
 
Study Intervention 
Investigational, non-marketed, guanfacine hydrochloride immediate release (GIR) 0.5 mg 
capsules and matching placebo capsules. 
 
Duration of Participant Participation  
Participants will undergo a screening period of up to 29 days. Eligible participants will receive 
GIR for up to 8 weeks plus a bridge or taper period, or placebo for up to 8 weeks. The treatment 
period will consist of study product administration from day 0 through day 56 with a masked 
dose-escalation period from day 0 through day 49. Unmasking of participant and site staff will 
occur after the week 8, in-person assessment, Day 56 (± 3 days).  
After unmasking, participants who were randomized to receive placebo will have a final 
telephone safety assessment 5 (+ 2) days after final study dose is administered. 
After unmasking, participants who were randomized to receive GIR will be given the option to 1) 
remain on GIR and to transition to open-label GIR per standard of care or 2) taper off of GIR. If 
the participant, in consultation with their clinical provider, chooses to remain on open-label GIR 
via standard of care, participants will have enough study product to allow for a 7-day bridge of 
manufactured GIR study drug to allow time to receive the routine clinical prescription of 
non-study provided GIR. A final telephone safety assessment will occur 5 (+ 2) days after final 
manufactured GIR study dose is administered. Alternatively, if the participant, in consultation 
with their clinical provider, chooses to discontinue GIR, a manufactured GIR taper will be 
instructed to proceed by a decrease of 1 mg every 3 days (maximum 6 day duration, depending 
on final study dose) to minimize rebound hypertension. A final telephone safety assessment will 
occur 5 (+ 2) days after the final manufactured GIR study dose is administered. 

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Biological Specimen Collection 
Blood will be collected at the Week 4 and Week 8 visits for PK analysis and lab assessments. 
 
Biological Specimen Retention Plan 
See Section 11. 
 
Safety 
All AEs, SAEs, and safety ESIs will be collected from the time of first study product 
administration through the end of study participation. 
 
Scientific Rationale for Study Design 
A randomized, double-masked, placebo-controlled trial will minimize bias and control for 
confounders. A 2:1 randomization will be used to improve recruitment capacity as parent 
representatives have indicated that it would be more desirable to enroll their children on a trial 
that has a greater probability of receiving study drug versus placebo. This was particularly 
important due to guanfacine being commercially available. Participants will be given an FDA 
cleared device for parent/legal guardian to measure HR and BP remotely. These assessments 
will be evaluated prior to each dose escalation. A guided dose-escalation will be used; however, 
investigators or their designee have flexibility to maintain or decrease a dose based on safety 
and/or efficacy assessments. Prior networks have utilized a guided dose escalation strategy 
based on clinical effect and tolerance, similar to dose escalation in clinical practice. This trial will 
prove the feasibility of masking and randomization, and obtain requisite plasma samples to 
allow measurement of drug exposure.  
 
Rationale for Dose Selection  
The recommended initial dose of GIR tablets for hypertension when given alone or in 
combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize 
somnolence. If after 3 to 4 weeks of therapy 1 mg does not give a satisfactory result, a dose of 
2 mg may be given. The current labeled dose range for GER is 0.05-0.08 mg/kg/day, with 
higher doses of 0.12 mg/kg once daily potentially offering additional benefit. A recommended 
dosing range for GER is 1 to 4 mg once daily.  
Dose escalation plans were created for children ≥ 25 kg, based on previous studies in IDD children 
who were treated with guanfacine,14 and were further refined by experts in the clinical care of 
children with DS. A starting dose of 0.5 mg at bedtime was determined to be the safest starting 
dose in children weighing ≥ 25 kg. Limiting the participants to children ≥ 25 kg was decided to 
allow for the safest dose-escalation plan of 0.5 mg increments. Details of the dose escalation plan 
are shown in Table 3. Prior to each dose escalation assessment, parent/legal guardian will be 
asked to measure HR and BP using the device given to them from the study team at the time of 
randomization. The maximum dose will be 3 mg daily, which is below the highest tolerated dose  
(4 mg daily for GER) in children aged 6-12 years old and ≥ 25 kg. This maximum dose was 
selected by experts in the field based on clinical practice, which dictates that if symptoms are not 
manageable with 3 mg daily, the patient is taken off GIR or an additional therapeutic agent is 
added. This dose range is within the dose range used in studies of neurotypical children aged  
6-12 years of age as referenced on the INTUNIV® (GER) label. 
Currently, there are no pharmacokinetic (PK) data for GIR specific to children with DS, and 
although significant differences in drug disposition are not expected, there is no evidence to 
confirm that the exposure of guanfacine in DS is similar to neurotypical children. 

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 Study Definition of Enrollment into Active Study 
Study enrollment into Active Study is defined as participant has provided informed consent, met 
all eligibility criteria, and is randomized. 
 Study Definition of Completion 
Study completion is defined as the last enrolled participant has completed the Final Telephone 
Safety Assessment 5 (+ 2) days after completion of study product. 
Each participant will reach study completion after they have completed the Final Telephone 
Safety Assessment 5 (+ 2) days after completion of study product or all assessments required 
for Early Study Withdrawal if they withdraw from the study early (Section 6.6). 

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5 STUDY POPULATION 
 
Selection of the Study Population 
A total of 60 eligible participants will be enrolled on this study.  
 
Inclusion/Exclusion Criteria 
Inclusion 
Criteria 
1. Parent/Legal Guardian can understand the consent process and is 
willing to provide informed consent/HIPAA authorization prior to the 
conduct of any study-related procedures. When applicable, the minor 
participant is willing to provide assent. 
2. Participant has clinical diagnosis of non-mosaic DS. 
3. Participant is between 6 and 12 years of age (inclusive) at time of 
consent. 
4. Participant weight is ≥ 25 kg. 
5. Participant has clinically significant symptoms of hyperactivity, inattention 
and impulsivity manifested as minimum scores of the following rating 
scales within 30 days of randomization: 
a. A minimum score of 18 on the parent-reported ABC-H subscale, 
AND 
b. A minimum score of moderate or greater (≥ 4) on the clinician 
reported Clinical Global Impression Severity (CGI-S) score specific 
to hyperactivity, inattention and impulsivity behaviors.  
6. Participant has co-morbid medical screening and clearance to proceed 
with a non-stimulant medication trial with GIR within 30 days of 
randomization. 
7. Participant is willing and able to comply with study procedures, including 
adherence to medication dosing schedule. 
 
Exclusion 
Criteria 
1. Participant has received guanfacine (any formulation) within 30 days of 
randomization. 
2. Participant has received any of the following concomitant medication 
classes within 30 days of randomization:  
a. Strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole) 
b. Strong CYP3A4 inducers (e.g., avasimibe, carbamazepine, 
phenytoin, rifampin, and St. John’s wort)  
3. Participant has a psychiatric comorbidity, such as major depressive 
disorder, bipolar disorder, obsessive-compulsive disorder, or a psychotic 
disorder, that requires a pharmacological treatment other than 
guanfacine. 

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4. For participants ≥ 8 years old at the time of consent, participant has 
a history of suicidality or positive screen on Ask Suicide-Screening 
Questions (asQ) Tool. 
5. Participant is currently in or plans to participate in another interventional 
study. 
6. Participant has a known hypersensitivity to guanfacine. 
7. Participant has had a previous guanfacine treatment failure, as 
determined by their primary treating physician. 
8. Participant has had a change in another medication intended to treat 
symptoms of hyperactivity, inattention, and impulsivity within the last  
2 weeks. 
9. Participant has had a seizure within the last 6 months. 
10. Participant has had a change in their anti-convulsant dose within the last 
4 weeks. 
11. Participant has a cardiac-related condition including: 
a. Significant symptomatic bradycardia;  
b. 2nd degree or 3rd degree (complete) heart block; 
c. Baseline heart rate (HR) or systolic blood pressure (BP) > 
2 standard deviations (SD) below mean for age as determined by 
medical examination; 
d. History of aborted sudden cardiac death, unexplained syncope or 
near syncope, or historical use of a pacemaker as determined by 
medical history will require clearance by cardiology prior to 
enrollment;  
e. Known history of congenital heart disease which requires ongoing 
care for monitoring or management will require clearance by 
cardiology prior to enrollment.  
12. Participant has a history of untreated severe obstructive sleep apnea 
defined as obstructive apnea hypopnea index (OAHI) ≥ 10 events per 
hour or aortic regurgitation (AR). Participants with an OAHI index > 10/hr 
are eligible if managed with continuous positive airway pressure (CPAP). 
13. Participant has untreated thyroid disease. 
14. Participant has a known hepatic impairment defined as aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) > 2x the 
upper limit of normal (ULN) for age.  
15. Participant has known impending or renal failure defined as:  
a. Anuria diagnosed within 12 hours prior to enrollment; 
b. Requiring renal replacement therapy. 
16. Participant is pregnant (refer to Section 7.6.1). 
17. Participant has any condition which would make the participant, in the 
opinion of the investigator, unsuitable for the study. 

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Screen Failures 
Participants who provide informed consent, but who are not ultimately randomized in the Active 
Study (Section 4.10), will be considered screen failures and will remain in the screening 
segment of the data system. The reason for screen failure will be captured in the data system. 
 
Treatment Assignment Procedures 
 Randomization Procedures 
Eligible participants will be randomly assigned in a 2:1 ratio to either GIR or placebo. The 
participant’s randomized treatment assignment will be obtained through the Advantage 
eClinical® enrollment module. In the event that Advantage eClinical® is not available at the time 
of randomization, a back-up system specified in the MOP will be used. Randomization will be 
stratified by study site. The randomization procedure will be conducted centrally through the 
study data system and randomization assignments will not be conveyed to participants or study 
sites. The DCC statistician will generate the randomization schedule using balanced blocks 
within site to ensure relative equality of assignment across treatment groups. A DCC statistician 
will review randomization data on a regular basis to ensure that the scheme is being 
implemented according to plan. A randomization assignment, once issued, will not be 
re-allocated. Details of the randomization process are described in a separate Randomization 
Plan. 
 
