Conditions: Anxiety Disorders,Generalized Anxiety Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 273
Healthy volunteers: no

Brief summary:
This is a study in minors (7 to 17 years old) diagnosed with generalized anxiety disorder (GAD) and evaluated using standard questionnaires as having at least moderate severity of GAD. Participating minors will be assigned to receive either the study drug escitalopram or a pill without any drug in it called a placebo. The purpose of this research is to study the safety and effectiveness of escitalopram in minors with GAD.

Detailed description:

Arms:
arm 1: Oral administration with the possibility of dose escalation to 20 mg/day at the investigator's discretion arm 2: Matching oral administration of placebo once daily

Interventions: intervention 1: Escitalopram intervention 2: Placebo
Intervention descriptions: intervention 1: 8-weeks of treatment followed by 1-week taper down period intervention 2: Matching oral administration of inactive substance once daily

Protocol document:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
A Randomized, Multicenter, Double-Blind, Flexibly-dosed, Efficacy and 
Safety Study of Escitalopram in the Treatment of Children and 
Adolescents With Generalized Anxiety Disorder 
 
 
Protocol Number: 
SCT-MD-60 
EudraCT Number: 
Not Applicable 
IND Number: 
058380 
Investigational Product: 
Escitalopram  
Phase: 
Phase 3 
Sponsor: 
Allergan 
5 Giralda Farms 
Madison, NJ 07940 
United States 
 
Contract Research Organization: Syneos Health 
1030 Sync Street 
Morrisville, NC 27560 
United States 
 
Protocol Date: 
Protocol Version 1.0: 27 Nov 2018 
Protocol Version 2.0: 15 Mar 2019 
Protocol Version 3.0: 30 June 2020 
 
Protocol Version: 
Version 3.0 
 
 
 
CONFIDENTIAL 
This protocol may not be reproduced or communicated to a third party without the 
written permission of Allergan. 
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1 
PROTOCOL APPROVAL SIGNATURES 
Protocol Title: 
A Randomized, Multicenter, Double-Blind, Flexibly-dosed, 
Efficacy and Safety Study of Escitalopram in the Treatment of 
Children and Adolescents With Generalized Anxiety Disorder 
Protocol Number: 
SCT-MD-60 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines for current Good Clinical Practice 
(cGCP) and applicable regulatory requirements. 
Sponsor Signatories 
 MS MD 
Vice President, Neuroscience Development 
AbbVie 
 
1 North Waukegan Road 
North Chicago, IL 60064 
United States 
 
 
 PhD DABT 
Vice President, Non-Clinical and Translational 
Sciences 
AbbVie 
2525 Dupont Drive 
Irvine, CA 92612 
United States 
 
 
 
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2 
STUDY PERSONNEL 
Sponsor Personnel 
Project Manager 
Name: 
 
Title: 
Associate Director, Clinical Trial Management 
Address: 
AbbVie 
2525 Dupont Drive 
Irvine, CA 92612 
United States 
Telephone No.: 
 
 
Statistician 
Name: 
 PhD 
Title: 
Director, Biostatistics 
Address: 
AbbVie 
5 Giralda Farms 
Madison, NJ 07940 
United States 
Telephone No.: 
 
 
Contract Research Organization Personnel 
Medical Director 
Name: 
 MD MBA 
Title: 
Senior Medical Director 
Address: 
Syneos Health 
1030 Sync Street 
Morrisville, NC 27560 
United States 
Telephone No.: 
 
 
In May 2020, AbbVie completed its acquisition of Allergan. Allergan remains sponsor 
of this study. AbbVie is used for the addressess of sponsor signatories and sponsor 
personnel.  
 
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3 
SYNOPSIS 
Protocol Number: 
SCT-MD-60 
Title: 
A Randomized, Multicenter, Double-Blind, Flexibly-dosed, Efficacy and Safety Study of Escitalopram in 
the Treatment of Children and Adolescents With Generalized Anxiety Disorder 
Investigational Product: 
Escitalopram 
Study Centers: 
Approximately 40 centers in the United States 
Phase: 
Phase 3 
Objectives: 
The primary objective of this study is to assess the safety and efficacy of escitalopram relative to placebo 
in the acute treatment of children (aged 7 through 11 years) and adolescents (aged 12 through 17 years) 
who meet criteria for generalized anxiety disorder (GAD) as defined in the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5).  
The secondary objective of this study is to characterize the pharmacokinetic (PK) profile of escitalopram 
in the pediatric population (aged 7 through 17 years). 
The exploratory objective of this study is to assess the exposure/dose-response relationship. 
Study Design: 
This is a randomized, multicenter, double-blind, flexibly-dosed, placebo-controlled parallel group study.  
During the coronavirus disease 2019 (COVID-19) pandemic, remote study visits are possible to avoid 
missing efficacy data, but not preferred over clinic visits.  
Number of Subjects: 
Approximately 430 subjects will be screened and a total of approximately 256 subjects are planned to be 
randomized in a 1:1 ratio to either escitalopram or placebo. The randomization schedule will be stratified 
by age at randomization (grouped as 7–11 years vs. 12–17 years) and sex, and blocked. The sample size 
may be increased based on the outcome of a blinded interim analysis but the number of subjects in each 
treatment arm will be capped at 160. 
Treatment: 
Subjects will begin with a 10 mg/day dose of escitalopram (taken orally) or matching placebo for the first 
2 weeks of double-blind treatment. At the end of Week 2, subjects who can tolerate the current dose of 
10 mg/day may have a dose escalation to 20 mg/day of escitalopram or matching placebo. Dose 
escalation will be at the investigator’s discretion taking into account the Clinical Global Impression of 
Severity (CGI-S) score. Subjects who remain on the 10 mg/day dose of escitalopram or matching placebo 
will be evaluated again at Week 4 for a possible dose escalation to 20 mg/day at the investigator’s 
discretion. The dose may be decreased from 20 mg/day to 10 mg/day following discussion with the 
medical director if the subject does not tolerate the 20 mg/day dose. 
Study Duration: 
The study design incorporates an up to 3-week screening period, an 8-week double-blind, acute treatment 
period, and a 1-week double-blind down taper period with a follow-up telephone contact 1 week after the 
end of the double-blind down taper period. 
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Study Population: 
Key inclusion criteria: 
• 
Subjects, male or female, must be between 7 and 17 years old, inclusive, at the time of 
consent/assent and at the Baseline Visit. 
• 
Subject meets DSM-5 criteria for a primary diagnosis of GAD at Screening established by a 
comprehensive psychiatric evaluation and confirmed/supported using the Mini-International 
Neuropsychiatric Interview for Children and Adolescents (MINI Kid). 
• 
Diagnosis of moderate or greater severity of GAD as determined by the following: 
a. 
Presence of ≥4 symptoms identified on the generalized anxiety subsection of the 
Pediatric Anxiety Rating Scale (PARS) symptom checklist, 2 of which are “excessive 
worry” and “dread or fearful anticipation” (nonspecific) at the Screening and Baseline 
Visits.  
b. PARS severity score of ≥15 at the Screening and Baseline Visits for symptoms 
identified on the generalized anxiety subsection of PARS symptom checklist, derived 
by summing 5 of the 7 severity/impairment/interference items (2, 3 5, 6, and 7). 
c. 
Clinical Global Impression of Severity (CGI-S) rating of ≥4 at the Screening and 
Baseline Visits. 
• 
Male subjects who are sexually active with a partner of childbearing potential must use, with 
their partner, a condom plus an approved method of highly effective contraception from the time 
of informed consent until 14 days after the last dose of study drug. The following methods are 
acceptable: 
a. 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
i. oral 
ii. intravaginal 
iii. transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of ovulation 
i. oral 
ii. injectable 
iii. implantable intrauterine device 
iv. intrauterine hormone-releasing system 
c. 
Surgical sterilization (vasectomy or bilateral tubal occlusion) 
• 
Female subjects who are not of childbearing potential do not need to use any methods of 
contraception. This includes preadolescent and adolescent females who have not reached 
menarche. 
• 
Female subjects who are sexually active and are of childbearing potential must use, with their 
partner, an approved method of highly effective contraception from the time of informed consent 
until 14 days after the last dose of study drug. In this patient population, a subject would be 
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considered sexually active if they participate in any behaviors which may result in pregnancy. 
The following methods are acceptable: 
a. 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation and a barrier method (ie, condom for male partner): 
i. oral 
ii. intravaginal 
iii. transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of ovulation and a 
barrier method (ie, condom for male partner): 
i. oral 
ii. injectable 
iii. implantable intrauterine device 
iv. intrauterine hormone-releasing system 
c. 
Surgical sterilization (vasectomy or bilateral tubal occlusion)  
• 
Strict abstinence is acceptable when it is in line with the subject’s preferred and usual lifestyle. If 
a subject is usually not sexually active but becomes active, they, with their partner, must comply 
with the contraceptive requirements detailed above.  
• 
Female subjects of childbearing potential must have a negative serum beta-human chorionic 
gonadotropin pregnancy test at the Screening Visit, a negative urine pregnancy test at the 
Baseline Visit, and must not be breastfeeding.  
• 
Subject must be in general good health, weigh at least 20 kg and be within the 3rd to 97th 
percentile for gender specific body mass index (BMI)-for-age from the Centers for Disease 
Control and Prevention growth charts at the Screening and Baseline Visits. 
Key exclusion criteria: 
• 
Current diagnosis of a major depressive episode, or lifetime diagnosis of 
attention-deficit/hyperactivity disorder, bipolar disorder, psychotic depression, schizophrenia or 
other psychotic disorder, feeding and/or eating disorder, obsessive-compulsive disorder, conduct 
disorder, oppositional defiant disorder, post-traumatic stress disorder, panic disorder, or 
pervasive development disorder.  
• 
Suspected or previously diagnosed intellectual disability disorder. 
• 
DSM-5-defined substance use disorder within a year (12 months) prior to Screening Visit. 
• 
Any secondary DSM-5 disorder that requires pharmacologic treatment or would be a potential 
confound to the study assessments or ability to participate in all study procedures, as determined 
by the investigator. 
• 
Environmental stressor (current or historic – eg, history of abuse/trauma, significant change in 
psychosocial status, significant injury) that, in the opinion of the investigator, may confound 
assessments or subject’s ability to complete all protocol requirements. 
• 
One or more first-degree relatives with diagnosed bipolar I disorder. 
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• 
Subject answers “yes” to “Suicidal Ideation” item 3 (active suicidal ideation with any methods, 
not plan, without intent to act), item 4 (active suicidal ideation with some intent to act, without 
specific plan) or item 5 (active suicidal ideation with specific plan and intent) within the past 
6 months and/or a lifetime history of suicidal behavior, as assessed by the Columbia-Suicide 
Severity Rating Scale (C-SSRS). 
• 
Subject is currently considered at risk for suicide in the opinion of the investigator. 
• 
Lack of response to 2 or more adequate trials of antidepressants or other anti-anxiety 
medications at a clinically appropriate dose for a minimum of 4 weeks for GAD at the time of 
screening or, in the judgement of the investigator, the patient had treatment-resistant GAD. 
• 
Change to psychotherapy (start, stop, or change in type, intensity, or frequency) in the 6 weeks 
prior to the Screening Visit. 
• 
History of seizure disorder (other than febrile seizures). 
• 
History of electroconvulsive therapy at any time during the subject’s lifetime.  
• 
Serious or unstable medical illness, or clinically significant laboratory or electrocardiogram 
(ECG) result that, in the opinion of the investigator, would compromise participation in the 
study, confound results, or be likely to lead to hospitalization during the course of the study. 
• 
Hypo- or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no change in 
dosage for at least 3 months before the Screening Visit. If thyroid-stimulating hormone (TSH) is 
abnormal, the subject must have a normal triiodothyronine (T3) and thyroxine (T4). 
• 
Use of biotin as a dietary supplement at more than 2.5 mg total per day within 7 days of the 
Screening Visit.  
• 
Initiated or discontinued hormone therapy (including oral contraceptives for female subjects) 
within 3 months prior to screening. 
• 
Taking any medications that are contraindicated to escitalopram (escitalopram oxalate). 
• 
Treatment with any investigational drug within 30 days or 5 half-lives (whichever is longer) 
prior to study entry. 
 
Primary Endpoint: 
The primary efficacy endpoint is the change from baseline to acute treatment endpoint (Week 8) in the 
PARS severity score. 
The PARS severity score for GAD is assessed for all symptoms identified in the generalized anxiety 
section of the PARS symptom checklist. The PARS severity score for GAD will be derived by summing 
5 of 7 severity/impairment/interference items (2, 3, 5, 6, and 7). 
Secondary Endpoints: 
The secondary efficacy endpoints are as follows: 
• 
Response rate on the PARS at acute treatment endpoint (Week 8)  
o 
Response is defined as a 50% improvement on the PARS severity score for GAD. 
• 
Remission rate on the PARS at acute treatment endpoint (Week 8)  
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o 
Remission is defined as PARS severity score for GAD <8 (using 6 PARS items: 2, 3, 4, 
5, 6, and 7) 
• 
Change on the CGI-S from baseline to acute treatment endpoint (Week 8) 
o 
Remission rate on CGI-S at acute treatment endpoint (Week 8). Remission rate is 
defined as the percentage of subjects having a CGI-S score ≤2 at endpoint.  
• 
Change on the Children’s Global Assessment Scale (CGAS) from baseline to acute treatment 
endpoint (Week 8) 
o 
Remission rate on the CGAS at acute treatment endpoint (Week 8). Functional 
remission is defined as CGAS >70. 
• 
COVID-19 impact assessment score at each visit. 
The safety endpoints during the double-blind treatment period are as follows: 
• 
Incidence of treatment-emergent adverse events. 
• 
Observed values and change from baseline in vital signs (blood pressure, pulse rate, temperature, 
respiration rate, height, weight, BMI, height percentile, weight percentile, and BMI percentile); 
incidence of vital sign potentially clinically significant (PCS) values. 
• 
Observed values and changes from baseline in ECG intervals and interpretation; incidence of 
ECG PCS values. 
• 
Observed values and changes from baseline in clinical laboratory assessments (hematology, 
chemistry, and urinalysis); incidence of clinical laboratory PCS values. 
• 
Incidence of suicidal ideation and/or suicidal behavior as determined by the C-SSRS. 
The PK endpoint is as follows: 
• 
PK parameters of escitalopram using a nonlinear mixed effects approach. 
The exposure/dose-response endpoints are as follows: 
• 
Relationship between efficacy parameters and plasma exposure using a nonlinear mixed effects 
approach. The relationship between safety parameters and plasma exposure may also be 
explored. 
Efficacy Assessments: 
The efficacy assessments include the PARS severity score for GAD, CGI-S, the CGAS, and a global 
COVID-19 impact assessment. 
Safety Assessments: 
The safety assessments include adverse events, vital signs, physical examination, ECGs, laboratory 
assessments, and the C-SSRS. 
Pharmacokinetic Assessments: 
Plasma concentrations of escitalopram and S-demethylcitalopram. 
Statistical Analysis: 
For the analysis of the primary efficacy endpoint (change from baseline in PARS severity score), a mixed 
model for repeated measures (MMRM) will be used for the comparison of escitalopram to placebo at 
Week 8. The significance test for the difference in means at Week 8 will be based on least squares means 
using a 2-sided α of 0.05.  
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The secondary efficacy endpoints of response rate on the PARS, and remission rates on the PARS, 
CGI-S, and CGAS, will be analyzed using a repeated measures model for categorical outcomes. The 
change from baseline in CGI-S and CGAS will be analyzed using the same methodology described for 
the primary efficacy endpoint. The COVID-19 impact assessment score will be summarized at each visit. 
The safety endpoints will be analyzed descriptively.  
PK parameters of escitalopram will be derived using a nonlinear mixed effects approach. The 
exposure/dose-response relationship for efficacy and potentially safety parameters will be explored using a 
nonlinear mixed effects approach. 
 
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4 
TABLE OF CONTENTS 
1 
Protocol Approval Signatures ......................................................................... 2 
2 
Study Personnel ................................................................................................ 3 
3 
Synopsis ............................................................................................................. 4 
4 
Table of Contents............................................................................................ 10 
5 
List of Abbreviations ...................................................................................... 14 
6 
Introduction .................................................................................................... 16 
7 
Study Objectives ............................................................................................. 18 
7.1 
Primary Objective .......................................................................................... 18 
7.2 
Secondary Objective....................................................................................... 18 
7.3 
Exploratory Objective .................................................................................... 18 
8 
Investigational Plan ........................................................................................ 19 
8.1 
Overall Study Design and Plan: Description ............................................... 19 
8.1.1 
Study Design ................................................................................... 20 
8.1.2 
Schedule of Assessments................................................................. 21 
8.1.3 
Schedule of Assessments that Can Be Done Remotely .................. 23 
8.2 
Discussion of Study Design ............................................................................ 24 
8.2.1 
Study Design ................................................................................... 24 
8.2.2 
Quality Management and Risk Evaluation ...................................... 24 
8.2.2.1 
COVID-19 Specific Processes ........................................................ 25 
8.3 
Selection of Study Population ........................................................................ 26 
8.3.1 
Number of Planned Subjects ........................................................... 26 
8.3.2 
Inclusion Criteria ............................................................................. 27 
8.3.3 
Exclusion Criteria ............................................................................ 30 
8.3.4 
Re-screening .................................................................................... 32 
8.3.5 
Removal of Subjects From the Study .............................................. 32 
8.4 
Investigational Products ................................................................................ 33 
8.4.1 
Investigational Products Administered ........................................... 33 
8.4.2 
Identity of Investigational Products ................................................ 34 
8.4.3 
Packaging and Labeling .................................................................. 35 
8.4.4 
Method of Assigning Subjects to Treatment Groups ...................... 35 
8.4.5 
Selection of Doses in the Study ....................................................... 35 
8.4.6 
Selection and Timing of Dose for Each Subject ............................. 35 
8.4.7 
Blinding ........................................................................................... 36 
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8.4.8 
Prior and Concomitant Therapy ...................................................... 36 
8.4.8.1 
Prohibited Medication/Therapy ....................................................... 36 
8.4.9 
Treatment Compliance .................................................................... 37 
9 
Timing of Study Procedures .......................................................................... 37 
9.1 
Pre-treatment .................................................................................................. 37 
9.1.1 
Screening Visit (Visit 1) .................................................................. 37 
9.1.2 
Baseline Visit (Visit 2) .................................................................... 38 
9.2 
Treatment Period ........................................................................................... 38 
9.2.1 
Week 1 (Visit 3) .............................................................................. 38 
9.2.2 
Week 2 (Visit 4) .............................................................................. 39 
9.2.3 
Week 4 (Visit 5) .............................................................................. 39 
9.2.4 
Week 6 (Visit 6) .............................................................................. 40 
9.2.5 
Week 8 End of Treatment or Early Withdrawal (Visit 7) ............... 40 
9.3 
Down Taper Period ........................................................................................ 41 
9.3.1 
Week 9 (Visit 8) .............................................................................. 41 
9.4 
Follow-up ......................................................................................................... 42 
9.4.1 
Week 10 (Follow-up Telephone Contact) ....................................... 42 
9.5 
Unscheduled Visits ......................................................................................... 42 
9.6 
Duration of Treatment ................................................................................... 42 
9.7 
End of Study.................................................................................................... 42 
10 
Efficacy, Safety, and Pharmacokinetic Assessments ................................... 42 
10.1 Efficacy, Safety, and Pharmacokinetic Assessments ................................... 43 
10.1.1 
Efficacy Assessments ...................................................................... 43 
10.1.1.1 Pediatric Anxiety Rating Scale........................................................ 43 
10.1.1.2 Clinical Global Impression of Severity ........................................... 43 
10.1.1.3 Children’s Global Assessment Scale ............................................... 43 
10.1.1.4 Global COVID-19 Impact Assessment ........................................... 43 
10.1.2 
Safety Assessments ......................................................................... 44 
10.1.2.1 Columbia-Suicide Severity Rating Scale ........................................ 44 
10.1.2.2 Adverse Events ................................................................................ 44 
10.1.2.3 Clinical Laboratory Evaluation ....................................................... 50 
10.1.2.4 Vital Signs ....................................................................................... 51 
10.1.2.5 Physical Examination ...................................................................... 51 
10.1.2.6 Electrocardiogram ........................................................................... 52 
10.1.3 
Pharmacokinetic Assessments ......................................................... 52 
10.1.3.1 Study Drug Concentration Measurements ...................................... 52 
10.1.3.2 Handling of Biological Specimens .................................................. 53 
10.2 Appropriateness of Measurements ............................................................... 53 
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11 
Statistical Methods and Determination of Sample Size .............................. 53 
11.1 Subject Populations ........................................................................................ 53 
11.1.1.1 Screened Population ........................................................................ 53 
11.1.1.2 Randomized Population .................................................................. 53 
11.1.1.3 Safety Population ............................................................................ 53 
11.1.1.4 Modified Intent-to-Treat (mITT) Population .................................. 54 
11.1.1.5 Pharmacokinetic Population ............................................................ 54 
11.2 Disposition ....................................................................................................... 54 
11.3 Demographic and Other Baseline Characteristics ...................................... 55 
11.4 Extent of Exposure and Treatment Compliance ......................................... 55 
11.4.1 
Extent of Exposure .......................................................................... 55 
11.4.1.1 Investigational Product .................................................................... 55 
11.4.1.2 Prior and Concomitant Medication ................................................. 56 
11.4.2 
Measurement of Treatment Compliance ......................................... 56 
11.5 Efficacy Analysis............................................................................................. 56 
11.5.1.1 Primary Efficacy Analysis............................................................... 57 
11.5.1.2 Secondary Efficacy Parameters ....................................................... 58 
11.6 Safety Analysis ................................................................................................ 60 
11.6.1.1 Adverse Events ................................................................................ 60 
11.6.1.2 Vital Signs ....................................................................................... 61 
11.6.1.3 Electrocardiograms .......................................................................... 62 
11.6.1.4 Clinical Laboratory Evaluations ...................................................... 62 
11.6.1.5 Columbia-Suicide Severity Rating Scale ........................................ 63 
11.7 Pharmacokinetic and Exposure-Response Evaluation ............................... 63 
11.8 Interim Analyses ............................................................................................. 63 
11.9 Determination of Sample Size ....................................................................... 63 
11.10 Protocol Deviations......................................................................................... 64 
12 
Quality Assurance and Quality Control ....................................................... 64 
12.1 Audit and Inspection ...................................................................................... 64 
12.2 Monitoring ...................................................................................................... 64 
12.3 Data Management and Coding ..................................................................... 64 
12.4 Quality Management and Risk Evaluation .................................................. 65 
13 
Records and Supplies ..................................................................................... 66 
13.1 Drug Accountability ....................................................................................... 66 
13.2 Financing and Insurance ............................................................................... 66 
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14 
Ethics ............................................................................................................... 67 
14.1 Institutional Review Board ............................................................................ 67 
14.2 Regulatory Authorities................................................................................... 67 
14.3 Ethical Conduct of the Study ........................................................................ 67 
14.4 Informed Consent ........................................................................................... 67 
14.5 Subject Confidentiality .................................................................................. 68 
15 
Reporting and Publication, Including Archiving ........................................ 69 
16 
References ....................................................................................................... 70 
17 
Appendices ...................................................................................................... 72 
17.1 Prohibited Medications .................................................................................. 73 
17.2 Investigator Signature Page .......................................................................... 76 
17.3 Telehealth ........................................................................................................ 77 
17.4 Protocol Amendment Summary.................................................................... 78 
 