Participant Discontinuation/Withdrawal 
 Participant/Parent/Legal Guardian Decides to Withdraw Consent 
Participants or their parent/legal guardian may voluntarily withdraw consent to participate in the 
study at any time. Participants or their parent/legal guardian are not obligated to state the 
reason for withdrawal. The reasons for withdrawal, or failure to provide a reason, must be 
documented by the investigator. No additional study procedures or data should be collected 
after consent has been withdrawn. 
 Participant/Parent/Legal Guardian Decides to Withdraw from Study Product 
Participants or their parent/legal guardian may also withdraw from receiving the study product 
for any reason but continue to be followed for safety, including safety ESIs.  
Participants or their parent/legal guardian are not obligated to state the reason for withdrawal.  
At the time of withdrawal from study product, participants (and site staff) will be unmasked and 
asked to complete an electrocardiogram (ECG), as well as provide a PK blood sample. 
Participants, who were randomized to receive GIR, will be transitioned off of GIR according to 
the dose taper process described in Section 6.13.2 followed by a final telephone safety 
assessment 5 (+ 2) days after the final study dose administered. Participants who were 
randomized to receive placebo will have a final telephone safety assessment 5 (+ 2) days after 
final study dose administered. The parent/legal guardian will be asked to complete the Aberrant 
Behavior Checklist (ABC) and the treating clinician will be asked to perform a CGI-I. Unmasking 
should only occur following completion of the other Early Withdrawal / Termination Visit 
Assessments (Section 6.6). Refer to the MOP for details. 
 Study Investigator/Sponsor Decides to Withdraw Participant 
The study doctors or sponsor may decide to take the participant out of this study without 
consent if: 

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• 
Participant’s condition changes and the study is no longer in their best interest 
• 
Participant/parent/legal guardian non-compliance with the study protocol 
• 
The entire study is stopped by the FDA or the sponsor 
A participant may be withdrawn from receiving study product if they experience a clinically 
significant AE that requires discontinuation of treatment, at the discretion of the study doctor or 
sponsor. 
If any of the above occurs, the participant/parent/legal guardian will be informed and the 
investigator will discuss other options. 
 
Handling of Withdrawals 
The reasons for withdrawal, or failure to provide a reason, must be documented by the 
investigator. 
Reasons of withdrawal may include: 
• 
Parents/legal guardians of participants who withdraw consent and request no further 
follow-up 
• 
If minor participants decide not to remain in the study, they will be withdrawn even if 
the parent/legal guardian of the minor participant has not withdrawn consent. 
• 
Study Investigator/Sponsor decision 
 Early Withdrawal/Discontinuation Assessments 
Refer to Section 6.13.2 for study product taper requirements. The following assessments will be 
collected at the time of early termination/withdrawal: ABC, ECG, a PK blood sample, and CGI-I. 
If a participant/legal guardian withdraws consent, no further follow-up will occur following 
withdrawal of consent. Participants who are discontinued from study drug due to an AE, whether 
serious or non-serious, must be followed by the investigator until the AE is resolved or 
considered stable. The medical monitor (MM) or study investigator must be notified if the AE 
may relate to overdose of study treatment; the package insert should be consulted for details of 
any specific actions to be taken. 
 Replacements 
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6 STUDY PROCEDURES 
 
Summary of Procedures 
Table 1. Schedule of Study Procedures and Assessments 
 
Screening 
Study 
Intervention 
(Weeks 1-3) 
Study 
Intervention 
(Week 4) 
Study 
Intervention 
(Weeks 5-7) 
Study 
Intervention 
(Week 8) 
Taper/ 
Bridge 
Follow-Up 
Early With- 
drawal/ 
Discon-
tinuation 
 
Day -29 
to 01 
Day 11-21 
(± 1 day) 
Day 22-28 
(± 3 days) 
Day 29-49 
(± 1 day) 
Day 50-56  
(± 3 days) 
 
5 (+ 2) 
days post 
final study 
dose 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
Distribution of device for 
remote HR and BP 
assessment 
 
X3 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Exam 
X 
X3 
 
 
 
 
 
 
Weight/height 
 
 
X 
 
X 
 
 
 
Vital Signs 
X 
X3 
X 
 
X 
 
 
 
Concomitant 
Medications of Interest 
X 
 
X 
 
X 
 
 
 
ECG 
X 
 
X 
 
X 
 
 
X 
Lab assessments 
X 
 
X11 
 
 
 
 
 
Pregnancy test13 
X 
 
 
 
 
 
 
 
Blood Collection for PK 
 
 
X2 
 
X2 
 
 
X2 
Randomization 
 
X3 
 
 
 
 
 
 
Dose escalation with HR 
and BP assessment 
 
X4 
X4 
X4 
 
 
 
 
Study product 
administration 
 
X5 
X 
X 
X 
 
 
 
Unmasking 
 
 
 
 
X 
 
 
X 
Study drug taper/bridge 
 
 
 
 
 
X6 
 
X 
Study Diary  
 
Continuous 
X6 
X6 
 
CGI-S 
X 
 
 
 
 
 
 
 
CGI-I 
 
X7 
X 
X7 
X 
 
 
X 
ABC 
X 
 
X 
 
X 
 
 
X 
asQ Tool12 
X 
 
X 
 
X 
 
 
 
Sleep assessments  
 
X3 
X 
 
X 
 
 
 
Safety Events8 
X9 
X 
X 
X 
X 
X 
X10 
X 
1 – Day 0 and Day 1 may be the same calendar day. 
2 – Preferred sampling: within 60 minutes prior to study product dose or 30-120 minutes after study product dose. 
3 – Randomization; distribution of device for remote HR and BP assessment; physical exam, including weight/height; vital signs; and sleep 
assessments occur only on Day 1 prior to study product administration. 
4 – Just prior to dose escalation time point, every 5 (+ 2) days, parent/legal guardian will be asked to measure HR and BP. 
5 – Initial dose occurs on Day 1, Day 0 and Day 1 may be the same calendar day. The initial dose will be administered before bedtime on Day 1. 
Subsequent doses occur according to Section 6.13.1. 
6 – For GIR arm only. Participants who choose to discontinue GIR will be tapered off study drug at 1 mg every 3 days. Participants who choose 
to transition to standard of care GIR will continue on up to 7 days of study drug to bridge to standard of care GIR. See Section 6.13.2. 
7 – Weekly CGI-I, beginning at first weekly telephone assessment. 
8 – Includes AEs, SAEs, and safety ESIs, as described in Section 7.1.2. 
9 – Only AEs directly related to study procedures (e.g., blood collection) during the screening period will be collected. 
10 – A final Telephone Safety Assessment, including all safety events, will occur at 5 (+ 2) days after final study product administration. 
11 – In the rare event that blood cannot be collected for any reason at Week 4, blood for LFTs can be collected at the Week 8 visit. 
12 – Only used in participants ≥ 8 years old, as described in Section 6.10. 
13 – For participants who have reached menarche only, either urine or blood test is acceptable. 

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Screening (Day -29 to 0) 
The investigator will screen participants in accordance with the eligibility criteria detailed 
previously (Section 5.2). The investigator will not exercise selectivity so that bias is prevented.  
The following assessments/procedures will occur during the Screening period: 
• 
Informed consent/assent 
• 
Demographics, including identified gender, race, ethnicity, and date of birth 
• 
Complete Medical history  
• 
Physical exam, including weight and height  
• 
Vital signs, including BP and HR 
• 
Concomitant medications of interest 
• 
ECG 
• 
Lab assessments for baseline complete blood count (CBC) w/differential, basic 
metabolic panel (BMP), liver function tests (LFTs), Thyroid function studies (Thyroid 
Stimulating Hormone [TSH], free T4) 
• 
For participants who have reached menarche only, pregnancy test (urine or blood test is 
acceptable) 
• 
CGI-S for Eligibility (Section 6.9.3) 
• 
ABC for Eligibility (Section 0) 
• 
asQ for Eligibility, as appropriate, for participants ≥ 8 years old who do not have prior 
known suicidality (Section 6.10) 
• 
AEs directly related to study procedures  
 
Study Intervention (Day 1 to 56 ± 3 days) 
Day 1 (Day 0 and Day 1 may be the same calendar day): 
• 
Randomization 
• 
Physical exam, including weight and height 
• 
Vital signs, including BP and HR 
• 
Study product administration – single dose at bedtime on Day 1 
• 
Study Diary completion training and provision 
• 
Safety Events, including AEs, SAEs, and safety ESIs; collection of safety events will be 
initiated after the first study product administration 
• 
Parent/legal guardian-completed sleep assessments (Section 6.9.2) 
Weeks 1-3 (Day 1-21 ± 1 day): 
• 
Study-product administration 
• 
Dose escalation with BP and HR assessment (Section 6.8), prior to dose escalation time 
point, every 5 (+ 2) days. 
• 
Safety Events, including AEs, SAEs, and safety ESIs 

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• 
Study Diary review 
• 
Clinician completed weekly CGI-I, beginning at first weekly telephone assessment 
(approximately Day 5) (Section 6.9.3) 
Week 4 (Day 22-28 ± 3 days): 
• 
Concomitant medications of interest 
• 
Weight/height 
• 
Vital signs, including HR and BP 
• 
ECG 
• 
Lab assessments for liver toxicity: LFTs  
• 
Blood Collection for PK 
• 
Dose-escalation assessment (Section 6.8) 
• 
Study-product administration  
• 
Study Diary review 
• 
Clinician-completed CGI-I (Section 6.9.3) 
• 
Parent/legal guardian-completed ABC (Section 0) 
• 
Parent/legal guardian-completed sleep assessments (Section 6.9.2) 
• 
asQ, as appropriate, for participants ≥ 8 years old (Section 6.10) 
• 
Safety Events, including AEs, SAEs, and safety ESIs 
Weeks 5-7 (Day 29-49 ± 1 day): 
• 
Dose-escalation with BP and HR assessment (Section 6.8), prior to dose escalation time 
point, every 5 (+ 2) days 
• 
Study-product administration 
• 
Study Diary review 
• 
Clinician-completed weekly CGI-I (Section 6.9.3) 
• 
Safety Events, including AEs, SAEs, and safety ESIs 
Week 8 (Day 50-56 ± 3 days): 
• 
Weight/height 
• 
Vital signs, including HR and BP 
• 
Concomitant medications of interest 
• 
ECG 
• 
Lab assessments for liver toxicity: LFTs, only if unable to collect at the Week 4 visit  
• 
Blood Collection for PK  
• 
Study-product administration 
• 
Study Diary review 