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5 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CGAS 
Children’s Global Assessment Scale 
cGCP 
current Good Clinical Practice 
CGI-S 
Clinical Global Impression of Severity 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GAD 
generalized anxiety disorder 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
IRB 
institutional review board 
IXRS 
Interactive Response System 
LOCF 
last observation carried forward 
LS 
least squares 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI Kid 
Mini-International Neuropsychiatric Interview for Children and 
Adolescents 
mITT 
modified Intent-to-Treat 
MMRM 
mixed-effects model for repeated measures 
MMRM-CAT 
categorical MMRM 
n 
number of observations 
NEAE 
newly emergent adverse event 
PARS 
Pediatric Anxiety Rating Scale 
PCS 
potentially clinically significant 
PK 
pharmacokinetic 
PT 
preferred term 
QTcB 
Bazett’s correction of QT interval 
QTcF 
Fridericia’s correction of QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SID 
subject identification 
SOC 
system organ class 
SSRI 
selective serotonin reuptake inhibitor 
SUSAR 
suspected unexpected serious adverse reaction 
T3 
triiodothyronine 
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T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 
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6 
INTRODUCTION 
Generalized anxiety disorder (GAD) is one of the most frequently occurring childhood 
anxiety disorders1. In the United States, an estimated 2.2% of adolescents (aged 13 
through 18 years) had GAD, with an estimated 0.9% having severe impairment based 
on data published in 2010. The prevalence of GAD among adolescents was higher for 
females (3.0%) than for males (1.5%)2. 
An anxiety disorder such as GAD in children and adolescents increases the risk for 
substance abuse and suicidal ideation and suicide attempts, and also increases the risk 
for anxiety or depressive disorders in adulthood3,4,5. However, anxiety disorders are 
often untreated in children and adolescents6.  
There is increasing evidence to suggest that selective serotonin reuptake inhibitors 
(SSRIs) are effective treatments for youth with GAD and are generally well tolerated7. 
Escitalopram, the S-enantiomer of racemic citalopram, is an SSRI primarily responsible 
for the serotonin reuptake inhibition produced by citalopram. Escitalopram binds 
preferentially to the serotonin transporter and has very low or no affinity for 
neurotransmitter receptors or for the dopamine and norepinephrine transporters. The 
mechanism of antidepressant action of escitalopram is presumed to be linked to 
potentiation of serotonergic activity in the central nervous system resulting from its 
inhibition of central nervous system neuronal reuptake of serotonin 
(5-hydroxytryptamine).  
Five clinical studies evaluating the efficacy and safety of escitalopram in adult patients 
with GAD have been completed. Three of the 5 studies were placebo-controlled; one 
was an open-label extension study; and one was a relapse-prevention study. The 
efficacy of escitalopram in the acute treatment of GAD was demonstrated in the three, 
8-week, flexible-dose, placebo-controlled studies. In all 3 studies, escitalopram showed 
statistically significant greater mean improvement compared to placebo on the Hamilton 
Anxiety Scale. Results from the relapse-prevention study showed that treatment with 
escitalopram at 20 mg/day significantly reduced the risk of relapse of GAD. 
The most commonly observed adverse reactions in the placebo-controlled double-blind 
studies in adult escitalopram patients (incidence of approximately 5% or greater and 
approximately twice the incidence in placebo patients) were nausea, ejaculation disorder 
(primarily ejaculatory delay), insomnia, fatigue, decreased libido, and anorgasmia. 
Escitalopram has not been evaluated in pediatric patients in clinical studies in GAD. In 
pediatric patients (aged 6 through 17 years) in studies in major depressive disorder 
(MDD), the overall profile of adverse reactions was generally similar to that seen in 
adult studies. However, the following adverse reactions were reported at an incidence of 
at least 2% for escitalopram and greater than placebo: back pain, urinary tract infection, 
vomiting, and nasal congestion. 
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The single- and multiple-dose pharmacokinetics (PK) of escitalopram are linear and 
dose-proportional in a dose range of 10 to 30 mg/day. The mean terminal half-life is 
about 27 to 32 hours. Following a single oral dose (20 mg tablet or solution) of 
escitalopram, peak blood levels occur at about 5 hours. With once-daily dosing, steady 
state plasma concentrations are achieved within approximately one week. Escitalopram 
is metabolized to S-demethylcitalopram and S-didemethylcitalopram. At steady state, 
the concentration of S-demethylcitalopram in plasma is approximately one-third that of 
escitalopram. The level of S-didemethylcitalopram was not detectable in most subjects8. 
In a single-dose study of 10 mg escitalopram, the area under the plasma 
concentration-time curve (AUC) of escitalopram decreased by 19%, and the maximum 
plasma concentration (Cmax) increased by 26% in healthy adolescent subjects (12 to 
17 years of age) compared to adults8. Following multiple dosing of 40 mg/day 
citalopram, steady state Cmax and AUC were similar in adolescent patients with MDD 
(12 to 17 years of age) compared to adult patients8.  
Escitalopram is approved in the United States (under the trade name Lexapro®) for the 
acute and maintenance treatment of MDD in adults (aged 18 through 65 years) and 
adolescents (aged 12 through 17 years) and the acute treatment of GAD in adults at 
once-daily doses of 10 to 20 mg. Outside the United States, escitalopram is approved for 
the treatment of MDD, GAD, panic disorder, obsessive-compulsive disorder, and social 
anxiety disorder under the trade names Cipralex® and Esertia® at a dosage of 5 to 
20 mg/day. 
The United States Food and Drug Administration (FDA) required a Post-Marketing 
Requirement (PMR) study in the pediatric population for the treatment of GAD under 
the Pediatric Research Equity Act (PREA). 
The current study is designed to evaluate the safety, efficacy, and PK of (10 to 
20 mg/day) escitalopram in pediatric subjects (aged 7 through 17 years) for the 
treatment of GAD. 
For further details of nonclinical and clinical studies, PK, and toxicology, please see the 
package insert for escitalopram8. 
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7 
STUDY OBJECTIVES 
7.1 
Primary Objective 
The primary objective of this study is to assess the safety and efficacy of escitalopram 
relative to placebo in the acute treatment of children (aged 7 through 11 years) and 
adolescents (aged 12 through 17 years) who meet criteria for GAD as defined in the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).  
7.2 
Secondary Objective 
The secondary objective of this study is to characterize the PK profile of escitalopram in 
the pediatric population (aged 7 through 17 years).  
7.3 
Exploratory Objective 
The exploratory objective of this study is to assess the exposure/dose-response 
relationship.  
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8 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design and Plan: Description 
This is a randomized, multicenter, double-blind, flexibly-dosed, placebo-controlled 
parallel group study of escitalopram in the treatment of children (aged 7 through 
11 years) and adolescents (aged 12 through 17 years) with GAD. 
The study design incorporates an up to 3-week screening period, an 8-week double-
blind, acute treatment period, and a 1-week double-blind down taper period. 
Approximately 430 subjects will be screened and a total of approximately 256 subjects 
are planned to be randomized in a 1:1 ratio to either escitalopram or placebo. The 
randomization schedule will be stratified by age at randomization (grouped as 
7-11 years vs. 12–17 years) and sex, and blocked. 
Subjects will begin with a 10 mg/day dose of escitalopram (taken orally) or matching 
placebo for the first 2 weeks of double-blind treatment. At the end of Week 2, subjects 
who can tolerate the current dose of 10 mg/day may have a dose escalation to 
20 mg/day of escitalopram or matching placebo. Dose escalation will be at the 
investigator’s discretion taking into account the Clinical Global Impression of Severity 
(CGI-S) score. Subjects who remain on the 10 mg/day dose of escitalopram or matching 
placebo will be evaluated again at Week 4 for a possible dose escalation to 20 mg/day at 
the investigator’s discretion. Dose escalations cannot be made at any other time during 
the study. The dose may be decreased from 20 mg/day to 10 mg/day following 
discussion with the medical director if the subject does not tolerate the 20 mg/day dose. 
At the end of the treatment period or at early withdrawal, subjects will enter a 1-week 
double-blind down taper period with a follow-up telephone contact 1 week after the end 
of the double-blind down taper period. 
A blinded interim analysis will be conducted when 75% of randomized subjects have 
either completed or discontinued the study in order to check the assumptions in the 
sample size calculation. Based on this, the sample size may be increased to ensure an 
adequate power. However, due to the difficulties in recruiting pediatric subjects with 
GAD, the number of subjects in each treatment arm will be capped at 160.  
The study design is shown in Figure 1. 
The coronavirus disease 2019 (COVID-19) pandemic (and any other naming 
conventions used) developed after this study began and this protocol has been amended 
to account for study procedures that need to be modified in association with adhering to 
local safety guidelines or regulations.  
During the COVID-19 pandemic, remote study visits, in which data are collected via 
telephone or videoconference, are possible but not preferred. Nearly all scheduled safety 
assessments, with exception of the Columbia-Suicide Severity Rating Scale (C-SSRS), 
are not possible by remote visit and must be collected in person via clinic visits. To 
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accommodate changes sites may need to implement during the pandemic, 
Section 8.1.2 outlines the conduct of study assessments during in-clinic visits, which is 
the preferred method of conducting the study, while study assessments for remote visits 
are included in Section 8.1.3. 
8.1.1 Study Design 
Figure 1 Flow Chart of the Study 
 
 
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8.1.2 Schedule of Assessments 
Period 
Screening 
Period 
Double-blind Acute Treatment Period 
 
Double-blind 
Down Taper 
Period 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7/ETa 
8b 
Telephone 
Contact 
Day/Week 
Day -21 
to -1 
Baseline 
Day 1 
Week 1c 
Week 2c 
Week 4c 
Week 6c 
Week 8/ETc 
Week 9c 
Week 10c 
Subject Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
Parent Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Psychiatric History  
X 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
MINI Kid 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
X 
 
 
Body Mass Index (BMI) 
X 
 
 
 
X 
 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Vital Signsd 
X 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
X 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
X 
 
 
Screen for HBsAg, HCVAb, HIV 
X 
 
 
 
 
 
 
 
 
Clinical Chemistry including Thyroid 
Xe 
 
 
 
 
 
X 
 
 
Hematology 
X 
 
 
 
 
 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
 
Pregnancy Testf 
X 
X 
 
 
 
 
X 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGAS 
X 
X 
X 
X 
X 
X 
X 
 
 
PARS  
X 
X 
 
X 
 
 
X 
 
 
CGI-S  
X 
X 
 
X 
 
 
X 
 
 
Global COVID-19 Impact Assessmentg 
X 
X 
X 
X 
X 
X 
X 
 
 
Evaluate for Dose Escalationh 
 
 
 
X 
X 
 
 
 
 
PK Blood Samplesi 
 
 
 
 
X 
 
X 
 
 
Dispense Study Drug 
 
Xj 
X 
X 
X 
X 
X 
 
 
Study Drug Accountability  
 
 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
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Period 
Screening 
Period 
Double-blind Acute Treatment Period 
 
Double-blind 
Down Taper 
Period 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7/ETa 
8b 
Telephone 
Contact 
Day/Week 
Day -21 
to -1 
Baseline 
Day 1 
Week 1c 
Week 2c 
Week 4c 
Week 6c 
Week 8/ETc 
Week 9c 
Week 10c 
Concomitant Medications 
◄-------------------------------------------------------------------------------------------------------------------------------------------► 
Abbreviations: BMI = body mass index; CGAS = Children’s Global Assessment Scale; CGI-S = Clinical Global Assessment of Severity; COVID-19 = coronavirus disease 2019; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ET = End of Treatment; HBsAg = hepatitis B surface antigen; HCVAb = hepatitis C virus 
antibody; HIV = human immunodeficiency virus; MINI Kid = Mini-International Neuropsychiatric Interview for Children and Adolescents; PARS = Pediatric Anxiety 
Rating Scale; PK = pharmacokinetic. 
a End of Treatment or Early Withdrawal. 
b If a site becomes aware of any adverse events after study completion (occurring outside of a defined study visit, including any contact up to 30 days after receiving the last dose 
of study drug), all adverse events reported by the patient or patient representative or observed or otherwise identified by the investigator or other study personnel must be 
documented. 
c Visit window ± 3 days. Refer to Section 8.2.2.1, Table 1 for visit windows for safety assessments (physical examination, BMI, vital signs, ECG, urine drug screen, clinical 
chemistry including thyroid, hematology, urinalysis, pregnancy test) and/or PK assessments missed due to remote visits.    
d Vital signs (blood pressure, pulse rate, temperature, and respiration rate) will be recorded at every visit. Height and weight will be recorded at Visit 1 (Screening), Visit 5 
(Week 4), and Visit 7 (Week 8/ET) only. 
e Fasting blood sample.  
f A serum pregnancy test will be performed at Visit 1 (Screening); a urine pregnancy test will be performed at Visit 2 (Baseline) and Visit 7 (Week 8/ET) for females of 
childbearing potential. 
g To be completed last after all other study assessments.  
h Subjects who can tolerate the current dose of 10 mg/day may have a dose escalation to 20 mg/day at the investigator’s discretion taking into account the CGI-S score. 
i For PK blood sampling for assented/consented subjects at Visit 5 (Week 4) and Visit 7 (Week 8/ET), 2 blood samples per subject will be collected at each of these visits for 
escitalopram and S-demethylcitalopram analysis at the following times: Visit 5 (Week 4): for subjects receiving dose in the morning, at 0 h (predose) and ≥ 1 h postdose and for 
subjects receiving dose in the evening, 2 samples at random times during the visit (ie, postdose from the dose received the previous evening), collected at least 2 hours apart from 
each other; and Visit 7 (Week 8/ET): 2 samples at random times during the visit (ie, postdose from the dose received in the morning or the previous evening), collected at least 
2 hours apart from each other.   
j Subjects should take their first dose of study drug in clinic.   
 
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8.1.3 Schedule of Assessments that Can Be Done Remotely 
Period 
Double-blind Acute Treatment Period 
 
Double-blind 
Down Taper 
Period 
Follow-up 
Visit 
2 
3 
4 
5 
6 
7/ETa 
8b 
Telephone 
Contact 
Day/Week 
Baseline 
Day 1 
Week 1c 
Week 2c 
Week 4c 
Week 6c 
Week 8/ETc 
Week 9c 
Week 10c 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
 
CGAS 
X 
X 
X 
X 
X 
X 
 
 
PARS  
X 
 
X 
 
 
X 
 
 
CGI-S  
X 
 
X 
 
 
X 
 
 
Global COVID-19 impact assessmentd 
X 
X 
X 
X 
X 
X 
X 
 
Evaluate for Dose Escalatione 
 
 
X 
X 
 
 
 
 
Dispense Study Drugf 
Xg 
X 
X 
X 
X 
X 
 
 
Study Drug Accountability  
 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
◄---------------------------------------------------------------------------------------------------------------------------► 
Concomitant Medications 
◄---------------------------------------------------------------------------------------------------------------------------► 
Abbreviations: CGAS = Children’s Global Assessment Scale; CGI-S = Clinical Global Assessment of Severity; COVID-19 = coronavirus disease 2019; C-SSRS = Columbia-
Suicide Severity Rating Scale; ET = End of Treatment; PARS = Pediatric Anxiety Rating Scale; PK = pharmacokinetic. 
Notes for Remote Study Visits: 
• 
The Baseline Visit can be remote but it is not preferred. For all female subjects of childbearing potential, the Baseline Visit must take place as an in-clinic visit with all 
assessments outlined in Section 8.1.2. 
• 
Subject data are collected via telephone or telehealth video calls using a technology provider (see Appendix 17.3). Sites should remain consistent with either methods 
(video or telephone) for each subject. 
• 
In-clinic safety and PK assessments missed due to remote visits may be collected per Section 8.2.2.1, Table 1. 
a End of Treatment or Early Withdrawal. 
b If a site becomes aware of any adverse events after study completion (occurring outside of a defined study visit, including any contact up to 30 days after receiving the last dose 
of study drug), all adverse events reported by the patient or patient representative or observed or otherwise identified by the investigator or other study personnel must be 
documented. 
c Visit window ± 3 days.  
d To be completed last after all other study assessments.  
e Subjects who can tolerate the current dose of 10 mg/day may have a dose escalation to 20 mg/day at the investigator’s discretion taking into account the CGI-S score. 
f For remote visits study drug will be sent to subjects via curbside (preferred) or courier.   
g In case of a remote Baseline Visit, subjects will receive and take their first dose of study drug via curbside (preferred) or they will receive it by courier and take it at home.   
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8.2 
Discussion of Study Design 
8.2.1 Study Design 
This study will be performed in pediatric subjects (aged 7 through 17 years) with GAD 
in order to assess safety and efficacy in this patient population. 
In order to standardize the subject population and to make it as homogeneous as 
possible, all subjects must meet the DSM-5 criteria for diagnosis of GAD and have at 
least moderate severity of GAD assessed using standard rating scales. In addition, the 
randomization schedule will be stratified so that there is treatment balance within the 
age group and sex group strata. 
There is a known placebo effect in this indication9 so this study will use a parallel-group 
design with a placebo-control arm. As some of the endpoints (eg, safety, clinical 
assessments) are potentially subjective, this study will be performed in a double-blind 
manner. 
Subjects randomized to the escitalopram treatment arm will receive escitalopram at an 
initial dose of 10 mg/day with the possibility to increase the dose to 20 mg/day after 
2 weeks and 4 weeks. The dose can only be increased if the subject tolerates the current 
dose. Further details on the selection of doses in this study are provided in Section 8.4.5. 
A double-blind treatment period of 8 weeks was selected because it is expected to see a 
treatment effect within this period and the efficacy of escitalopram in the treatment of 
GAD beyond 8 weeks has not been systematically studied. The study includes a 1-week 
double-blind down taper period at the End of Treatment to minimize symptoms 
associated with discontinuation of escitalopram. 
Analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and 
others) showed that these drugs increase the risk of suicidal ideation and behavior 
(suicidality) in children, adolescents, and young adults (aged 18 through 24 years) with 
MDD and other psychiatric disorders. In order to monitor this, the C-SSRS will be 
completed at the Screening, Baseline, and each study visit (see Section 10.1.2.1 for 
further details). 
8.2.2 Quality Management and Risk Evaluation 
This protocol was evaluated to identify risks to those processes and data that are critical 
to assure human subject protection and reliability of study results. To mitigate these 
risks, on-site and remote risk-based monitoring standard operating procedures will be 
employed to ensure site compliance with International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) current Good 
Clinical Practice (cGCP). Concurrent medical review by the contract research 
organization represents an integral component of the study’s centralized monitoring 
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activities by monitoring subject safety and ensuring scientific integrity of the study data 
through the assessment of critical study data identified during the risk assessment for 
the study. Issues identified during on-site or remote monitoring or during medical 
review that may affect subject safety, data quality and/or the study’s scientific integrity 
will be communicated to the study team triggering increased frequency of site 
communication until issues are remediated.  
8.2.2.1 COVID-19 Specific Processes 
To promote subject safety and data quality during the COVID-19 pandemic, the 
following processes will be implemented: 
• Exclusion of subjects whose anxiety is significantly impacted by COVID-19 as 
assessed by investigator (see Section 8.3.3). 
• Global COVID-19 impact assessment (see Section 10.1.1.4). 
• Visit conduct options allowing remote visits as outlined below: 
During remote study visits data are collected via telephone or videoconference 
(see Appendix 17.3). 
Any clinical assessment (including physical examination, vital signs, urine, or 
blood tests) necessary as part of evaluation of a reported adverse event (AE) must 
be performed immediately. If the study site is closed or the subject is unable to 
travel to the study site, alternate arrangements for in-person clinical assessment 
should be secured. 
Option 1: In-Clinic Visits  
This is the preferred option. All study visits are performed as in-clinic visits with all 
assessments outlined in the Schedule of Assessments in Section 8.1.2.  
Option 2: Remote Visits (except Screening for all subjects and Baseline Visit for female 
subjects of childbearing potential)  
This option is only to be used if local guidance and regulations are preventing the site or 
subject from completing an in-clinic visit. Screening must take place as an in-clinic visit 
with all assessments outlined in the Schedule of Assessments in Section 8.1.2. The 
Baseline Visit must take place as an in-clinic visit for all female subjects of childbearing 
potential with all assessments outlined in the Schedule of Assessments in Section 8.1.2 
(including pregnancy test). All other visits can be completed remotely with the 
assessments outlined in Section 8.1.3. 
Table 1 outlines allowed visit windows if a subject comes into the clinic to complete 
physical examination, body mass index (BMI), vital signs, electrocardiogram (ECG), 
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urine drug screen, safety lab (clinical chemistry including thyroid, hematology, 
urinalysis), pregnancy test, and/or PK.    
All attempts should be made to collect all safety assessments within 6 weeks of the 
Visit 7 date, if logistically possible. 
If a subject is able to switch from remote visits to in-clinic visits, the investigator should 
contact the study monitor for guidance. 
Table 1 
Visit Windows for Safety and PK Assessments Missed due to Remote Visits 
Visit 
Assessment 
Limits for allowance of out-of-window collection 
Visit 5/Week 4 
PK 
up to 3 weeks early or late (± 21 days) (Section 10 1.3) 
 
BMI 
up to 3 weeks late (+ 21 days)  
Visit 7/Week 8 or ET 
PK 
up to 1 week late (+ 7 days) (Section 10.1.3) 
 
Clinical chemistry, hematology, urine 
drug screen 
up to 1 week late (+ 7 days)*  
 
Physical examination, BMI, vital 
signs, ECG, urinalysis, pregnancy test 
up to 1 week late (+ 7 days)*  
Visit 8/Week 9 
Vital signs 
up to 1 week late (+ 7 days)*  
Abbreviations: BMI = body mass index; ECG = electrocardiogram; ET = End of Treatment; PK = pharmacokinetic. 
Note, if subjects cannot do the assessments within these timeframes, it will be noted as missing assessment(s) for that visit. 
NOTE: PK assessments outside the above visit windows should not be done at all.  
* For purposes of including as safety endpoints, these assessments will be included in the safety analysis if collected up to 
1 week late. Any safety data collected 8 days to 42 days late will be considered missing for analysis purposes. The 6-week 
window is allowed to capture any follow-up safety data on the participant and will be noted in the final study report (see 
also Section 11.6).  
 
8.3 
Selection of Study Population 
8.3.1 Number of Planned Subjects  
A total of approximately 430 subjects will be screened and approximately 256 subjects 
(128 per treatment arm) are planned to be randomized in approximately 40 centers in 
the United States. It is assumed that approximately 115 subjects per treatment arm will 
be evaluable (ie, have at least one postbaseline assessment).  
A blinded interim analysis will be conducted when 75% of randomized subjects have 
either completed or discontinued the study in order to check the assumptions in the 
sample size calculation. Based on this, the sample size may be increased to ensure an 
adequate power due to variance assumption deviation as well as increased variance due 
to COVID-19 remote visits. However, due to the difficulties in recruiting pediatric 
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subjects with GAD, the number of subjects in each treatment arm will be capped at 160 
(see Section 11.8). 
Re-screening of subjects who do not meet the entry criteria is not allowed, except for 
the reasons outlined in Section 8.3.4. A subject can only be re-screened once.  
The statistical considerations on which the sample size is based are provided in 
Section 11.9. 
8.3.2 Inclusion Criteria 
To be eligible for study entry subjects must satisfy all of the following criteria: 
1. Subject’s parent/legal representative must give written informed consent, 
including privacy authorization, prior to study participation. The subject will 
complete an informed assent prior to study participation. 
2. Subject's parent/legal representative and the subject, if capable, are judged to be 
reliable by the investigator to keep all appointments for clinical visits, tests, and 
procedures required by the protocol. 
3. Subject’s parent/legal representative and the subject, if capable, must have a 
degree of understanding such that they can communicate intelligently with the 
investigator and study coordinator. 
4. Subjects, male or female, must be between 7 and 17 years old, inclusive, at the 
time of consent/assent and at the Baseline Visit. 
5. Subject meets DSM-5 criteria for a primary diagnosis of GAD at Screening 
established by a comprehensive psychiatric evaluation and confirmed/supported 
using the Mini-International Neuropsychiatric Interview for Children and 
Adolescents (MINI Kid). 
6. Diagnosis of moderate or greater severity of GAD as determined by the 
following: 
a. Presence of ≥4 symptoms identified on the generalized anxiety 
subsection of the Pediatric Anxiety Rating Scale (PARS) symptom 
checklist, 2 of which are “excessive worry” and “dread or fearful 
anticipation” (nonspecific) at the Screening and Baseline Visits.  
b. PARS severity score of ≥15 at the Screening and Baseline Visits for 
symptoms identified on the generalized anxiety subsection of PARS 
symptom checklist, derived by summing 5 of the 7 
severity/impairment/interference items (2, 3 5, 6, and 7). 
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c. CGI-S rating of ≥4 at the Screening and Baseline Visits. 
7. Male subjects who are sexually active with a partner of childbearing potential 
must use, with their partner, a condom plus an approved method of highly 
effective contraception from the time of informed consent until 14 days after the 
last dose of study drug. The following methods are acceptable: 
a. Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation: 
i. oral 
ii. intravaginal 
iii. transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of 
ovulation 
i. oral 
ii. injectable 
iii. implantable intrauterine device 
iv. intrauterine hormone-releasing system 
c. Surgical sterilization (vasectomy or bilateral tubal occlusion) 
8. Female subjects who are not of childbearing potential do not need to use any 
methods of contraception. This includes preadolescent and adolescent females 
who have not reached menarche. 
9. Female subjects who are sexually active and are of childbearing potential must 
use, with their partner, an approved method of highly effective contraception 
from the time of informed consent until 14 days after the last dose of study drug. 
In this patient population, a subject would be considered sexually active if they 
participate in any behaviors which may result in pregnancy. The following 
methods are acceptable: 
a. Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation and a barrier 
method (ie, condom for male partner): 
i. oral 
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ii. intravaginal 
iii. transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of 
ovulation and a barrier method (ie, condom for male partner): 
i. oral 
ii. injectable 
iii. implantable intrauterine device 
iv. intrauterine hormone-releasing system 
c. Surgical sterilization (vasectomy or bilateral tubal occlusion)  
10. Strict abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. If a subject is usually not sexually active but becomes active, 
they, with their partner, must comply with the contraceptive requirements 
detailed above. 
11. Female subjects of childbearing potential must have a negative serum 
beta-human chorionic gonadotropin pregnancy test at the Screening Visit, a 
negative urine pregnancy test at the Baseline Visit, and must not be 
breastfeeding.  
12. Subject must have venous access sufficient to allow blood sampling and be 
compliant with blood draws as per the protocol. 
13. Subject must be in general good health (defined as the absence of any clinically 
relevant abnormalities as determined by the investigator) based on screening 
physical and neurological examinations, vital signs, medical history, and clinical 
laboratory values (hematology, chemistry, and urinalysis). Note: If any of the 
hematology, chemistry, or urinalysis results are not within the laboratory’s 
reference range, then the subject may be included only if the investigator 
determines the deviations to be not clinically relevant.  
14. Subject weighs at least 20 kg and is within the 3rd to 97th percentile for gender 
specific BMI-for-age from the Centers for Disease Control and Prevention 
(CDC) growth charts at the Screening and Baseline Visits. 
15. Subject’s living environment is determined to be stable by the investigator. 
 