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• 
Clinician-completed CGI-I (Section 6.9.3) 
• 
Parent/legal guardian-completed ABC (Section 0) 
• 
Parent/legal guardian-completed sleep assessments (Section 6.9.2) 
• 
asQ, as appropriate, for participants ≥ 8 years old (Section 6.10) 
• 
Safety Events, including AEs, SAEs, and safety ESIs 
• 
Unmasking of participant to determine standard of care plan 
 
GIR Taper/Bridge (Up to 6 days post last study product administration) 
Procedures will vary for those participants who are randomized to receive study drug, 
depending on their decision for GIR treatment following unmasking. 
• 
Participants randomized to receive study drug, who choose to discontinue GIR: 
o See Dose Discontinuation/Taper (Section 6.13.2) 
o Study Diary completion 
• 
Participants randomized to receive study drug, who choose to transition to open-label 
GIR per standard of care: 
o Participants will have enough study product to allow for a 7-day bridge of 
manufactured GIR and will be instructed to contact their heathcare provider in order to 
obtain a clinical prescription of GIR within 7 days. 
o Study Diary completion 
Note: Participants randomized to receive placebo will proceed directly to the Telephone Safety 
Follow-up (Section 6.5) 
 
Telephone Safety Follow-up (5 + 2 days after final study product 
administration) 
A Telephone Safety Assessment, including a Study Diary review will be conducted for all 
participants, at 5 (+2) days after final study-provided product administration. 
 
Early Withdrawal / Termination Visit  
 
If a participant withdraws from study product administration or terminates from the study early, 
the study team will attempt to collect the following at an in-person visit, if an in-person visit is not 
feasible, a telephone assessment will occur to obtain the following assessments/procedures: 
• 
Safety Events, including AEs, SAEs, and safety ESIs  
• 
ECG (in-person only) 
• 
Parent/legal guardian-completed ABC (Section 0) 
• 
Clinician-completed CGI-I (Section 6.9.3) 
• 
Blood collection for PK analysis (in-person only) 
• 
Unmasking of participant and manage GIR Taper/Bridge per Section 6.4. Unmasking 
should only occur following completion of the other Early Withdrawal / Termination Visit 
Assessments above. 

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Laboratory Evaluations  
 
 Pharmacokinetic Specimens  
  
Opportunistic blood collection for PK analysis will occur at the Week 4 and Week 8 visits. 
Samples will be derived from the plasma matrix. 
Collect study product information for up to 8 doses prior to the sampling dose (last dose 
prior to PK biological sample collection): 
• Exact date and time of previous study product dose administration 
• Dose amount 
• Dose number 
• Dose frequency 
• Dosing weight  
• Actual weight from physical exam at corresponding week 
• Height from physical exam at corresponding week 
• Formulation (i.e., capsule swallowed or capsule contents mixed with food) 
• Food intake [yes (fed); no (fasted)] 
• If food intake yes, please enter what food was mixed with contents 
Sampling Information to be collected at time of blood draw: 
• Exact date and time the sample is drawn 
• Exact date and time the sample is frozen/stored 
• Sample volume (estimated) 
• Sample type (i.e., plasma, whole blood, etc.) 
• Source of blood sample (i.e., arterial vs. venous) 
• Sampling site 
Concomitant Medications of Interest Information: 
• Presence of concomitant medications of interest* within 24 hours before and after the 
dose of study product closest to the time of biological sample collection 
• Total dose amount (per day) 
• Route of administration 
*Only concomitant medications of interest (see Section 6.17) for specific drugs will be 
recorded on the eCRF. 
Timing of Sample Collection: Preferred Sampling Windows for PK include: 
1) Peak sample: within 30 to 120 minutes after study product dose* 
2) Trough sample: within 60 minutes prior to next study product dose* 
*Samples obtained outside those windows are not protocol deviations.  
 Clinical Laboratory Determinations 
The following hematologic values are required to be collected at screening: hematocrit, white 
blood cell (WBC) count, platelet count, and differential. The following serum chemistry values 
are required to be collected at screening: blood urea nitrogen (BUN), serum creatinine, 
potassium, sodium, AST, ALT, total bilirubin, and albumin. Thyroid function will be measured, 
including TSH and free thyroxine, T4. If these values were obtained via standard of care within 
30 days of enrollment, these values can be used; otherwise, they must be obtained prior to 
enrollment. 

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At the Week 4 visit, clinical labs will be collected to assess for liver toxicity: LFTs. If the blood 
sample for LFTs cannot be drawn at the Week 4 visit for any reason (e.g., parent/legal guardian 
request to cease blood draw attempts, participant uncompliance, etc.), the clinical lab draw for 
LFTs may be collected at the Week 8 visit.  
 
Dose Escalation Assessments 
Every 5 (+ 2) days through Week 7, just prior to each dose escalation assessment, parent/legal 
guardian will be asked to measure HR and BP using the device given to them from the study 
team at the time of randomization. A telephone or in-person assessment by the treating clinician 
will occur to determine dose escalation. If the participant reaches the maximum dose of  
3 mg/day, prior to Week 7, no dose escalation will occur. Alternatively, a CGI-I will be 
determined by the treating clinician and any score of 3 or worse (higher) will warrant dose 
escalation, provided no significant safety concerns exist. AEs and safety ESIs will be recorded 
to assess safety.  
Clinically significant findings that would prevent dose escalation include, but are not limited to: 
• 
CGI-I score of 2 or 1 
• 
HR and BP values that are considered unsafe to dose escalate: 
o Clinically significant hypotension, defined as systolic BP percentile less than the 
5th percentile.31,34 This corresponds to systolic BP percentiles for neurotypical 
children under the 8th percentile for males and under the 10th percentile for 
females. 
o Clinically significant bradycardia, defined as HR > 2 SD below mean for age 
• 
Any AEs or safety ESIs that make it unsafe to dose escalate, at the discretion of the 
treating clinician  
• 
Any other finding that indicates it is not safe to dose escalate, at the discretion of the 
treating physician and/or principal investigator (PI). 
 
Clinical Outcome Assessments  
Identifying measures to evaluate cognition and behavior in children with IDD and DS 
specifically, within clinical trials has traditionally been challenging.10 Leading clinician and 
scientist experts were assembled by the NIH to review existing measures and identify those that 
are appropriate for clinical trials in individuals with IDD and specifically DS.11 The ABC, 
ESS-CHAD, and CSHQ will be collected using Electronic Participant Reported Outcomes 
(ePRO), see Section 15.3. Details regarding which individual(s) complete(s) each measure at 
the various visits are included in Table 2. 
 
 
 

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Table 2. Frequency of measures and who completes each measure. 
Measure 
Frequency Parent/ 
Legal Guardian 
Completes 
Frequency Clinician 
Completes 
ABC (Section 0) 
Screening, Week 4, 
Week 8, Early 
Withdrawal 
N/A 
Sleep Assessments 
(Section 6.9.2) 
Day 1, Week 4, 
Week 8 
N/A 
CGI-I (Section 6.9.3)  
N/A 
Weeks 1-8, Early 
Withdrawal 
CGI-S (Section 6.9.3) N/A 
Screening 
 
 Aberrant Behavioral Checklist (ABC) 
The ABC is a rating scale that measures the severity of a range of problem behaviors commonly 
observed in individuals with IDD.12 It is an empirically developed scale designed to measure 
psychiatric symptoms and behavioral disturbance exhibited by individuals with IDD across 
5 domains: Irritability (Agitation, & Crying); Lethargy/Social Withdrawal; Stereotypic Behavior; 
Hyperactivity (Noncompliance); and Inappropriate Speech, and it has been used extensively in 
pediatric and adult behavioral and psychiatric studies due to its high reliability and 
validity.11,13 The ABC-H subscale has been the primary outcome measure in the only trial of GIR 
for ADHD and disruptive behaviors in children with DS, as well as in several trials of ADHD with 
and without ASD in children.14-17 For this study, the ABC will be completed by parent(s)/legal 
guardian(s). 
 Sleep Assessments 
Epworth Sleepiness Scale: The ESS-CHAD is a self-administered 8–item questionnaire to 
assess daytime sleepiness. For this study, the parent/legal guardian will complete the 
assessment. 
Child’s Sleep Habits Questionnaire (CSHQ): The abbreviated CSHQ includes 35 items that 
are divided into the following sections: bedtime, sleep behavior, waking during the night, and 
morning wake up. For this study, the parent/legal guardian will complete the assessment. 
 CGI-Severity for Eligibility and CGI-Improvement for Improvement 
The CGI is a well-established research rating tool that can be used in the context of any 
psychiatric disorder. It consists of two parts including a 7-item assessment of the severity of 
psychopathology (CGI-S) and a 7-item assessment on the change from initiation of treatment 
(CGI-I). The CGI-S asks raters to indicate the frequency and severity of symptoms over a 7 day 
rating timeframe and establishes a baseline for each participant.18 The CGI-I is an objective 
measure of a single participant’s change (improvement or worsening) compared to baseline. For 
this study, the CGI assessments will be completed by clinicians. 
 