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8.3.3 Exclusion Criteria 
Subjects will be excluded from the study if one or more of the following criteria is 
applicable: 
1. Current diagnosis of a major depressive episode, or lifetime diagnosis of 
attention-deficit/hyperactivity disorder, bipolar disorder, psychotic depression, 
schizophrenia or other psychotic disorder, feeding and/or eating disorder, 
obsessive-compulsive disorder, conduct disorder, oppositional defiant disorder, 
post-traumatic stress disorder, panic disorder, or pervasive development 
disorder.  
2. Suspected or previously diagnosed intellectual disability disorder. 
3. DSM-5-defined substance use disorder within a year (12 months) prior to 
Screening Visit. 
4. Any secondary DSM-5 disorder that requires pharmacologic treatment or would 
be a potential confound to the study assessments or ability to participate in all 
study procedures, as determined by the investigator. 
5. Environmental stressor (current or historic – eg, history of abuse/trauma, 
significant change in psychosocial status, significant injury) that, in the opinion 
of the investigator, may confound assessments or subject’s ability to complete 
all protocol requirements. 
6. One or more first-degree relatives with diagnosed bipolar I disorder. 
7. Subject answers “yes” to “Suicidal Ideation” item 3 (active suicidal ideation 
with any methods, not plan, without intent to act), item 4 (active suicidal 
ideation with some intent to act, without specific plan), or item 5 (active suicidal 
ideation with specific plan and intent) within the past 6 months and/or a lifetime 
history of suicidal behavior, as assessed by the C-SSRS. 
8. Subject is currently considered at risk for suicide in the opinion of the 
investigator. 
9. Lack of response to 2 or more adequate trials of antidepressants or other 
anti-anxiety medications at a clinically appropriate dose for a minimum of 
4 weeks for GAD at the time of screening or, in the judgement of the 
investigator, the patient had treatment-resistant GAD. 
10. Change to psychotherapy (start, stop, or change in type, intensity, or frequency) 
in the 6 weeks prior to the Screening Visit. 
11. History of seizure disorder (other than febrile seizures). 
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12. History of electroconvulsive therapy at any time during the subject’s lifetime.  
13. Had a positive urine drug screen for any substances of abuse or excluded 
medication. 
14. Known hypersensitivity to escitalopram (escitalopram oxalate) or citalopram or 
any of the inactive ingredients, or had frequent or severe allergic reactions to 
multiple medications. 
15. Have used escitalopram (at a minimum required dose and duration per FDA 
approval) and had a suboptimal effect as determined by the investigator. 
16. Serious or unstable medical illness, or clinically significant laboratory or ECG 
result that, in the opinion of the investigator, would compromise participation in 
the study, confound results, or be likely to lead to hospitalization during the 
course of the study. 
17. Hypo- or hyperthyroidism, unless stabilized on appropriate pharmacotherapy 
with no change in dosage for at least 3 months before the Screening Visit. If 
thyroid-stimulating hormone (TSH) is abnormal, the subject must have a normal 
triiodothyronine (T3) and thyroxine (T4). 
18. Use of biotin as a dietary supplement at more than 2.5 mg total per day within 
7 days of the Screening Visit. 
19. Initiated or discontinued hormone therapy (including oral contraceptives for 
female subjects) within 3 months prior to screening. 
20. Taking any medications that are contraindicated to escitalopram (escitalopram 
oxalate). 
21. Inability to speak, read, or understand English well enough to complete the 
assessments. 
22. Treatment with any investigational drug within 30 days or 5 half-lives 
(whichever is longer) prior to study entry. 
23. Unlikely to comply with study requirements or unsuitable for any reason, 
including any indication the subject may be significantly impacted by the 
COVID-19 (or associated virus) pandemic, based on investigator judgement.  
24. Employees or relatives of employees of investigational site, Syneos Health, or 
Allergan. 
25. Family members or individuals living in the same household as the study 
subject.  
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8.3.4 Re-screening 
Re-screening is allowed only under the following exceptional circumstances. Note a 
subject can only be re-screened once. 
• Logistical reasons (eg, scheduling of visits). 
• Subjects who have not yet completed washout of fluoxetine at screening can be 
re-screened once washout is completed. The medical monitor is to be contacted 
in these cases.  
• For subjects who failed screening according to the BMI criteria based on World 
Health Organization (WHO) growth charts. 
• Screen failures due to a recruitment hold. Subjects can be re-screened once the 
recruitment hold is lifted. 
8.3.5 Removal of Subjects From the Study 
A subject may voluntarily withdraw or be withdrawn from the study at any time for 
reasons including, but not limited to, the following: 
• Withdrawal of consent 
• Use of non-permitted concurrent therapy 
• Noncompliance with the study drug or study schedule 
• Lost to follow-up 
• Adverse event 
• Investigator request 
• Intercurrent illness 
• Protocol deviation 
• Pregnancy 
• Sponsor request 
• Lack of efficacy 
• Due to the COVID-19 pandemic 
• Death 
Subjects who do not complete the study will not be replaced.  
Subjects are free to withdraw from the study at any time without providing reason(s) for 
withdrawal and without prejudice to further treatment. The reason(s) for withdrawal will 
be documented in the electronic case report form (eCRF). 
Subjects withdrawing from the study will be encouraged to complete the same final 
evaluations as subjects completing the study according to this protocol, particularly 
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safety evaluations. The aim is to record data in the same way as for subjects who 
completed the study.  
Subjects who withdraw early from the study should complete the End of Treatment 
Visit and enter the 1-week down taper period. 
Subjects should be monitored for the following symptoms when discontinuing 
treatment: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (eg, 
paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, 
emotional lability, insomnia, and hypomania. A gradual reduction in dose rather than 
abrupt cessation is recommended, whenever possible.  
Reasonable efforts will be made to contact subjects who are lost to follow-up (eg, 
3 attempts to contact the subject by telephone/letter). These efforts must be documented 
in the subject’s file.  
The sponsor has the right to terminate the study at any time in case of serious adverse 
events (SAEs) or if special circumstances concerning the investigational product or the 
company itself occur, making further treatment of subjects impossible. In this event, the 
investigator(s) will be informed of the reason for study termination. 
Pregnancy 
Subjects will be instructed that known or suspected pregnancy occurring during the 
study, in subjects or female partners of male subjects, should be confirmed and reported 
to the investigator, who will then withdraw the subject from the study after appropriate 
safety follow-up. The investigator should discuss down tapering with the medical 
director for any subject being withdrawn as a result of pregnancy.  
The investigator should also be notified of pregnancy occurring during the study but 
confirmed after completion of the study. In the event that a subject is subsequently 
found to be pregnant after inclusion in the study, any pregnancy will be immediately 
reported to the sponsor by the investigator. All pregnancies will be followed to term by 
the investigator, and pregnancy outcome, as well as the health status of mother and child 
will be reported to the sponsor.  
Full details will be recorded on the withdrawal page of the eCRF, and a pregnancy form 
will be completed (see Section 10.1.2.2.2).  
8.4 
Investigational Products 
8.4.1 Investigational Products Administered 
Subjects randomized to the escitalopram arm will receive escitalopram 10 mg/day for 
the first 2 weeks. At the end of Week 2, subjects who can tolerate the current dose of 
10 mg/day may have a dose escalation to 20 mg/day. Dose escalation will be at the 
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investigator’s discretion taking into account the CGI-S score. Subjects who remain on 
10 mg/day will be evaluated again at Week 4 for a possible dose escalation to 
20 mg/day at the investigator’s discretion. Dose escalations cannot be made at any other 
time during the study. The dose may be decreased from 20 mg/day to 10 mg/day 
following discussion with the medical director if the subject does not tolerate the 
20 mg/day dose.  
At the end of the 8-week double-blind acute treatment period, or at withdrawal, the 
subject will enter a 1-week double-blind down taper period.  
For subjects receiving escitalopram 10 mg/day, the doses given during the double-blind 
down taper period will be as follows: 
• Week 9: Subjects will receive placebo. 
For subjects receiving escitalopram 20 mg/day, the doses given during the double-blind 
down taper period will be as follows:  
• Week 9: Subjects will receive 10 mg/day. 
Subjects randomized to the placebo arm will receive matching placebo during the 
double-blind treatment period. Subjects will be evaluated at the end of Week 2 and 
Week 4 and subjects tolerating 10 mg/day matching placebo may be indicated for dose 
escalation by the investigator but in a blinded fashion will continue to receive matching 
placebo. Subjects receiving placebo will follow a similar down tapering schedule at the 
end of the double-blind treatment period. 
For details on overdose of escitalopram, please see Section 10.1.2.2.5. 
8.4.2 Identity of Investigational Products 
Escitalopram (S-(+)-1-[3-dimethyl-aminopropyl]-1-(p-fluorophenyl)-5-
phthalancarbonitrile oxalate) is the S-enantiomer of racemic citalopram.  
Encapsulated escitalopram 10 mg tablets will be provided for both the 10 mg and 20 mg 
doses. The active study medication will be provided in single-dose capsules that are 
identical in appearance, and contain one 10 mg tablet for the 10 mg dose, or two 10 mg 
tablets for the 20 mg dose. Escitalopram tablets are film-coated, round tablets 
containing escitalopram oxalate in strengths equivalent to 10 mg escitalopram base.  
Matching placebo capsules are similar but do not contain active escitalopram. 
Investigational products should be stored at 25 °C (77 °F); excursions to 15 °C to 30 °C 
(59 °F to 86 °F) are permitted. 
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8.4.3 Packaging and Labeling 
The investigational product will be provided in 10 count bottles.  
All packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory 
requirements. 
8.4.4 Method of Assigning Subjects to Treatment Groups 
After successfully meeting study entry criteria, subjects will be randomized in a 1:1 
ratio to escitalopram or placebo. The randomization schedule will be stratified by age at 
randomization (grouped as 7–11 years vs. 12–17 years) and sex, and blocked. 
Approximately 430 subjects will be screened and a total of approximately 256 subjects 
are planned for randomization.  
An Interactive Response System (IXRS) will be used to manage the randomization, 
assignment of treatment during the study, and if necessary emergency unblinding of 
subjects during the study conduct. The IXRS will assign a randomization number, 
distinct from the subject number, at the time of randomization.  
8.4.5 Selection of Doses in the Study 
In this study in GAD, the initial dose will be 10 mg/day with a possible increase to 
20 mg/day after a minimum of 2 weeks for both pediatric subjects (aged 7 through 
11 years) and adolescents (aged 12 through 17 years). Clinical assessment at the Week 2 
Visit may provide information for the investigator to increase the dose at that time. 
There is no standard of care for when doses should be adjusted. As there is no Week 3 
Visit, allowing an evaluation for dose escalation at the Week 2 Visit is an ideal option. 
8.4.6 Selection and Timing of Dose for Each Subject 
Subjects will be randomly allocated to receive escitalopram or placebo. 
For in-clinic visits according to Option 1 in Section 8.2.2.1: 
Subjects will receive their first dose of study drug on site on Day 1. Subjects will then 
self-administer the investigational product on an outpatient basis once a day. Subjects 
should be instructed to administer investigational product at approximately the same 
time each day including on days when clinic visits occur. Subjects may take the 
investigational product with or without food. To allow for PK sampling during in-clinic 
visits, subjects receiving study drug in the morning will be instructed to withhold taking 
the morning dose on the day of the Week 4 Visit (Visit 5) and to bring their study drug 
to the visit. Subjects receiving study drug in the evening should take their dose in the 
evening before the visit. 
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For remote visits according to Option 2 in Section 8.2.2.1:  
Subjects will receive and take their first dose of study drug on Day 1 via curbside 
(preferred) or they will receive it by courier and take it at home. Subjects will then self-
administer the investigational product on an outpatient basis once a day. Subjects should 
be instructed to administer investigational product at approximately the same time each 
day including on days when remote visits are scheduled. Subjects may take the 
investigational product with or without food. 
Details of dose escalation and down tapering are provided in Section 8.4.1. 
8.4.7 Blinding 
The escitalopram and placebo capsules are the same in appearance. The investigators, 
study center staff, subjects, study contract research organization staff, and study sponsor 
staff will be blinded to the treatment assignments. The only planned unblinding will be 
at the conclusion of the study, when the database has been cleaned, statistical 
populations have been defined, and approval for database lock has been given by 
Allergan.  
The blind for a specific subject can be broken by the investigator (emergency code 
breaking) only if the investigator considers the information indispensable to the safety 
of the subject. Any subject whose treatment is unblinded by the investigator will be 
withdrawn at the moment of unblinding, with the reason for unblinding given as the 
reason for discontinuation from the study.  
Bioanalytical representatives will be unblinded for PK sample bioanalysis during the 
conduct of the study. The unblinding of bioanalytical representatives will be carried out 
in a secure manner following the sponsor’s standard operating procedures. Extreme care 
and diligence will be taken to ensure no other individuals outside the bioanalytical team 
will be unblinded. 
8.4.8 Prior and Concomitant Therapy 
8.4.8.1 Prohibited Medication/Therapy 
Subjects must stop all antidepressant treatment (except for fluoxetine) at least 14 days 
prior to randomization. Antidepressant treatment includes SSRIs, serotonin-
norepinephrine reuptake inhibitors (SNRIs), bupropion, and tricyclic antidepressants. 
Subjects must stop fluoxetine at least 28 days prior to randomization. If the subject is 
taking fluoxetine at the time of screening, the subject may need to be screen failed and 
then re-screened once the washout is complete. Please contact the medical monitor for 
guidance (see Section 8.3.4). 
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Subjects should not have initiated or discontinued hormone therapy (including oral 
contraceptives for female subjects) within the 3 months prior to screening. 
A table listing prohibited concomitant medications during the study is presented in 
Appendix 17.2. 
8.4.9 Treatment Compliance 
Compliance with study medication will be monitored at each visit during treatment. 
Subjects will be instructed to bring all unused study medication with them to each visit. 
At the investigator’s discretion, noncompliance could result in termination of the subject 
from the study. 
9 
TIMING OF STUDY PROCEDURES 
Each subject will complete an informed assent and the subject’s parent/legal 
representative will provide written informed consent before any study-related 
procedures are performed. 
The planned study assessments are in Section 8.1.2. 
9.1 
Pre-treatment 
9.1.1 Screening Visit (Visit 1) 
• Assess for eligibility (against the inclusion and exclusion criteria). 
• Collect full medical history, including concomitant illnesses/diseases and 
concomitant medications. 
• Collect psychiatric history. 
• Record demographic data, such as ethnic origin, race, year of birth, and sex. 
• Record historical disease data and diagnostic information (including MINI Kid). 
• Complete Children’s Global Assessment Scale (CGAS), PARS, and CGI-S. 
• Complete C-SSRS.  
• Complete global COVID-19 impact assessment. 
• Record vital signs (blood pressure, pulse rate, temperature, respiration rate, height, 
and weight). 
• Record BMI. 
• Perform a physical examination (including neurological examination). 
• Perform an ECG. 
• Collect samples for hematology, clinical chemistry including thyroid (fasting 
sample), urinalysis, and pregnancy (if applicable) tests. 
• Collect samples for hepatitis B surface antigen (HBsAg), hepatitis C virus 
antibody (HCVAb), and human immunodeficiency virus (HIV) tests. 
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• Collect urine sample for drug screening (alcohol, opioids, benzodiazepines, 
tetrahydrocannabinol, barbiturates, and amphetamines). 
9.1.2 Baseline Visit (Visit 2) 
The following procedures will be performed at the Baseline Visit: 
• Reassess for eligibility against the inclusion and exclusion criteria. 
• Randomization will take place for eligible subjects and each will receive a 
randomization number. 
• Record any AEs that have occurred since the previous visit and any changes in 
concomitant medications. 
• Complete CGAS, PARS, and CGI-S. 
• Complete C-SSRS. 
• Complete global COVID-19 impact assessment. 
• Record vital signs (blood pressure, pulse rate, temperature, and respiration rate). 
• Perform a urine pregnancy test, if applicable. 
When all the baseline procedures have been performed and the investigator has 
confirmed the subject’s eligibility for the study, the study drug will be dispensed to the 
subject. Subjects should take their first dose of study drug in clinic on Day 1.  
Refer to Section 8.1.3 for procedures and assessments if Visit 2 is done remotely. For 
remote visits, subjects will receive and take their first dose of study drug via curbside 
(preferred) or they will receive it by courier and take it at home. 
9.2 
Treatment Period 
9.2.1 Week 1 (Visit 3) 
The Week 1 Visit (Visit 3) will take place 7 days ± 3 days after the Baseline Visit. The 
following procedures will be performed at Visit 3: 
• Perform an accountability check on any remaining study drug as well as empty 
study drug bottles. 
• Record any AEs that have occurred since the previous visit and any changes in 
concomitant medications. 
• Complete CGAS. 
• Complete C-SSRS.  
• Complete global COVID-19 impact assessment. 
• Record vital signs (blood pressure, pulse rate, temperature, and respiration rate). 
When all of these procedures have been performed, the study drug will be dispensed 
and the next visit scheduled. 
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Refer to Section 8.1.3 for assessments if Visit 3 is done remotely. Study drug will be 
delivered to subjects via curbside (preferred) or courier.  
9.2.2 Week 2 (Visit 4) 
The Week 2 Visit (Visit 4) will take place 14 days ± 3 days after the Baseline Visit. The 
following procedures will be performed at Visit 4: 
• Perform an accountability check on any remaining study drug as well as empty 
study drug bottles. 
• Record any AEs that have occurred since the previous visit and any changes in 
concomitant medications. 
• Complete CGAS, PARS, and CGI-S. 
• Complete C-SSRS. 
• Complete global COVID-19 impact assessment. 
• Record vital signs (blood pressure, pulse rate, temperature, and respiration rate). 
• Assess the subject for dose escalation: subjects who can tolerate the current dose 
may have a dose escalation at the investigator’s discretion, taking into account 
the CGI-S score. 
When all of these procedures have been performed, and the dose has been confirmed, 
the study drug will be dispensed and the next visit scheduled. Subjects receiving study 
drug in the morning will be instructed to withhold taking the morning dose on the day 
of the Week 4 Visit (Visit 5) and to bring their study drug to the visit. 
Refer to Section 8.1.3 for assessments if Visit 4 is done remotely. Study drug will be 
delivered to subjects via curbside (preferred) or courier. 
9.2.3 Week 4 (Visit 5)  
The Week 4 Visit (Visit 5) will take place 4 weeks ± 3 days after the Baseline Visit. The 
following procedures will be performed at Visit 5: 
• Perform an accountability check on any remaining study drug as well as empty 
study drug bottles. 
• Record any AEs that have occurred since the previous visit and any changes in 
concomitant medications. 
• Complete CGAS. 
• Complete C-SSRS. 
• Complete global COVID-19 impact assessment. 
• Record vital signs (blood pressure, pulse rate, temperature, respiration rate, height, 
and weight). 
• Record BMI. 
• Subjects on morning dosing:  
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o Collect a predose PK blood sample.  
o Administer study drug. 
o Collect a PK blood sample at ≥ 1 hour postdose. 
• Subjects on evening dosing: 
o Collect 2 PK blood samples at random times during the visit (ie, 
postdose from the dose received the previous evening), at least 2 hours 
apart from each other. 
• Assess the subject for dose escalation: subjects who can tolerate the current dose 
may have a dose escalation at the investigator’s discretion, taking into account 
the CGI-S score. 
When all of these procedures have been performed, the study drug will be dispensed 
and the next visit scheduled. 
Refer to Section 8.1.3 for assessments and to Table 1 for assessment windows if Visit 5 
is done remotely. Study drug will be delivered to subjects via curbside (preferred) or 
courier. 
9.2.4 Week 6 (Visit 6) 
The Week 6 Visit (Visit 6) will take place 6 weeks ± 3 days after the Baseline Visit. The 
following procedures will be performed at Visit 6: 
• Perform an accountability check on any remaining study drug as well as empty 
study drug bottles. 
• Record any AEs that have occurred since the previous visit and any changes in 
concomitant medications. 
• Complete CGAS. 
• Complete C-SSRS. 
• Complete global COVID-19 impact assessment. 
• Record vital signs (blood pressure, pulse rate, temperature, and respiration rate). 
When all of these procedures have been performed, the study drug will be dispensed 
and the next visit scheduled. 
Refer to Section 8.1.3 for assessments if Visit 6 is done remotely. Study drug will be 
delivered to subjects via curbside (preferred) or courier. 
9.2.5 Week 8 End of Treatment or Early Withdrawal (Visit 7) 
The Week 8 End of Treatment or Early Withdrawal Visit (Visit 7) will take place 
8 weeks ± 3 days after the Baseline Visit or at early withdrawal. The following 
procedures will be performed at Visit 7: 
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• Perform an accountability check on any remaining study drug as well as empty 
study drug bottles. 
• Record any AEs that have occurred since the previous visit and any changes in 
concomitant medications. 
• Complete CGAS, PARS, and CGI-S. 
• Complete C-SSRS. 
• Complete global COVID-19 impact assessment. 
• Record vital signs (blood pressure, pulse rate, temperature, respiration rate, height, 
and weight). 
• Record BMI.  
• Record any changes from baseline in physical examination. 
• Perform an ECG. 
• Collect samples for hematology, clinical chemistry including thyroid, and 
urinalysis tests. 
• Collect urine sample for drug screening (alcohol, opioids, benzodiazepines, 
tetrahydrocannabinol, barbiturates, and amphetamines). 
• Perform a urine pregnancy test, if applicable. 
• Collect 2 PK blood samples at random times during the visit (ie, postdose from 
the dose received in the morning or the previous evening), at least 2 hours apart 
from each other. 
When all of these procedures have been performed, the study drug for the down taper 
period will be dispensed and the next visit scheduled. 
Refer to Section 8.1.3 for assessments and to Table 1 for assessment windows if Visit 7 
is done remotely. Study drug will be delivered to subjects via curbside (preferred) or 
courier. All attempts should be made to collect safety labs within 6 weeks of the Visit 7 
date. 
9.3 
Down Taper Period 
9.3.1 Week 9 (Visit 8) 
The Week 9 Visit (Visit 8) will take place 9 weeks ± 3 days after the Baseline Visit. The 
following procedures will be performed at Visit 8: 
• Perform an accountability check on any remaining study drug as well as empty 
study drug bottles. 
• Record any AEs that have occurred since the last visit and any changes in 
concomitant medications. 
• Complete C-SSRS. 
• Record vital signs (blood pressure, pulse rate, temperature, and respiration rate). 
• Schedule a follow-up telephone contact in 1 week’s time. 
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Refer to Section 8.1.3 for assessments and to Table 1 for assessment windows if Visit 8 
is done remotely. 
9.4 
Follow-up 
9.4.1 Week 10 (Follow-up Telephone Contact)  
The follow-up telephone contact to review subject safety will take place at Week 10 
(10 weeks ± 3 days after the Baseline Visit). 
9.5 
Unscheduled Visits 
Unscheduled visits can be performed if safety concerns arise and at the discretion of the 
investigator. Additional examinations may be performed as necessary to ensure the 
safety and well-being of the subjects during the study. 
9.6 
Duration of Treatment 
The duration of treatment will be up to 9 weeks (an 8-week double-blind, acute 
treatment period, and a 1-week double-blind down taper period). 
9.7 
End of Study  
A subject will have fulfilled the requirements for study completion when the subject has 
completed all study periods, including the last scheduled follow-up telephone contact at 
Week 10 as indicated in the Schedule of Assessments in Section 8.1.2. 
The end of the study will be the last subject’s last scheduled follow-up telephone 
contact at Week 10 as indicated in the Schedule of Assessments in Section 8.1.2. 
10 EFFICACY, SAFETY, AND PHARMACOKINETIC ASSESSMENTS 
The planned Schedule of Assessments is in Section 8.1.2. 
The modified Schedule of Assessments in conjunction with the COVID-19 pandemic is 
in Section 8.1.3 and the options for conducting remote visits are outlined in 
Section 8.2.2.1. For any efficacy or safety assessment data that are collected during a 
remote visit, the appropriately trained study center staff may conduct the assessment by 
telephone or videoconference. Sites should remain consistent with the method used for 
each subject. 
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10.1 Efficacy, Safety, and Pharmacokinetic Assessments  
10.1.1 Efficacy Assessments  
The efficacy assessments will be completed by the investigator or appropriately 
qualified study center staff. Every effort should be made to ensure that each instrument 
is completed by the same assessor at each visit.  
10.1.1.1 Pediatric Anxiety Rating Scale 
The PARS is a clinician-rated instrument for assessing the severity of anxiety symptoms 
associated with common anxiety disorders including GAD in children10,11.  
The PARS severity score for GAD will be assessed for all symptoms identified in the 
generalized anxiety section of the PARS symptom checklist and the scores recorded on 
the eCRF.  
10.1.1.2 Clinical Global Impression of Severity 
The CGI-S was developed for use in clinical trials to provide an assessment of the 
clinician's view of the patient's global functioning prior to and after initiating a study 
medication12,13. 
The CGI-S will be completed using a 7-point scale and the scores recorded on the 
eCRF.  
10.1.1.3 Children’s Global Assessment Scale 
The CGAS can be used as a measure of global functioning and impairment14. 
The CGAS will be completed by the clinician using a 100-point scale ranging from 1 to 
100, with higher scores indicating better functioning. The scores will be recorded on the 
eCRF.  
10.1.1.4 Global COVID-19 Impact Assessment 
A global COVID-19 impact assessment will be used to evaluate the impact of the 
coronavirus disease pandemic on the severity of the subject’s GAD during the last 
1 week. The rating will include scores from 0 (not applicable, subject not enrolled in the 
trial during the pandemic) to 7 (extreme impact). Raters will also evaluate whether the 
impact was an improvement or worsening of the subject’s GAD. The global COVID-19 
impact assessment will be completed last after all study assessments by appropriately 
qualified study center staff and the scores recorded on the eCRF. Every effort should be 
made to ensure that the assessments are completed by the same assessor at each visit. 
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10.1.2 Safety Assessments 
10.1.2.1 Columbia-Suicide Severity Rating Scale 
The C-SSRS is an instrument designed to systematically assess and track suicidal 
ideation and behavior15. The strength of this suicide classification system is in its ability 
to comprehensively identify suicidal events while limiting the over-identification of 
suicidal behavior. 
The C-SSRS will be completed by the investigator or appropriately qualified study 
center staff and the scores recorded on the eCRF. Every effort should be made to ensure 
that the assessments are completed by the same assessor at each visit. 
Any positive score should be reported to the medical director and immediate subject 
care should be implemented and documented. Any positive score should be recorded as 
an AE or SAE, as appropriate.  
In addition to the planned assessments, the investigator must continually evaluate 
suicidality risk throughout the subject’s participation in the study.  
10.1.2.2 Adverse Events 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical study subject 
administered a medicinal product which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not it is related to the 
medicinal (investigational) product. This includes an exacerbation of pre-existing 
conditions or events, intercurrent illnesses, drug interaction or the significant worsening 
of the indication under investigation that is not recorded elsewhere in the eCRF under 
specific efficacy assessments. Anticipated fluctuations of pre-existing conditions, 
including the disease under study that do not represent a clinically significant 
exacerbation or worsening need not be considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the 
study. AEs will be elicited by asking the subject a nonleading question, for example, 
“Have you experienced any new or changed symptoms since we last asked/since your 
last visit?”. AEs should be reported on the appropriate page of the eCRF. 
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Assessment of Severity 
Each AE will be assigned a category by the investigator as follows: 
Mild: 
An AE that is easily tolerated by the subject, causes minimal discomfort 
and does not interfere with everyday activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal 
everyday activities; intervention may be needed. 
Severe: 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed. 
If there is a change in severity of an AE, it must be recorded as a separate event. 
Assessment of Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, 
to the study drug. Causality should be assessed using the categories presented in the 
following table: 
Unrelated: 
Clinical event with an incompatible time relationship to study drug 
administration, and that could be explained by underlying disease or 
other drugs or chemicals or is incontrovertibly not related to the study 
drug. 
Unlikely: 
Clinical event whose time relationship to study drug administration 
makes a causal connection improbable, but that could plausibly be 
explained by underlying disease or other drugs or chemicals. 
Possible: 
Clinical event with a reasonable time relationship to study drug 
administration, but that could also be explained by concurrent disease 
or other drugs or chemicals. 
Probable: 
Clinical event with a reasonable time relationship to study drug 
administration, and is unlikely to be attributed to concurrent disease 
or other drugs or chemicals. 
Very 
Likely/Certain: 
Clinical event with plausible time relationship to study drug 
administration, and that cannot be explained by concurrent disease or 
other drugs or chemicals. 
Action Taken 
The investigator will describe the action taken in the appropriate section of the eCRF, as 
follows: 
• None 
• Study drug stopped 
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• Study drug temporarily interrupted 
• Concomitant medication 
• Other, specify. 
Follow-up of Adverse Events 
All investigators should follow up subjects with AEs until the event is resolved or until, 
in the opinion of the investigator, the event is stabilized or determined to be chronic. 
Details of AE resolution must be documented in the eCRF. 
Documentation and Reporting of Adverse Events 
All AEs from the signing of the informed consent form (ICF) until 30 days after 
receiving the last dose of study drug will be collected according to the procedures 
outlined above at the timepoints specified in the Schedule of Assessments 
(Section 8.1.2/8.1.3), and as observed or reported spontaneously by study participants. 
AEs should be reported and documented in accordance with the procedures outlined 
below. All AEs occurring during the study must be documented on the relevant eCRF 
pages. The following data should be documented for each AE: 
• Description of the symptom event 
• Classification of ‘serious’ or ‘not serious’ 
• Severity 
• Date of first occurrence and date of resolution (if applicable) 
• Action taken 
• Causal relationship 
• Outcome of event (unknown, recovered, recovering, not yet recovered, recovered 
with sequelae, death [with date and cause reported]). 
10.1.2.2.1 Serious Adverse Events 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence or effect that, at any dose, 
• Results in death. 
• Is life-threatening (an AE is life-threatening if the subject was at immediate risk of 
death from the event as it occurred, ie, it does not include a reaction that might 
have caused death if it had occurred in a more serious form). 
• Requires or prolongs inpatient hospitalization. (Complications occurring during 
hospitalization are AEs and are SAEs if they cause prolongation of the current 
hospitalization. Hospitalization for elective treatment of a pre-existing 
non-worsening condition is not, however, considered an AE. The details of such 
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hospitalizations must be recorded on the medical history or physical examination 
page of the eCRF). 
• Results in persistent or significant disability/incapacity. (An AE is incapacitating 
or disabling if it results in a substantial and/or permanent disruption of the 
subject’s ability to carry out normal life functions). 
• Results in a congenital anomaly/birth defect. 
In addition, medical and scientific judgement is required to decide if prompt notification 
is required in situations other than those defined for SAEs above. This may include any 
event that the investigator regards as serious that did not strictly meet the criteria above 
but may have jeopardized the subject or required intervention to prevent one of the 
outcomes listed above, or that would suggest any significant hazard, contraindication, 
side effect, or precaution that may be associated with the use of the investigational 
product. 
Reporting of Serious Adverse Events 
Any SAEs from the signing of the ICF until 30 days after receiving the last dose of 
study drug will be collected according to the procedures outlined above at the 
timepoints specified in the Schedule of Assessments (Section 8.1.2/8.1.3), and as 
observed or reported spontaneously by study participants, whether or not the SAE is 
considered to be related to the investigational product.  
The sponsor is required to inform worldwide regulatory authorities of SAEs that meet 
specific criteria. Therefore, the sponsor must be notified immediately regarding any 
SAE that occurs after informed consent is obtained. 
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the 
study center personnel must report the event to Global Drug Safety on the SAE Form 
for Clinical Trials. The medical director may also be notified by telephone, however, 
notification of the medical director by telephone does not substitute for reporting of the 
event to the sponsor by email/fax of the SAE form for Clinical Trials within the 
required time period. 
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for 
an SAE, that AE should be recorded as a new SAE. 
The study center must transmit the SAE Form for Clinical Trials to the SAE email 
address or fax number shown below. Even if an initial report is made by telephone, the 
SAE Form for Clinical Trials completed with all available details must still be faxed or 
emailed within 24 hours of knowledge of the event at the study center. 
Supplemental information should be submitted as soon as available and may include 
laboratory results, radiology reports, progress notes, hospital admission and emergency 
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room notes, holding and observation notes, discharge summaries, autopsy reports, and 
death certificates. 
The investigator is expected to take all therapeutic measures necessary for resolution of 
the SAE. Any medications or procedures necessary for treatment of the SAE must be 
recorded on the appropriate pages of the subject’s eCRF. All SAEs are to be followed 
by the study staff until resolution or until the SAE is deemed stable. The sponsor may 
contact the study center to solicit additional information or follow up on the event. 
Fax or email the SAE Form for Clinical Trials to the following SAE fax number/email 
address: 
Fax Number:  
+1-714-796-9504 (back-up fax number: +1-714-246-5295) 
Email: 
 