The asQ Tool was created by the National Institute of Mental Health as a suicide risk screening 
tool for ages 8 years and above. Prior to initiating the asQ, the treating clinician will use their 
judgement to answer the following questions: does the participant (1) have the language skills 

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adequate to understand death and suicide and (2) the verbal ability to respond to “yes/no” and 
“how/when” questions about suicide.  
• 
If yes, proceed to asQ. The participant should be excluded from the study if further 
clinical assessment and/or judgement are needed. 
• 
If no or < 8 years old, do not screen for suicidal ideation. 
The asQ tool uses 4 screening questions. If the participant answers “no” to all of the screening 
questions, they are not identified as a suicide risk and the screening is complete. If the 
participant answers “yes” to any of the questions, they are identified as a positive screen and 
are asked a 5th question to assess acuity of the suicidality. If the participant answers “yes” to the 
5th question, they are identified as an acute positive screen, if they answer “no” they are 
identified as a non-acute positive screen.35 All sites should follow local guidelines if a participant 
screens positive for suicidality. Per eligibility criteria, a participant who has an acute positive 
screen at Screening will be excluded from the study. 
 Specimen Preparation, Handling, Storage, and Shipping 
Samples collected for the research will be labeled with a unique number via a study provided 
barcode label. Instructions for collection, labeling, preparation, handling, and storage of 
specimens will be detailed in the MOP. 
 Study Product Description 
Guanfacine hydrochloride immediate release, brand name Tenex, is a centrally acting small 
molecule antihypertensive that comes in a tablet form for oral administration. Guanfacine 
hydrochloride is a white to off-white powder that is sparingly soluble in water and alcohol and 
slightly soluble in acetone. The tablets contain the following inactive ingredients: FD&C Red 
40 aluminum lake (1 mg tablets only), lactose, microcrystalline cellulose, providone, and stearic 
acid.32 United States commercially available guanfacine tablets will be purchased and used as 
the source for the manufactured 0.5 mg dose guanfacine capsules with matching placebo by the 
University of Iowa Pharmaceuticals (UIP) to be used in this study. Guanfacine tablets will be 
milled and placed into capsules of 0.5 mg of active product.  
The placebo will be a study drug-matched capsule filled with microcrystalline cellulose.  
 
 Dose Timing 
Dose escalation 
Study product will be administered once daily (q.h.s.) during the first 5 (+ 2) days of study 
product administration and then twice daily thereafter. Twice daily doses may be administered in 
uneven BID dosing; for example, a total daily dose of 2.0 mg can be divided into 0.5 mg in the 
morning and 1.5 mg in the evening, at the discretion of the clinical provider. Dose escalation will 
occur based on the details in Table 3 with the highest dose being dose level 6. Participants in 
both the GIR and placebo arms will be evaluated for potential dose escalation every 5 (+ 2) 
days via a Dose Escalation Assessment (via telephone during Weeks 1-3 and 5-7 or in-person 
at Week 4) described in Section 6.8. Parent/legal guardian will be asked to measure HR and BP 
prior to each dose escalation assessment. If there is a safety concern during the weekly Dose 
Escalation Assessments (via telephone during Weeks 1-3 and 5-7 or in-person at Week 4) as 
stated in Section 6.8, or for any other reason, the sites will be instructed on the following: 
1. Hold at current dose/schedule for 5 (+ 2) days (or advance directly to step #3 or step 
#5 below, if deemed appropriate by the clinical provider) 

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2. Reassess at next dose-escalation assessment 
3. If sedation is a significant concern, divide the total daily dose and give higher dose 
proportion at bedtime (q.h.s); example: 2 mg totally daily dose split as 0.5 mg in the 
morning and 1.5 mg q.h.s and  
4. Reassess at next dose-escalation assessment 
5. If safety concern remains, reduce total daily dose to the lower dose previously tolerated 
Table 3. Dose Escalation Plan* 
Dose Level 
Total daily dose for weight ≥ 25 kg (mg) 
1 
0.5  
2 
1.0  
3 
1.5  
4 
2.0  
5 
2.5  
6 
3.0  
* Parent/legal guardian will be asked to measure HR and BP prior to each dose escalation 
assessment. 
 Dose Discontinuation /Taper  
If a participant randomized to receive GIR withdraws from study early or chooses not to 
continue treatment with GIR via standard of care at the end of Week 8 unmasking, a drug taper 
plan will be employed for all participants whose final drug dose is > 1 mg/day. The dose taper 
will be a decrease in increments of 1 mg every 3 days. The taper will last a maximum of 6 days, 
but may be shorter if starting taper dose is less than 3 mg/day. Study Diary will be completed 
during the discontinuation/taper period.  
Participants receiving < 1 mg at the final study drug administration will stop study drug treatment 
and will follow procedures for early withdrawal/termination (as applicable) or will proceed to 
Telephone Safety Follow-up (Section 6.5). 
 Formulation, Packaging, and Labeling 
The University of Iowa will manufacture 0.5 mg GIR capsules and matching placebo capsules 
adhering to Good Manufacturing Practice (GMP) and United States Pharmacopeia and National 
Formulary (USP/NF) from the purchase of United States-marketed GIR uncoated tablets.  
The study product will be packaged (80 capsules per bottle) into High Density Polyethylene 
(HDPE) bottles, with a length of polyester coil and desiccant pack, and sealed with 
polypropylene (PP) child-resistant induction-sealed closures.  
The University of Rochester Clinical Materials Services Unit (CMSU) will package and label kits 
containing 4 bottles (80 capsules per bottle). The kit box label will include an unique Kit 
identification (ID) number and a masked packaging code (PO#). The four bottles inside each kit 
will include labels with the Kit ID Number (matching the Kit ID Number on the kit box), a PO#, 
and a bottle number (1 through 4). Each randomized participant will be assigned one 4-bottle kit 
box. 
The study product will be distributed by the site to the participant. The site will provide enough 
study product per participant for weeks 1-4 (1 bottle) on the day of randomization and for weeks 
5-9 (3 bottles) at the Week 4 visit. See MOP for more details.  

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 Product Storage and Stability 
The study products should be stored at a controlled temperature between 20°C and 25°C in a 
tight, light-resistant container. Upon receipt and quality audit release of the manufactured GIR 
and matching placebo, CMSU will store the GIR in an ambient warehouse storage space 
(between 20°C and 25°C) prior to distributing to the clinical study sites. The study product will 
ship to sites in a qualified, controlled room-temperature shipper, and include a 
temperature-monitoring device while in transit. The site must acknowledge receipt of the kits in 
order for them to be available for dispensing. See MOP for more details.  
 Preparation and Administration of Study Product 
Study product will be packaged and shipped from University of Rochester’s CMSU to local sites 
who will be masked to the study-treatment assignment. Description on the masking procedures 
will be provided in the MOP. Local sites will distribute the appropriate respective study product 
on 1) the day of randomization (Day 1), and 2) the Week 4 in-person clinical assessment. 
Participants will self-administer each oral dose. If the participant is unable to swallow the 
capsule whole, instructions to open the capsule and mix with food will be provided. 
 Modification of Study Product for a Participant 
Dose reduction may occur according to the details in Section 6.13.1. See MOP for more details. 
 Accountability Procedures for the Study Product(s) 
Refer to MOP for more details. 
 Replacement Kits 
If a study product bottle or kit is broken or unusable, a replacement kit with a new unique Kit ID 
Number will be provided. Replacement kits may be requested via contact information provided 
in the MOP. Any missed or forgotten doses will be documented in the Study Diary, refer to the 
MOP for details. 
 Disposition of Study Products Upon Study Completion or Expiration 
Following notification from the sponsor, upon completion of the study, or upon notice of the 
study products’ expiration, the study product should be disposed of at the site, after the drug 
accountability logs have been reviewed by the monitors, pursuant to the ICH/GCP guidelines 
and the investigators’ institutional policies. 
 Concomitant Medications of Interest/Treatments 
Concomitant medications of interest include the following: central nervous system (CNS) 
depressants (example: benzodiazepines, barbiturates, opioids), anti convulsants (example: 
carbamazepine), CNS stimulants or non-stimulants to treat ADHD (e.g., methylphenidate, 
dexmethylphenidate, amphetamines, clonidine, atomoxetine, bupropion) and antibiotics (e.g., 
ciprofloxacin, clarithromyscin, erythromycin, fluconazole, itraconazole, voriconazole, rifampin). 

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7 ASSESSMENT OF SAFETY 
 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in humans, whether or not 
considered drug-related, which occurs during the conduct of a clinical trial. Any change in 
clinical status, ECGs, routine labs, x-rays, physical examinations, etc. that is considered 
clinically significant by the study investigator is considered an AE. 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility that 
the drug caused the event. A reasonable possibility implies that there is evidence that the drug 
caused the event. An adverse reaction is any AE caused by the drug.  
A serious, unexpected, suspected adverse reaction (SUSAR) is defined as a SAR that is 
both serious and unexpected for which a reasonable causal relationship with the drug use is 
suspected but not confirmed. 
 Unexpected Adverse Event  
An Unexpected Adverse Event is defined as any AE, of which the nature, specificity or severity 
is not consistent with the applicable product information (e.g., package insert/approved label) or 
investigational plan. 
 Safety Events of Special Interest (ESIs) 
A safety ESI is a select safety event that could be related to the study drug. Safety ESIs will be 
solicited for their occurrence (No or Yes) at weekly dose-escalation assessments, including 
in-person assessments (Week 4 and Week 8), and the final telephone safety assessment  
(5 + 2 days) after the final dose of study drug. The safety ESIs documented will be assessed by 
the investigator/delegate (defined as a clinician licensed to make a diagnosis) for intensity, 
causality, and association to provide uniform data collection of all events. Any reported ESIs 
should be managed, as needed, according to clinical judgement and local guidelines. 
Safety ESIs include: 
• 
Syncope/passing out 
• 
Sedation 
• 
Trouble falling asleep 
• 
Trouble staying asleep 
• 
Trouble waking up 
• 
Drowsiness 
• 
Decreased Energy/Fatigue 
• 
Trouble concentrating 
• 
Trouble breathing 
• 
Constipation 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
• 
Skin rash 
• 
Itching 
• 
Change in appetite 
• 
Anxious/fearful 

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• 
Sadness/depressed mood 
• 
Self-injurious behavior 
• 
Clinically significant hypotension, defined as systolic BP percentile less than the 5th 
percentile.31,34 This corresponds to systolic BP percentiles for neurotypical children 
under the 8th percentile for males and under the 10th percentile for females. 
• 
Clinically significant bradycardia, defined as HR > 2 SD below mean for age 
 
The following safety ESIs will only be assessed at in-person visits (Week 4 and Week 8): 
• 
Any clinically significant cardiac event (e.g., clinically significant changes on ECG) 
• 
Suicidality via the asQ Tool (see Section 6.10) 
 
Guidelines for Determining Seriousness  
A serious adverse event (SAE) or serious suspected adverse reaction or serious adverse 
reaction or serious event of special interest as determined by the investigator or the sponsor 
is any event that results in any of the following outcomes: 
• 
Death 
• 
Life-threatening AE (“life-threatening” means that the study participant was, in the 
opinion of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred and required immediate intervention) 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Congenital anomaly or birth defect 
• 
Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention 
to prevent one of the outcomes listed in the above definition of serious event 
 
Guidelines for Assessing Intensity  
The investigator/delegate (defined as a clinician licensed to make a diagnosis) will use the 
following definitions when assessing intensity of an event: 
• 
Mild - Participant is aware of symptoms or has minor findings but tolerates them well, 
and no or minimal intervention required  
• 
Moderate - Participant experiences enough symptoms or findings to require intervention  
• 
Severe - Participant experiences symptoms or findings that require significant 
intervention  
 
Guidelines for Assessing Causality  
The investigator/delegate (defined as a clinician licensed to make a diagnosis) will use the 
following question when assessing causality of an event to study drug: Is there a reasonable 
possibility that the drug caused the event? “Reasonable possibility” means that there is 
evidence to suggest a causal relationship between the study drug and the AE. An affirmative 
answer designates the event as a SAR. 
 
Collection Period and Reporting Procedures  
AE information will be gained from direct monitoring of the study participants as well as from 
clinician observation and self-reporting by the study participants or their guardians. The 
investigator/delegate (defined as a clinician licensed to make a diagnosis) must document their 

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assessment of severity and causality in the participant records in a timely manner and submit 
safety reports as required by their institutional review board (IRB)/research ethics board 
(REB)/institutional ethics committee (IEC). 
AEs, safety ESIs, SAEs and SUSARs will be collected for all participants, following the first 
study product administration through 5 (+ 2) days after the last study product dose. AEs directly 
related to study procedures (e.g., blood collection) during the screening period will also be 
collected. 
Safety ESIs will be captured on the Dose Assessment Form electronic case report forms 
(eCRFs) to provide uniform data collection and will not be reported separately as AEs. As these 
are expected pre-specified safety ESIs, they will not be reported in an expedited manner but will 
be reviewed by the MM and the BPCA Data Safety Monitoring Board (DSMB) convened by 
NICHD and reported to the FDA in the annual report.  
Safety ESIs that are associated with any of the criteria that define the event as an SAE will be 
reported on the AE/SAE CRF set. 
Deaths occurring during the study participation, irrespective of causality will be reported on the 
AE/SAE CRF set. 
 
Safety Event Follow up and Sponsor Reporting 
AEs and SAEs directly related to study procedures will be followed until resolution even if this 
extends beyond the study-reporting period. Resolution of an AE is defined as the return to 
pretreatment status or stabilization of the condition with the expectation that it will remain 
chronic. If the event resolves during the study or follow-up period, a resolution date should be 
documented on the eCRF.  
AEs directly related to study procedures and safety ESIs (that are not defined as an SAE) will 
be reported in the data system within 7 days of identification/site awareness.  
SAEs, SUSARs, and safety ESIs that are associated with any of the criteria that define the 
event as an SAE will be reported in the data system within 24 hours of identification/site 
awareness. Upon entry in the Electronic Data Capture (EDC) system, these events will generate 
an automatic email notification to the DCC, DCC MM, and the sponsor. The 
investigator/delegate (defined as a clinician licensed to make a diagnosis) must document their 
assessment of severity and causality in the participant records in a timely manner and submit 
safety reports as required by their IRB/REB/IEC. 
The DCC MM will review all events at the time they are reported. Any event that requires 
expedited reporting based on federal regulations (21CFR 312.32) will be forwarded to the IND 
sponsor or the in-country designee. The IND sponsor or its representative will submit expedited 
safety reports (e.g., IND safety reports) to the regulatory agencies as necessary. 
For non-US sites, the sponsor investigator’s in-country designee must comply with all local 
regulatory requirements related to submitting reportable events to a regulatory authority and 
IEC. Documentation of the submissions must be retained for each reported event (annual or 
expedited) and provided to the DCC. The sponsor-investigator (or designee) will inform the 
investigators of any SUSAR safety reports submitted to a regulatory authority. 
 Pregnancy 
Contraception is allowed but will not be required for participants. Although not considered an 
AE, if a pregnancy occurs during the study, it must be reported immediately by the site. The 
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given an appropriate referral, and followed until resolution of the pregnancy. At the time of study 
product discontinuation, the participant will be asked to complete an ECG and provide a PK 
blood sample and their parent(s)/legal guardian(s) will be asked to complete the ABC. No 
further procedures will be done. Participants will then be followed for safety for at least 5 (+ 2) 
days after the last study dose. The site must document that they have informed the Sponsor, 
advised the participant to obtain appropriate prenatal medical care, and referred the participant 
for such care.  
The site may be required to inform parent(s)/legal guardian(s) about pregnancies according to 
local/state laws. In addition, per the consent, researchers will follow the participant for the 
duration of the pregnancy and to obtain information (via direct examination or medical record 
review) to determine whether the resulting fetus/newborn survived delivery or had any 
congenital abnormalities. If the fetus/newborn does not survive delivery or any congenital 
abnormalities are present, these must be reported as an SAE following the usual requirements 
for SAE reporting. Please note that if a pregnancy is reported, the participant’s subsequent 
weight, vital sign, and laboratory data will not be included in analyses for these variables. If the 
pregnancy is terminated, elective or otherwise, within the first 12 weeks of the pregnancy, 
inclusion of the participant’s subsequent weight/height, vital signs, and laboratory data in the 
analyses will be determined by the PTN study team. 
 
Regulatory Reporting  
Any event that requires expedited reporting based on federal regulations will be forwarded to 
the IND sponsor via reporting on the study specific eCRF. The IND sponsor or its representative 
as detailed in the Transfer of Regulatory Obligations (TORO) will submit expedited safety 
reports (e.g., IND safety reports) to the FDA and other regulatory agencies as necessary and 
will inform the investigators of such regulatory reports. Site investigators must submit safety 
reports as required by their IRB/REB/IEC. Documentation of the submission and receipt by the 
IRB/REB/IEC must be retained for each expedited safety report.  
Any event that requires reporting to Regulatory Authorities (e.g., SUSARS) based on applicable 
national regulations will be forwarded to the IND sponsor in time to meet reporting requirements. 
 
Data & Safety Oversight (Medical Monitor/Data Safety Monitoring Board) 
The study will be monitored by the BPCA DSMB. The DSMB is chartered by NIH to support all 
research activities conducted under the PTN. 
In addition, the study has designated a qualified and experienced physician not otherwise 
associated with this protocol to serve as the MM and review all SAEs at the time they are 
reported and/or updated. The MM may request additional information regarding a site reported 
SAE; the site PI is expected to provide requested information or materials to the MM in an 
expeditious manner to support the writing/submission of study safety reports. The MM will be 
available to study sites as needed. The study IND sponsor will also review all SAEs to 
determine regulatory reporting and will be available to sites as needed. 
If safety concerns are identified, the MM may request a meeting of the DSMB to review safety 
data. The MM will also provide an initial report to the study PI/sponsor and an unbiased written 
report to the DSMB of the event per the DSMB charter/safety monitoring plan. At a minimum, 
the MM will comment on the outcomes of the SAE and the relationship of the SAE to the study 
product. The MM will also indicate whether they concur with the details of the report provided by 
the study site investigator. If no SAEs prompt review at an earlier time point, the DSMB will 
review AEs and SAEs per the DSMB charter. 

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The DSMB will convene and make recommendations on termination of the study based on 
review of safety reports and halting rules. The safety data will be compiled by the DCC. Based 
on the recommendations of the DSMB, PTN, and NIH/NICHD, the IND sponsor will make a 
decision to terminate or continue the study. 
Ad Hoc Meetings of the DSMB: The DSMB may convene an ad hoc meeting to discuss any 
issue of data and safety raised by the site investigator, the MM, the IND sponsor, NICHD, or a 
member of the DSMB. At the discretion of the investigators, the IND sponsor, NICHD, and 
DSMB members, a non-serious AE that is associated with the product or procedures may be 
considered as a trigger for an ad hoc DSMB meeting to assess the safety of the product, without 
resulting in halting the enrollment of the trial. 

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8 STUDY HALTING/TERMINATION 
 
Study or Site Halting Criteria/Termination Criteria 
This study may be terminated at any time by NICHD, the IND sponsor, or via recommendations 
by the DSMB to NICHD. 
Reasons for termination include, but are not limited to, if in their judgment, there are no further 
benefits to be achieved from the study or if the treatment presents an unreasonable and 
significant risk to participants. If the study is terminated, notifications will be made to the 
regulatory authorities (e.g., FDA), investigators, IRBs/REBs, or study participants, in accordance 
with all applicable regulations governing the study and site/investigator. 
A participating site/investigator may be terminated at any time by the sponsor, regulatory 
authority or by a ruling of the IRB/REB. Possible reasons for termination of the study at a site 
include, but are not limited to: 
• 
Non-compliance with signed agreements, statements, or undertakings 
• 
Safety concerns 
• 
Inaccurate or incomplete data collection 
• 
Falsification of records 
• 
Failure to adhere to the protocol 
If the site/investigator is terminated, notifications will be made to regulatory authorities, 
IRBs/REBs, or other concerned parties in accordance with the applicable regulations governing 
the study and site/investigator. 
 
Halting Rules  
No halting rules are planned.  
 

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9 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of study 
participants are protected, that the reported study data are attributable, legible, 
contemporaneous, original, accurate, complete (ALCOA-C), and that the conduct of the study is 
in compliance with the currently approved protocol/amendment(s), with ICH GCP [E6 (R2)], and 
with applicable regulatory requirement(s), including 21 CFR 312 Subpart D Responsibilities of 
Sponsors and Investigators. 
The PTN PI or the DCC as detailed in the TORO, or their designee will conduct site-monitoring 
visits. Site visits will be made at standard intervals as defined by the clinical site monitoring plan 
appendix but may be made more frequently as directed by the DCC, IND sponsor, and/or 
NICHD. Monitoring visits will include, but are not limited to, review of regulatory files, 
accountability records, data collection forms, informed consent forms, medical and laboratory 
reports, and protocol compliance. Study monitors will meet with investigators to discuss any 
problems and actions to be taken and document visit findings and discussions. 
The study-specific clinical site monitoring plan appendix will supplement the BPCA project-wide 
clinical monitoring plan based on protocol risk assessments. 