IR-Clinical-SAE@allergan.com 
10.1.2.2.2 Reporting of Pregnancies Occurring During the Study  
Study site personnel must report every pregnancy from the time the subject signs the 
ICF until 30 days after receiving the last dose of study drug. Within 24 hours of learning 
of the pregnancy, the study site personnel must report the event to the sponsor’s Global 
Patient Safety department on the Clinical Trial Pregnancy Form and fax/email it to the 
following SAE/pregnancy fax number/email address, even if no AE has occurred:  
Fax Number:  
+1-714-796-9504 (back-up fax number: +1-714-246-5295) 
Email:  
 
IR-Clinical-SAE@allergan.com  
Pregnancies in female partners of male subjects occurring during the time frame 
described above must also be reported.  
The pregnancy must be followed to term and the outcome reported by completing a 
follow-up Clinical Trial Pregnancy Form. If the pregnancy is associated with an SAE 
(eg, if the mother is hospitalized for hemorrhage), a separate SAE Form for Clinical 
Trials must be filed with the appropriate serious criterion (eg, hospitalization) indicated 
in addition to the Clinical Trial Pregnancy Form. 
10.1.2.2.3 Unexpected Adverse Reactions 
Unexpected Adverse Reaction Definition 
An unexpected adverse reaction is any untoward and unintended response that is related 
to the administration of the study drug at any dose that is not consistent with the 
applicable product information (eg, investigators brochure for an unauthorized 
investigational medicinal product or summary of product characteristics for an 
authorized product). 
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All suspected unexpected serious adverse reactions (SUSARs) will be the subject of 
expedited reporting. The sponsor shall ensure that all relevant information about a 
SUSAR that is fatal or life-threatening is reported to the relevant competent authorities 
and institutional review board (IRB) within 7 days after knowledge by the sponsor of 
such a case and that relevant follow-up information is communicated within an 
additional 8 days. All other SUSARs will be reported to the relevant competent 
authorities and IRB within 15 days after knowledge by the sponsor of such a case. All 
investigators should follow up SUSARs until the event is resolved or until, in the 
opinion of the investigator, the event is stabilized or determined to be chronic. Post 
study SUSARs that occur after the subject has completed the clinical study must be 
reported by the investigator to the sponsor. 
10.1.2.2.4 Warnings and Precautions  
Clinical Worsening/Suicide Risk: subjects should be monitored for clinical worsening, 
suicidality and unusual change in behavior, especially at the start of therapy or at times 
of dose changes. (See Section 10.1.2.1 for use of the C-SSRS). 
Serotonin Syndrome: serotonin syndrome has been reported with SSRIs, including 
escitalopram, when taken alone, but especially when co-administered with other 
serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, 
tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort). Serotonin 
syndrome symptoms may include mental status changes (eg, agitation, hallucinations, 
delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, 
dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (eg, 
tremor, rigidity, myoclonus, hyperreflexia, and incoordination) seizures, and/or 
gastrointestinal symptoms (eg, nausea, vomiting, and diarrhea). If symptoms of 
serotonin syndrome occur, escitalopram should be discontinued and supportive 
treatment initiated. 
Hyponatremia: hyponatremia may occur as a result of treatment with SSRIs, including 
escitalopram. Subjects taking diuretics or who are otherwise volume depleted may be at 
greater risk. Discontinuation of escitalopram should be considered in subjects with 
symptomatic hyponatremia and appropriate medical intervention should be instituted. 
Caution should be used when escitalopram is taken in combination with other centrally 
acting drugs. 
Full details of the Warnings and Precautions associated with escitalopram are available 
in the prescribing information. 
10.1.2.2.5 Overdose 
Symptoms most often accompanying escitalopram overdose, alone or in combination 
with other drugs and/or alcohol, include convulsions, coma, dizziness, hypotension, 
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insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes 
(including QT prolongation and very rare cases of torsade de pointes). Acute renal 
failure has been very rarely reported accompanying overdose. 
In managing overdosage, consider the possibility of multiple-drug involvement. The 
physician should consider contacting a poison control center for additional information 
on the treatment of any overdose. 
10.1.2.2.6 Potential Hy’s Law Cases 
Criteria for potential Hy’s law cases are as follows: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 × upper 
limit of normal (ULN) AND 
• Total bilirubin ≥ 2 × ULN AND 
• Alkaline phosphatase < 2 × ULN 
Study site personnel must report every subject who meets these criteria. Typically, all 
3 analytes will be obtained from the same sample, but they may come from multiple 
samples taken within a 24-hour period. This requirement applies from the time the 
subject signs the ICF for the study until 30 days after receiving the last dose of study 
drug. 
A laboratory alert for potential Hy’s laws cases will be in place, and the laboratory must 
notify investigators and the sponsor immediately when the above criteria have been met. 
A potential Hy’s law case must be reported to the sponsor on an SAE form as soon as 
possible (within 24 hours of learning of the potential Hy’s law case) to the 
SAE/pregnancy fax number, even if no AE has occurred. The eCRF for potential Hy’s 
law cases must be completed within 7 calendar days. Every effort to determine the 
cause of the liver enzyme abnormalities must be made, and close monitoring should be 
initiated in conjunction with the Study Medical Monitor and in accordance with the 
FDA Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, July 2009. The patient should return to the study site and be evaluated as 
soon as possible, preferably within 48 hours from the time the investigator becomes 
aware of the abnormal results. This evaluation should include laboratory tests, detailed 
history, and physical examination. 
10.1.2.3 Clinical Laboratory Evaluation 
The hematology, clinical chemistry, urinalysis, and other laboratory variables analyses 
(see Section 10.1.2.3.1) will be performed at a central laboratory. Reference ranges will 
be used by the investigator to assess the laboratory data for clinical significance and 
pathological changes. The following laboratory safety tests will be performed at the 
times outlined in the Schedule of Assessments in Section 8.1.2. Information on 
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collection, processing, and shipping of samples will be provided in the Laboratory 
Manual. 
Hematology 
Hemoglobin, hematocrit, white blood cell count (total and differential), red blood cell 
count, platelet count, mean cell volume, mean cell hemoglobin (MCH), and MCH 
concentration. 
Clinical Chemistry 
Creatinine, urea (or blood urea nitrogen), aspartate transferase, alanine transferase, 
gamma glutamyltransferase, alkaline phosphatase, lactate dehydrogenase, total 
bilirubin, albumin, total protein, sodium, potassium, chloride, glucose, uric acid, 
calcium, phosphorus, TSH, T3, and T4. 
Urinalysis 
pH, glucose, ketones, blood, protein, and microscopy. 
10.1.2.3.1 Other Laboratory Variables 
Screening for pregnancy using serum β-HCG will be performed at the Screening Visit. 
Urine pregnancy tests will be performed at the Baseline Visit and the Week 8/End of 
Treatment Visit (Visit 7). 
Urine drug screen (alcohol, opioids, benzodiazepines, tetrahydrocannabinol, 
barbiturates, amphetamines) will be performed at the Screening Visit and the 
Week 8/End of Treatment Visit (Visit 7). 
Screening for HBsAg, HCVab, and HIV will be performed at the Screening Visit only. 
10.1.2.4 Vital Signs 
Vital signs (blood pressure, pulse rate, temperature, and respiration rate) will be 
recorded in a standardized manner (ie, after the subject has rested in the sitting position 
for 5 minutes). Height, weight, and BMI will also be recorded at specified visits. The 
times of assessment are outlined in the Schedule of Assessments in Section 8.1.2.  
10.1.2.5 Physical Examination 
A complete physical examination (including neurological examination) will be 
performed at the Screening Visit (Visit 1) and at the end of Week 8/ET (Visit 7) by a 
professionally trained physician or health professional listed on Form FDA 1572 and 
licensed to perform physical examinations. Any untoward clinically relevant changes 
will be recorded as AEs.  
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10.1.2.6 Electrocardiogram 
A 12-lead single trace ECG will be performed at the times outlined in the Schedule of 
Assessments in Section 8.1.2 in a standardized manner (ie, after the subject has rested in 
the semi-supine position for at least 5 minutes). Measurements will include ventricular 
heart rate, RR interval, PR interval, QRS interval, QT interval, and QTc interval. The 
QTc interval will be calculated using both the Bazett correction (QTcB = QT/(RR)½) 
and the Fridericia correction (QTcF = QT/(RR)⅓). 
The ECGs will be centrally read. The date and an overall interpretation of the ECG will 
be recorded in the eCRF. Any abnormalities will be assessed as clinically significant or 
not clinically significant and recorded on the eCRF.  
10.1.3 Pharmacokinetic Assessments 
10.1.3.1 Study Drug Concentration Measurements 
PK blood samples for measurement of escitalopram and S-demethylcitalopram plasma 
concentrations will be collected from assented/consented subjects at Visit 5 (Week 4) 
and Visit 7 (Week 8). For subjects who cannot go the site for scheduled visits due to the 
COVID-19 pandemic, PK sample collection can occur at the times specified in 
Section 8.2.2.1, Table 1. Two PK blood samples per subject will be collected at each of 
these visits at the following times:  
Visit 5:  
• For subjects receiving dose in the morning, at 0 hour (predose) and ≥ 1 hour 
postdose 
• For subjects receiving dose in the evening, 2 samples at random times during the 
visit (ie, postdose from the dose received the previous evening), collected at least 
2 hours apart from each other 
Visit 7:  
• For subjects receiving dose in the morning or in the evening, 2 samples at random 
times during the visit (ie, postdose from the dose received in the morning or the 
previous evening), collected at least 2 hours apart from each other 
To allow for a predose sampling, subjects on a morning dosing schedule should be 
instructed to withhold their daily dose on the morning of Visit 5 and take study drug 
when instructed at the study center. 
 
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The actual date and clock times of the dose on the PK sampling date as well as the 
2 doses taken prior to the PK sampling date, and the actual date and clock times of all 
blood draws, will be recorded in the eCRF. Blood samples will be collected in 
prechilled 6 mL Vacutainer® tubes containing lithium heparin as an anticoagulant and 
processed, stored, and shipped as specified in the Laboratory Manual. 
 
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. Bioanalytical 
representatives will be unblinded for PK sample bioanalysis during the conduct of the 
study. The unblinding of bioanalytical representatives will be carried out in a secure 
manner following the sponsor’s standard operating procedures. Extreme care and 
diligence will be taken to ensure no other individuals outside the bioanalytical team will 
be unblinded. 
 
10.1.3.2 Handling of Biological Specimens 
PK samples obtained from subjects will be stored at the centralized clinical laboratory 
until ready for PK analyses by the bioanalytical laboratory using a validated method. 
 