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10 STATISTICAL CONSIDERATIONS 
Efficacy, PK, safety, and exploratory analyses will be conducted. Participant demographics will 
be summarized. In addition, the number of participants enrolled, completed or discontinued 
early from study, and the reasons for discontinuation will also be summarized. 
Descriptive statistics, such as the number of observations, mean, median, 95% confidence 
interval, standard deviation (SD), standard error, minimum, and maximum, will be considered for 
continuous variables (e.g., age, weight, etc.). Other descriptive statistics, such as counts, 
proportions, and/or percentages, will be presented to summarize discrete variables (e.g., sex, 
race, etc.).  
 Study Hypotheses 
Improvement in the ABC-H subscale from baseline over an 8-week trial will be greater with GIR 
compared to placebo in children with DS. 
 Study Endpoints 
 Primary Endpoint 
Primary Endpoint: 
• 
Change from baseline to Week 8 of the parent-rated ABC-H subscale score 
The following will serve as the secondary efficacy endpoints: 
• 
Change from baseline to Week 4 of the parent-rated ABC-H subscale score  
• 
Proportion of participants with a CGI-I score of 2 or better at Week 4 and Week 8 
 Secondary Endpoints 
The following safety endpoints will be collected throughout the Week-8 treatment period of the 
study: 
• 
Incidence of SAEs 
• 
Incidence of safety ESIs 
• 
Incidence of AEs 
 Exploratory Endpoints 
The following PK endpoints will be estimated at Week 4 and Week 8: 
• 
Guanfacine HCl plasma concentrations (Cmax,ss and Cmin,ss) 
• 
Time at peak concentration (Tmax,ss)  
• 
Apparent area under the concentration versus time curve at steady state (AUCss/F)  
• 
Apparent clearance (CLss/F) 
• 
Volume of distribution (V/F) 
• 
Half-life (t1/2) 
The following will be used to characterize the exposure-response relationship of GIR for the 
treatment of hyperactivity/impulsivity, inattention, and sleep quality in children with DS at Week 
4 and Week 8: 
• 
Guanfacine HCl plasma concentrations (Cmax,ss and Cmin,ss)  
• 
Area under the concentration time curve (AUCss) 
• 
ABC-H subscale score 
• 
CGI-I 

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• 
Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) 
• 
Child’s Sleep Habits Questionnaire (CSHQ) 
 Analysis Population 
 Intention-to-Treat (ITT) Population 
The ITT population consists of all randomized participants. 
 Per-Protocol Population 
Analyses may be conducted for a per-protocol population that only considers participants who 
are at least 70% compliant in taking study product for the 8-week study period and who receive 
the correct randomized treatment.  
 PK Population 
All participants enrolled with at least 1 evaluable PK sample will be included in the PK analysis. 
 Safety Population 
The safety population includes all participants who consume at least one dose of study product. 
This population may be identical to the ITT population. 
 Efficacy Population 
The efficacy population includes all ITT participants with at least 1 follow-up efficacy 
measurement at Week 4 or Week 8. This population may be identical to the ITT population. 
  Analysis Plan 
Descriptive statistics, such as number of observations, mean, median, SD, standard error, 
minimum, and maximum, will be presented for continuous variables (e.g., age, weight, etc.). 
Other descriptive statistics, such as counts, proportions, and/or percentages, will be presented 
to summarize discrete variables (e.g., race, sex, etc.). All descriptive analyses will be presented 
by appropriate treatment group and overall. A 95% confidence level will be used for confidence 
intervals. A detailed description of statistical methods and secondary analyses will be prepared 
and presented in the statistical analysis plan prior to data lock for final analyses. 
 Primary Analysis 
The primary objective of this study is to determine GIR efficacy for the treatment of 
hyperactivity, inattention, and impulsivity in children with DS using the ABC-H scale. This 
objective will be evaluated using the endpoint of change from baseline to Week 8 of the ABC-H 
subscale score. The ABC-H subscale is a continuous scale with a minimum score of zero to a 
maximum score of 48, so the primary analysis will be conducted assuming a normal distribution. 
A mixed effect model analysis will be conducted to compare the change in ABC-H subscale 
score from baseline. Analysis will be conducted in SAS statistical analysis software using a 
PROC MIXED procedure. Fixed effects in the model will include indicator for the treatment 
assignment (GIR vs. placebo), baseline ABC-H score, and assessment week. To account for 
the correlation of longitudinal scores collected at baseline, Week 4, and Week 8, a participant 
level random intercept will be included in the model. The primary endpoint (effect size, p-value, 
and 95% confidence interval) of difference in the change from baseline to Week 8 of the ABC-H 
subscale will be evaluated using a contrast statement in the model. Additional analysis to 
evaluate impact of other covariates, including age, sex, weight, comorbid diagnosis of ASD, use 
of alternative agents(s) to treat ADHD, site, cumulative dose, demographics, may also be 
conducted. A sensitivity analysis may also be performed to determine how the missing data 
mechanism affects the primary outcome results. 

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Secondary efficacy outcome measures: GIR effectiveness for the treatment of hyperactivity, 
impulsivity, and inattention in children with DS will also be assessed using change from baseline 
to Week 4 of the ABC-H subscale score and with the CGI-I specific to hyperactivity, inattention, 
and impulsivity behaviors. The change from baseline to Week 4 of the ABC-H subscale score 
will be analyzed using the mixed effects model described above. The CGI-I is measured on a 
7 point Likert scale from “very much improved” to “very much worse.” The proportion of 
participants with a CGI-I of “1-very much improved” or “2-much improved” will be analyzed as a 
dichotomous outcome. These dichotomized outcomes will be analyzed using a generalized 
linear mixed model with binary distribution and logit link. All mixed models for secondary efficacy 
endpoints will include covariates identified above for the analysis of primary efficacy endpoint. 
In addition to the modelling analysis to obtain the effect size, p-value, and 95% confidence 
intervals, summary statistics for continuous, nominal, and ordinal outcomes at each of the visits 
will be presented by treatment group (GIR vs. placebo) and overall. 
Table 4. Distribution of CGI-I for Secondary Efficacy Outcome Measure  
Scale 
Distribution of Outcome Scale 
Outcome Values 
The Clinical Global 
Impressions 
Scale - Improvement (CGI-I) 
Ordinal  
0 = not assessed 
1 = very much improved 
2 = much improved 
3 = minimally improved 
4 = no change 
5 = minimally worse 
6 = much worse 
7 = very much worse 
 
  Secondary Analysis 
Safety profile of GIR will be presented using AEs and solicited safety ESIs. Number of AEs, 
SAEs, and SUSARS will be summarized by treatment group (GIR vs. placebo) and overall, by 
severity, and by each Medical Dictionary for Regulatory Activities (MedDRA®) system organ 
class and preferred term. 
Incidence of safety ESIs will also be presented by treatment group (GIR vs. placebo) and 
overall. Additional model based analyses of safety ESIs will be performed to estimate treatment 
effect adjusted for baseline covariates and cumulative dose. 
 Exploratory Analysis 
Exploratory Analysis 1: Characterize GIR exposure in children with DS. 
The dosing, sampling, and demographic information collected by the study will be merged with 
bioanalytical information to create a PK dataset for GIR. Because a sparse sampling scheme 
will be employed in this study, population PK will be used to characterize GIR PK. If a 
relationship between exposure and response is observed, population PK or exposure-response 
models may be developed.  
A detailed description of PK/PD analyses will be described in the PK Analysis Plan. Briefly, the 
following analyses are anticipated depending on the adequacy of the collected data: 
 
 
 

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Population PK Analysis 
Pharmacokinetic (PK) models for the pooled concentration data of GIR will be explored by 
non-linear mixed effects modeling using NONMEM or Phoenix NLME software. Appropriate 
compartmental models will be examined, and between-participant variability on model 
parameters will be explored. Covariate analysis will examine the correlation between model 
parameters with demographic factors (e.g., weight, body mass index (BMI), sex, race, lab 
values, and obesity status) and co-administered medications. Appropriate covariates will be 
incorporated into the model using a standard forward-addition backward-elimination technique. 
Standard model diagnostic plots and procedures will be used to evaluate model 
appropriateness. Empiric Bayesian estimates of individual participant PK parameters will be 
generated from the final model. Model evaluation will be performed by visual predictive check 
and bootstrapping procedures, as needed. 
As appropriate, the following apparent PK parameters may be estimated at steady state: 
systemic clearance (CLss/F), volume of distribution (V/F), maximum concentration (Cmax,ss), 
minimum concentration (Cmin,ss), half-life (t1/2), and area under the curve (AUCss/F). Other PK 
parameters may be estimated according to the adequacy of sampling. 
Exploratory Analysis 2: Characterize the exposure-response relationship of GIR for the 
treatment of hyperactivity/impulsivity, inattention, and sleep quality in children with DS. 
Exposure-Response (ER) Analysis: 
A population ER analysis may be performed to characterize the PK/ER relationship between 
GIR exposure (e.g., Cmax,ss, AUCss) and selected safety and efficacy endpoints (e.g., 
hyperactivity, impulsivity, inattention, or sleep quality in children is observed). The sleep quality 
will be assessed via the CSHQ and ESS-CHAD (see Table 5). These are continuous outcomes 
that will be analyzed similar to the primary outcome using a mixed effects model. Epworth 
Sleepiness Scale for Children and Adolescents (ESS-CHAD) will also be analyzed as a 
dichotomous outcome; scores ≥ 10 are “sleepy” and scores <10 are “normal” using a 
generalized linear mixed model with binary distribution and logit link. 
Table 5. Distribution of Scales for Exploratory Outcome Sleep Quality Measures (CSHQ 
and ESS-CHAD) 
Scale 
Distribution of Outcome Scale Outcome Values 
Child’s Sleep Habits 
Questionnaire 
(CSHQ, Abbreviated 
Version) 
Continuous 
Minimum Total Score: 33 
Maximum Total Score: 99 
Epworth Sleepiness Scale 
for Children and 
Adolescents (ESS-CHAD) 
Continuous 
Minimum Total Score: 0 
Maximum Total Score: 24 
Different PK/ER models, including logistic regression model for binary safety outcomes, efficacy 
outcomes, and linear, log-linear, and Emax models for continuous safety/efficacy outcomes, may 
be explored. The ER model development, evaluation, and validation will be similar to that 
described above for population PK model. 
 Demographics and Baseline Characteristics 
The number of participants who either completed or discontinued early from the study will be 
summarized. Demographic and baseline characteristics will be summarized and compared 
between the study drug and placebo arms. Study product administration will be summarized in 
terms of number of days of dosing. 

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 Sample Size Considerations 
The primary hypothesis is that change from baseline on ABC-H subscale over the 8-week trial 
will be greater in GIR compared to placebo. In a randomized clinical trial of GER in ASD,15 the 
guanfacine group showed a 43.6% decline in scores on the ABC-H subscale (mean scores of 
34.2 at baseline to 19.3 at week 8 visit) compared with a 13.2% decrease in the placebo group 
(mean scores of 34.2 at baseline to 29.7 at week 8 visit; effect size Cohen’s d=1.67). Modal 
doses of GER in this trial were 3 mg/day (range 1 mg/day to 4 mg/day). In another single arm 
GIR trial,6 Capone et al. reported a mean decline in ABC-H scores from baseline to follow-up of 
25% (mean scores of 29 at baseline to 21.2 at follow-up visit, Cohen’s d = 0.9) over an average 
of 21 weeks. Average doses of GIR in the Capone study were 1.1 (± 0.5) mg/day, reflecting the 
more conservative approach to dose escalation in this patient population with DS. A decline in 
the ABC-H scale scores in the guanfacine group ranged from 25% to 43% across these studies. 
Although there are no identified studies characterizing a “clinically meaningful change” in ABC-H 
scores, the open-label Capone study revealed a significant improvement in target behaviors 
characterized as “inattention” and “activity” with the associated 25% improvement in ABC-H 
scores.6  
Based on these studies, a conservative effect size of Cohen’s d = 0.9 was assumed for the 
current randomized trial, which will be equivalent to assuming a 31.3% decline in the guanfacine 
arm (mean scores of 30 at Baseline to 20.6 at Week 8, SD = 6) compared with a 13.3% 
decrease in the placebo arm (mean scores of 30 at Baseline to 26 at Week 8, SD = 6). A 
sample size of 48 will achieve greater than 80% power to reject the null hypothesis of zero 
effect size when the population effect size is 0.90 and the significance level (alpha) is  
0.050 using a two-sided two-sample equal-variance t-test. If a 20% dropout is assumed,  
N=60 participants will need to be enrolled. 

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11 FUTURE USE OF STUDY RECORDS AND BIOLOGICAL 
SPECIMENS 
The medical data and study information entered in the participant’s medical records will be kept 
per individual site policies for medical record retention. Other study records held at the study 
site will be kept until the FDA has completed any necessary review of the study results, or for a 
minimum of 2 years after the study has ended – whichever is longer. The research data 
collected in this study, and provided to the sponsor, will be kept indefinitely.  
Information about this study, including study results, will be published without further permission 
from the participant as detailed in the informed consent form (ICF). Participants will not be 
identified in any publications or presentations made about the study.  
After the study is completed, information about the study, including study data, will be submitted 
to the NIH data repository (https://dash.nichd.nih.gov and referred to below as “DASH”). With 
NIH approval, the data submitted to DASH may be used by other researchers for future 
research. The study data submitted to DASH will be de-identified, meaning it will not include any 
information that can identify the participant. The study team may also share the de-identified 
study data with other researchers. When the participant’s de-identified study data are provided 
to other researchers for the purposes of future research, it will be done without obtaining 
additional permission from the participant.  
Biological specimens collected for study-specific testing will be labeled at the site with a 
study-provided barcode label. The specimen labels will only contain a unique code number; it 
will not include protected health information (PHI) or any other information that could identify the 
study participant. Specimens will be stored at the site and then shipped to a central lab for 
study-specific testing. After analysis, specimens will be stored until the FDA completes review of 
the final research study report and proposed drug label changes. Once FDA review of the study 
results is complete, and after consent for future use of these specimens is confirmed, the 
specimens will be submitted to an NIH storage facility. With NIH approval, the de-identified 
study specimens may be made available to other researchers for future research without 
obtaining additional permission from the participant. Although whole genome sequencing 
(WGS) is not part of this study, study specimens containing genetic materials, may be made 
available to other researchers who may conduct WGS in the future. The participant’s study 
specimens will not be sold to anyone; however, the use of these specimens may result in 
commercial profit. There is no provision to provide the participant with financial compensation 
beyond what is described in the ICF. Biological specimens may be stored indefinitely. If a 
participant decides to withdraw permission to use their study data or specimens, they will be 
instructed per the ICF to contact the site investigator. Study data and samples that have been 
recorded / collected prior to withdrawal will continue to be used, but no new data or specimens 
will be collected. 

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12 SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6 (R2), Section 4.9 and 21 CFR 312.62, and regulatory and institutional 
requirements for the protection of confidentiality of participants. Each site will permit authorized 
representatives of the sponsor, its designees, and appropriate regulatory agencies to examine 
(and, when required by applicable law, to copy) clinical records for the purposes of quality 
assurance reviews, audits, and evaluation of the study safety and progress. These 
representatives will be permitted access to all source data, which include, but are not limited to, 
hospital records, clinical and office charts, laboratory notes, memoranda, participants’ memory 
aid or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and participant files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. Data collection forms will be derived from the eCRFs and provided 
by DCC. 
 

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13 QUALITY CONTROL AND QUALITY ASSURANCE 
The site PI will provide direct access to all trial-related sites, source data/documents, data 
collection forms, and reports for the purpose of monitoring and auditing by the sponsor and its 
designees, and inspection by local and regulatory authorities. The PI will ensure that all study 
personnel are appropriately trained and applicable documentations are maintained on site. 
The BPCA-designated clinical monitors will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements. Clinical monitoring reports will be submitted to the PI, PTN, 
and NIH/NICHD. 
The DCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for prompt clarification and resolution. 

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14 ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 Informed Consent Process 
Informed consent is a process that is initiated prior to the participant/child’s parent/legal 
guardian agreeing to participate in the study and continuing throughout the individual’s study 
participation.  
This study enrolls children. Per 21 CFR 50.3 (o) and 45 CFR 46.402 (a), “children” is defined as 
persons who have not attained the legal age for consent to treatments or procedures involved in 
clinical investigations (or the research), under the applicable law of the jurisdiction in which the 
clinical investigation (or the research) will be conducted and so the legal age for consent may be 
different in different jurisdictions. The process for requesting permission from parents/legal 
guardians, pediatric assent, and adult informed consent are described in the MOP.  
 Permission from Parents, Legal Guardians, or Legally Authorized 
Representatives 
Under 21 CFR 50.3:  
• 
“permission” means “the agreement of parent(s) or legal guardian to the participation of 
their child or ward in a clinical investigation”; 
• 
“parent” means “a child’s biological or adoptive parent”; 
• 
“guardian” means “an individual who is authorized under applicable State or local law to 
consent on behalf of a child to general medical care”; and  
• 
“legally authorized representative” (LAR) means “an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective subject to the 
subject’s participant in the procedure(s) involved in the research. 
Per 21 CFR 50.55 and 45 CFR 46.408, where parental/legal guardian permission is to be 
obtained, the IRB of record at each site must determine whether permission from one parent or 
both parents is required. 
Extensive discussion of risks and possible benefits of participation in this study will be provided 
to the participant’s parent(s)/legal guardian(s). Consent forms describing in detail the study 
procedures and risks are given to the participant’s parent(s)/legal guardian(s), and written 
documentation of informed consent is required prior to enrolling in the study. Consent forms will 
be IRB-approved, and the participant’s parent(s)/legal guardian(s) will be asked to read and 
review the document. Upon reviewing the document, the investigator will explain the research 
study to the participant’s parent(s)/legal guardian(s) and answer any questions that may arise. 
The participant’s parent(s)/legal guardian(s) will provide consent prior to being enrolled in the 
study. 
The IND sponsor, or designee will provide the investigator, in writing, any new information that 
bears significantly on the participant’s risk to participating in the study. This new information will 
be communicated by the investigator to participants who consent to participate in the trial in 
accordance with IRB requirements. The informed consent document will be updated, and 
participants will be re-consented, if necessary. Site staff may employ IRB-approved recruitment 
efforts prior to the participant consenting; however, before any protocol-specific procedures are 
performed to determine protocol eligibility, an informed consent form must be executed. By 
providing informed consent, the participant agrees to complete all evaluations required by the 
trial, unless the participant withdraws voluntarily or is terminated from the trial for any reason. 
Participants may be asked to authorize exchange of information between the study staff and 
their primary care provider and/or other significant medical providers. 

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 Pediatric Assent 
The participant should be informed about the study to the extent compatible with the 
participant’s understanding. As required by local regulatory authorities, the participant should 
assent, sign, and personally date the written consent form. A separate IRB/REB/IEC-approved 
assent form, describing (in simplified terms) the details of the study, study procedures, and 
risks, may be used. Assent forms are not substitutes for the consent form signed by the 
participant’s legally acceptable representative. Consult with the institution’s policies regarding 
enrollment of participants who are unable to provide informed consent for themselves. 
Under 21 CFR 50.52, and 50.55, and 45 CFR Part 46.405, the IRB of record is responsible for 
determining that adequate provisions are made for soliciting the assent of children. 
  Assent Process 
This study includes minor participants who may be enrolled in the study only with the consent of 
their parent(s)/legal guardian(s). The minor participant should be informed about the study to 
the extent compatible with their neurodevelopmental abilities. Participants who are nonverbal or 
minimally verbal, have significant intellectual disability, are younger than seven to ten years old 
(depending on local standards), or have marked thought disorganization or positive psychotic 
symptoms are very unlikely to be considered developmentally able to provide assent. Sites 
should follow the minimal age requirements for assent, per their local standards. If the Site 
PI/designee, who is a clinician licensed to make a diagnosis, judges the participant to be 
developmentally able to understand the concepts of voluntary participation in research, the 
participant will be given a simplified, developmentally appropriate assent form to review, will be 
asked to share any questions they may have, and then will be asked to sign and personally date 
the assent form. 
Assent does not substitute for the permission form signed by the participant’s parent(s)/legal 
guardian(s). Sites should consult with their institution’s policies regarding enrollment of 
participants who are unable to provide informed consent. 
 Documentation of Permission, Assent, and Consent 
Permission, assent, and consent must be documented using forms and processes determined 
by the Duke University Health System (DUHS) IRB and the site’s IRB of record. 
Prior to enrollment of participants into this trial, the protocol, the applicable informed 
consent/assent template, and any materials or advertisements presented to participants will be 
reviewed and approved by the DUHS IRB. The consent/assent templates approved by DUHS 
IRB will then be provided to sites and revised as necessary to comply with local regulations and 
institutional requirements. Sites are required to submit all changes to the templates to the DCC, 
which ensures compliance with U.S. and international regulations and sponsor (NIH) policies, 
prior to submission and approval to the IRB/REB/IEC of record for each site. Notification of the 
IRB/REB/IEC’s approval, its composition, and the institution’s federal-wide assurance number 
(FWA) will be provided to the DCC. 
Should amendments to the protocol and consent/assent documents be required, the 
amendments will be written by the sponsor, approved by the DUHS IRB, and provided to the 
site investigator for submission to the site’s IRB/REB/IEC of record. 
Participants may be compensated for their participation in this study. Compensation will be in 
accordance with the local IRB/REB/IEC’s policies and procedures and requires IRB/REB/IEC 
approval, and must be documented in the permission/consent/assent forms.  

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The IRB of record will determine whether one or two parent signatures are required at each site, 
based on the risk level of study or local regulatory requirements, and the participant or the 
participant’s parent, guardian, or LAR will be asked to read and review the document. 
For non-English speakers, a fully translated consent or an oral presentation accompanied by a 
short form may be used to obtain informed consent. The fully translated consent and the short 
form must be approved by the site’s IRB of record and executed according to local 
requirements.  
As appropriate, children will have the study explained to them as well in an understandable way, 
and their refusal to take part will be honored. As required by local regulatory authorities, children 
may sign an assent form. Upon reviewing the document, the investigator will explain the 
research study to the participant and answer any questions that may arise. The 
participant/parent(s)/legal guardian(s) should have the opportunity to discuss the study and to 
think about it prior to agreeing to participate. Participant/parent(s)/legal guardian(s) must be 
informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. A copy of the executed informed consent document will be given to the 
participant/parent(s)/legal guardian(s) for their records.  
Site staff may employ IRB/REB/IEC-approved recruitment efforts prior to the participant 
consenting; however, before any protocol-specific procedures are performed to determine 
protocol eligibility, informed consent or waiver of informed consent must be obtained. The 
informed consent process will be conducted and the form fully executed, e.g., signed and dated, 
before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
The IND sponsor, or designee, will provide the investigator in writing with any new information 
that bears significantly on the participants' risk to receive the investigational product. This new 
information will be communicated by the site investigator to participants who consent to 
participate in the trial in accordance with IRB/REB/IEC requirements. The informed consent 
document will be updated, and participants will be re-consented, if necessary. 
 Confidentiality and Privacy 
All research activities will be conducted in as private a setting as possible. 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their agents. This confidentiality is extended to cover testing 
of biological specimens in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.  
The PI will ensure that the use and disclosure of PHI obtained during a research study complies 
with the HIPAA Privacy Rule. The rule provides United States federal protection for the privacy 
of PHI by implementing standards to protect and guard against the misuse of individually 
identifiable health information of participants participating in clinical trials. Authorization is 
required from each research participant (i.e., specific permission granted by an individual to a 
covered entity for the use or disclosure of an individual’s protected health information). A valid 
authorization must meet the implementation specifications under the HIPAA Privacy Rule. 
Authorization may be combined in the informed consent document (if approved by the IRB). 
The study monitor, other authorized representatives of the sponsor, representatives of the 
IRB/REB/IEC, and regulatory agencies may inspect all documents and records required to be 

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maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB/REB/IEC, Institutional policies, or 
sponsor requirements. Both the site PI and the Institution at which the study is contracted to be 
conducted will hold responsibility to maintain custody of all study records until the sponsor 
permits their destruction. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the DCC. Individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites and by the DCC research staff will be secured and 
password protected.  
To further protect the privacy of study participants, this study is covered by a Certificate of 
Confidentiality (CoC) from the National Institutes of Health. The CoC limits the ability of courts 
and other agencies from forcing the study team to share participant information or body fluids 
during a legal or legislative action without the participant’s permission. The CoC does not 
restrict the parents/legal guardian from sharing information voluntarily. 

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15 DATA HANDLING AND RECORD KEEPING 
The investigator is obligated to conduct this study in accordance with U.S. Federal Regulation 
21 CFR 312.60-68 as specified on the signed form FDA 1572, applicable state and federal laws, 
and the International Council for Harmonisation: Good Clinical Practice: Consolidation 
Guideline. The investigator is responsible for informing the IRB/REB/IEC of any safety issues 
related to the study and the study product, including reports of serious adverse events, and all 
IND safety reports, as required by their IRB/REB/IEC. 
 Data Handling 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. Data collection forms will be derived from the eCRFs and 
provided by the DCC to the sites to record and maintain data for each participant enrolled in the 
study. All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Permanent ink is required to ensure clarity of reproduced copies. When 
making a change or correction, the original entry should be crossed out with a single line, and 
the change should be initialed and dated. Do not erase, overwrite, or use correction fluid or tape 
on the original.  
Data reported in the eCRF should be consistent with the data collection form/source documents, 
or the discrepancies should be documented. The sponsor and/or its designee will provide 
guidance to investigators on making corrections to the data collection forms and eCRFs. 
 Data Management Responsibilities 
All data collection forms and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete. Adverse events must be 
graded, assessed for severity and causality by a licensed clinician, and reviewed by the site PI 
or designee. Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. During the study, the investigator must maintain complete, current and 
accurate documentation for the study. 
The DCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
 Data Capture Methods 
Clinical data (including AEs) will be entered into a 21 CFR Part 11-compliant web-based data 
capture system provided by the DCC. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the data 
collection forms/source documents. Some data, including the ABC, ESS-CHAD, CSHQ, and 
Study Diary will be collected via ePRO, a web-based platform for collecting data. The ePRO 
system can be used with an electronic device (computer, tablet, or phone). Paper completion, 
as well as telephone, email or text communication with site staff are options as well. A detailed 
description of the ePRO system is available in the MOP and study website. 
 Types of Data 
Data for this study will include behavioral/sleep quality/quality of life data, PK data, and safety. 
Details regarding specific data collected are described as endpoints in Sections 3 and 10.2. 
 

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 Timing/Reports 
The DSMB will convene and make recommendations on study continuation based on the safety 
data collected periodically. 
 Study Records Retention 
Study records and source documents will be kept until the FDA has completed any necessary 
review of the study results, or for a minimum of 2 years after the study has ended – whichever is 
longer. The research data collected in this study will be kept indefinitely.  
The disposition date related to FDA application will be posted on the PTN website for the 
Investigator’s reference.  
 Protocol Deviations 
A protocol deviation is any noncompliance/unplanned excursion from approved investigational 
plan (e.g., protocol, MOP), or ICH GCP guidelines. The noncompliance may be on the part of 
the participant, investigator, or site staff. Because of deviations, corrective actions are to be 
developed by the site and implemented promptly. For this study, participant/guardian refusal for 
blood collection or any missing Clinical Outcome Assessment (Section 6.9), except ABC score 
at Week 8 and those that are required to confirm eligibility, will not be considered protocol 
deviations in order to facilitate retention of participants for later study assessments, but will be 
tracked and reported to the sponsor. 
Each investigator must adhere to the investigational plan as detailed in the study protocol and/or 
associated study materials (e.g. MOPs, Forms Instructions, User Guides etc.). Each investigator 
will be responsible for the training of delegated staff and enrolling only those participants who 
have satisfied all protocol eligibility criteria. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation or within 5 working days of the 
scheduled protocol-required activity. All deviations must be promptly reported to the sponsor, 
via the DCC’s EDC system. 
All deviations from the protocol must be reported in the study records/data system. Protocol 
deviations must be submitted to the local IRB/REB/IEC per their guidelines. The site investigator 
and study staff are responsible for knowing and adhering to their IRB/REB/IEC requirements. 

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16 PUBLICATION POLICY  
Following completion of the study, the investigator may publish the results of this research in a 
scientific journal under the oversight/approval of the Publication Committee of the PTN. The 
PTN Publication Committee comprises representatives of the network cores, thought-leaders, 
DCC, and PTN and is responsible for generation and coordination of the publications that report 
scientific findings of the network. All public presentations (abstracts, manuscripts, slides and text 
of oral or other presentations, and text of any transmission through any electronic media) by 
participating investigators, participating institutions, DCC, and PTN that use PTN data and are 
intended to represent the PTN or are supported by the PTN will be reviewed by the Publication 
Committee per the Publication Committee charter.  
The Publication Committee guarantees that the study results are presented by experts in the 
field that have working knowledge of the study design, implementation, data synthesis/analysis, 
and interpretation. The committee goals are to ensure that any confidential or proprietary 
information is protected, and that all appropriate statistical analyses have been included.  
The PTN Publication Committee will adhere to the trials registration policy adopted by the 
International Committee of Medical Journal Editors (ICMJE) member journal. This policy 
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, 
which is sponsored by the National Library of Medicine. Other biomedical journals are 
considering adopting similar policies. It is the responsibility of the IND sponsor to register this 
trial in an acceptable registry. 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
participants to intervention or comparison groups to study the cause-and-effect relationship 
between a medical intervention and a health outcome. Studies designed for other purposes, 
such as to study pharmacokinetics or major toxicity (e.g., phase I trials), would be exempt from 
this policy. 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central an electronic version of their final, peer-reviewed 
manuscripts upon acceptance for publication, to be made publicly available no later than 
12 months after the official date of publication. The NIH Public Access Policy ensures the public 
has access to the published results of NIH-funded research. It requires investigators to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. Further, the policy stipulates that these papers must be 
accessible to the public on PubMed Central no later than 12 months after publication.  
Refer to: 
http://publicaccess.nih.gov/  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html 

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