10.2 Appropriateness of Measurements 
The efficacy and safety assessments planned for this study are widely used and 
generally recognized as reliable, accurate, and relevant to the disease condition. 
11 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
11.1 Subject Populations 
Five populations will be considered in the statistical analysis of the study, as specified 
below. 
11.1.1.1 Screened Population 
The Screened Population will consist of all subjects who underwent a Screening Visit 
and received a subject number, and signed the ICF. 
11.1.1.2 Randomized Population  
The Randomized Population will consist of all subjects in the Screened Population who 
are randomized to a treatment group in the study. 
11.1.1.3 Safety Population  
The Safety Population will consist of all subjects in the Randomized Population who 
took at least one dose of study medication. 
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11.1.1.4 Modified Intent-to-Treat (mITT) Population  
The modified Intent-to-Treat (mITT) Population is defined as all subjects who are 
randomized and receive at least one dose of study medication, and have both baseline 
and at least one postbaseline primary efficacy measure (ie, PARS severity score). The 
mITT population will be used for all of the efficacy analyses. 
11.1.1.5 Pharmacokinetic Population 
The PK Population is defined as all subjects in the Safety Population with at least one 
evaluable plasma concentration of escitalopram or S-demethylcitalopram. 
11.2 Disposition  
The number of subjects in the Screened Population will be summarized overall by study 
center. The number of subjects in the Randomized, Safety, and mITT Populations will 
be summarized by treatment group and study center. Subjects whose disposition status 
was impacted by the COVID-19 pandemic will also be summarized. 
Screen failures (ie, subjects who were screened but not included in the Randomized 
Population) and the associated reasons for failure will be tabulated overall. The reasons 
for premature discontinuation from the double-blind treatment period as recorded on the 
termination pages of the eCRF will be summarized (number and percentage) by 
treatment group for the Safety Population. 
The number and percentage of subjects with significant protocol deviations will be 
summarized overall and by treatment group for the Randomized Population. Deviations 
related to the following categories will be included: 
• inclusion or exclusion criteria 
• withdrawal criteria 
• treatment or dose 
• concomitant medications 
These and any additional significant protocol deviations will be reviewed and 
documented before database lock and unblinding of treatment codes. 
Protocol deviations that occur due to COVID-19 will be summarized and listed 
separately. 
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11.3 Demographic and Other Baseline Characteristics  
Demographic parameters (eg, age, age group [7-11 vs. 12-17 years], sex, race, ethnicity, 
weight, weight z-score, height, height z-score, BMI, BMI z-score) and other baseline 
characteristics will be summarized by treatment group for the Safety and mITT 
Populations. Descriptive statistics (n, mean, standard deviation, minimum, median, and 
maximum) will be presented for continuous variables, and frequency distributions 
(counts and percentages) will be presented for categorical variables. 
Medical history terms will be encoded using the latest available Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. Summaries of medical history will be 
produced by system organ class (SOC) and preferred term (PT).  
Psychiatric history and results from the MINI Kid will be summarized descriptively.  
Prior and concomitant medications, including prior treatment for GAD, will be coded 
using the latest available WHO Drug dictionary. Drug classes and preferred names will 
be summarized by randomized treatment. 
11.4 Extent of Exposure and Treatment Compliance  
11.4.1 Extent of Exposure 
11.4.1.1 Investigational Product 
Total exposure to double-blind investigational product for the Safety Population during 
the double-blind treatment period will be summarized, calculated as the number of days 
from the date of the first dose of double-blind investigational product taken to the date 
of the last dose taken through the Week 8 End of Treatment or Early Withdrawal Visit, 
inclusive. Descriptive statistics (n, mean, standard deviation, minimum, median, and 
maximum) will be presented by treatment group. Similarly, the treatment duration in the 
down taper period, defined as the first dose in the down taper period to the last dose in 
the down taper period, inclusive, will be summarized. The total duration of double-blind 
investigational product exposure, defined as the sum of the treatment duration through 
Week 8 and the duration in the down taper period will be summarized. 
The number and percentage of subjects who had their dosage escalated at Week 2 from 
10 mg/day to 20 mg/day will be summarized by treatment group. The denominator will 
be the number of subjects who had study medication dispensed at Week 2. Similarly, 
the number and percentage of subjects who had their dosage escalated at Week 4 from 
10 mg/day to 20 mg/day will be summarized by treatment group. The number of 
subjects who required a dose reduction from 20 mg/day to 10 mg/day will be 
summarized by treatment group. The number of days from first date of escalation to 
20 mg/day to the dose reduction will be summarized using descriptive statistics. 
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The weekly and overall mean daily dose of investigational product will be summarized 
by treatment group for the Safety Population. 
11.4.1.2 Prior and Concomitant Medication 
Prior medication is defined as any recorded medication taken before the date of the first 
dose of double-blind investigational product. Concomitant medication is defined as any 
recorded medication used on or after the date of the first dose of double-blind 
investigational product. A medication may be classified as both a prior medication and 
concomitant medication. 
Prior and concomitant medications, used for treatment of GAD and for other 
indications, will be summarized by the number and proportion of subjects in each 
treatment group receiving each medication within each therapeutic class for the Safety 
Population. Multiple medication use by a subject will only be counted once. Any 
recorded medications started after last dose of double-blind investigational product will 
not be summarized but will be included in listings. 
11.4.2 Measurement of Treatment Compliance 
Dosing compliance for a specified period will be defined as the total number of capsules 
actually taken by a subject during that period divided by the number of capsules 
prescribed to be taken for the same period multiplied by 100. This information will be 
obtained from the investigational product record of the subject’s eCRF. 
The total number of capsules actually taken during a specific time period is calculated 
based on the study medication record. The number of capsules prescribed to be taken 
for a specific treatment period will be calculated by multiplying the number of days in 
that period by the number of capsules to be taken per day. 
Descriptive statistics for investigational product compliance will be presented by 
treatment group for each period between 2 consecutive visits, as well as for the entire 
double-blind treatment period, the period from first dose to the Week 8 End of 
Treatment or Early Withdrawal Visit, and the down taper period.  
11.5 Efficacy Analysis 
The efficacy analyses will be based on the mITT Population. Baseline for efficacy is 
defined as the last non-missing efficacy assessment recorded at or before the date of the 
first double-blind dosing. All statistical tests will be 2-sided hypothesis tests performed 
at the 5% level of significance. For efficacy analyses in which study center is a factor, a 
small center will be defined as a center with less than 2 subjects in at least 1 treatment 
group in the mITT Population. A pooling algorithm for the pooling of small centers will 
be specified in the statistical analysis plan (SAP). By-visit analysis based on the 
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mixed-effects model for repeated measures (MMRM) using the observed case approach 
will be performed for all continuous efficacy parameters. 
11.5.1.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the change from Baseline to Week 8 in the PARS 
severity score. 
The PARS severity score for GAD is assessed for all symptoms identified in the 
generalized anxiety section of the PARS symptom checklist. The PARS severity score 
for GAD will be derived by summing 5 of 7 severity/impairment/interference items 
(2, 3, 5, 6, and 7). 
The primary analysis will be performed using an MMRM with treatment group, age 
group strata (7-11 vs. 12-17 years), sex, study center, visit, and treatment group-by-visit 
interaction as the fixed effects and the baseline value and baseline value-by-visit 
interaction as the covariates. An unstructured covariance matrix will be used to model 
the covariance of within-subject scores. The Kenward-Roger approximation16 will be 
used to estimate denominator degrees of freedom for the unstructured covariance 
matrix. If the model convergence for the unstructured covariance matrix fails, then the 
Fisher scoring algorithm will be used to provide better initial values of the covariance 
parameters. In the event that the model still does not converge after using those initial 
values, simplified covariance structures will be used to fit the model in the following 
order until the model converges: (1) ante-dependence, (2) heterogeneous autoregressive, 
(3) Toeplitz, and (4) compound symmetry. If a structured covariance is used, then a 
robust sandwich estimator will be used for estimating the variance of the treatment 
effect estimate. 
The MMRM analysis will be performed based on all post-baseline scores using only the 
observed cases without imputation of missing values. 
The significance test for the difference in means at Week 8 will be based on least 
squares (LS) means using a 2-sided α of 0.05. Differences between treatments at the 
other post-baseline visits will also be estimated based on LS means. 
Sensitivity analyses will be conducted on the primary efficacy endpoint to assess the 
missing at random assumption of the MMRM model and the impact of COVID-19 
using remote home assessments. Details will be provided in the SAP. 
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11.5.1.1.1 Estimand for the Primary Efficacy Analysis 
The following describes the estimand approach for the primary efficacy analysis 
described in ICH E9 (R1) (2017)17.  
Target Population 
As noted above in Section 11.5, the target population is the mITT population. 
Variable 
The variable is the same as the definition of the primary efficacy analysis described in 
Section 11.5.1.1. 
Accounting for Intercurrent Events 
The primary analysis will treat measurements after study withdrawal as missing in the 
MMRM modeling, leading to an estimate of the treatment effect while on treatment. 
The impact of the missing at random assumption of MMRM will be assessed using 
2 different approaches. The first will be a simple last observation carried forward 
(LOCF) approach. The second will be a sensitivity analysis using a pattern-mixture 
model. The details of this sensitivity analyses will be provided in detail in the SAP. 
Population-level Summary 
The population-level summary for the primary endpoint is the difference in primary 
variable means between the escitalopram group and placebo, while remaining on the 
study treatment. 
11.5.1.2 Secondary Efficacy Parameters  
Inferential testing for the secondary endpoints will be reported with nominal p-values. 
No adjustments for multiplicity will be made. All confidence intervals will be 2-sided 
95% confidence intervals, unless stated otherwise. 
The secondary efficacy endpoints are as follows: 
• Response rate on the PARS at acute treatment endpoint (Week 8)  
o Response is defined as a 50% improvement on the PARS severity score 
for GAD. 
• Remission rate on the PARS at acute treatment endpoint (Week 8)  
o Remission is defined as PARS severity score for GAD <8 (using 6 PARS 
items: 2, 3, 4, 5, 6, and 7) 
• Change on the CGI-S from baseline to acute treatment endpoint (Week 8) 
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o Remission rate on CGI-S at acute treatment endpoint (Week 8). 
Remission rate is defined as the percentage of subjects having a CGI-S 
score ≤2 at endpoint.  
• Change on the CGAS from baseline to acute treatment endpoint (Week 8) 
o Remission rate on the CGAS at acute treatment endpoint (Week 8). 
Functional remission is defined as CGAS >70. 
• COVID-19 impact assessment score at each visit. 
The response rate of the PARS will be analyzed using a repeated measures model for 
categorical outcomes. Modeling will be completed using a categorical MMRM 
(MMRM-CAT) approach, in which a pseudo-likelihood-based repeated measures 
analysis will be used and implemented in SAS procedure GLIMMIX. A binary 
distribution with logit link will be used for the dependent variable. Classification 
variables for treatment, age group, sex, visit (as a categorical variable), 
treatment-by-age group interaction, treatment-by-sex interaction, treatment-by-visit 
interaction, and treatment-by-age group-by-sex interaction, and baseline score as a 
covariate will be considered in the modeling. 
11.5.1.2.1 Analysis of Remission in PARS 
The remission rate on the PARS will be analyzed using the same MMRM-CAT as the 
response rate on the PARS.  
11.5.1.2.2 Change on the CGI-S from Baseline to Acute Treatment Endpoint 
(Week 8) 
The change in the CGI-S will be analyzed using the same methodology described for 
the primary efficacy endpoint. The analysis of the remission rate for the CGI-S will use 
the same methodology described for the analysis of the response rate on the PARS.  
11.5.1.2.3 Change on the CGAS from Baseline to Acute Treatment Endpoint 
(Week 8)  
The change in the CGAS will be analyzed using the same methodology described for 
the primary efficacy endpoint. The analysis of the remission rate for the CGAS will use 
the same methodology described for the analysis of the response rate on the PARS.  
11.5.1.2.4 COVID-19 Impact Assessment Score at each Visit 
The COVID-19 impact assessment score will be summarized at each visit. 
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11.6 Safety Analysis  
The safety analysis will be performed for the double-blind treatment period and 
double-blind down taper period separately using the Safety Population. The safety 
parameters will include AEs, clinical laboratory parameters, vital sign measurements, 
and ECG parameters. For each safety parameter, the last assessment made before the 
first dose of double-blind investigational product will be used as the baseline for all 
analyses of that safety parameter. 
Safety data collected outside of planned visit windows but within allowance limits (up 
to 1 week late for Visits 7 and 8) will be included in the summary tables. Safety data 
collected outside of planned visit windows and outside of the allowance limits (>1 week 
to 6 weeks late for Visits 7 and 8) will be listed, but will not be included in the summary 
tables. Subgroup analyses may be performed to assess the impact of COVID-19 on the 
safety analyses. 
The safety endpoints during the double-blind treatment period are as follows: 
• Incidence of treatment-emergent adverse events (TEAEs). 
• Observed values and change from baseline in vital signs (blood pressure, pulse 
rate, temperature, respiration rate, height, weight, BMI, height percentile, weight 
percentile, and BMI percentile); incidence of vital sign potentially clinically 
significant (PCS) values. 
• Observed values and changes from baseline in ECG intervals and interpretation; 
incidence of ECG PCS values. 
• Observed values and changes from baseline in clinical laboratory assessments 
(hematology, chemistry, and urinalysis); incidence of clinical laboratory PCS 
values. 
• Incidence of suicidal ideation and/or suicidal behavior as determined by the 
C-SSRS. 
 
11.6.1.1 Adverse Events  
AEs will be coded to an SOC and PT using the latest available version of MedDRA. An 
AE (classified by PT) not present before the date of the first dose of the double-blind 
treatment period or during the double-blind down taper period or that was present 
before the first dose but increased in severity or seriousness will be considered a TEAE. 
An AE that starts more than 30 days after the date of the last dose of double-blind 
investigational product will not be counted as a TEAE. 
An AE that starts during the double-blind down taper period or that increases in severity 
or seriousness during the double-blind down taper period will be considered a newly 
emergent AE (NEAE). The NEAEs during the double-blind down taper period will be 
summarized by SOC, PT, and treatment group for all subjects who enter the 
double-blind down taper period. 
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The number and percentage of subjects reporting TEAEs in each treatment group will 
be tabulated by SOC and PT; by SOC, PT, and severity; and by SOC, PT, and causal 
relationship to the investigational product. If more than one AE is coded to the same PT 
for the same subject, the subject will be counted only once for that PT using the most 
severe and most related occurrence for the summarization by severity and by causal 
relationship to the investigational product, respectively. 
The distribution of TEAEs by severity and causal relationship to the investigational 
product will be summarized by treatment group. The incidence of common (≥ 2% of 
subjects in any treatment group) TEAEs during the double-blind treatment period will 
be summarized by PT and treatment group.  
An SAE that occurred between the date of the first dose of double-blind investigational 
product and 30 days after the date of the last dose of double-blind investigational 
product in the study, inclusive, will be considered an on-therapy SAE. The incidence of 
SAEs and AEs leading to premature discontinuation of the study will also be 
summarized by study period (separately for double-blind treatment period and double-
blind down taper period), SOC, PT, and treatment group. Listings will be presented for 
subjects with SAEs, subjects with AEs leading to premature discontinuation, and 
subjects who died. All subjects with SAEs, including those reported during the 
screening period or more than 30 days after the date of the last dose of the double-blind 
investigational product, and subjects discontinuing due to AEs before the start of 
double-blind investigational product will be included in these listings. 
Each AE summary described above will be presented as all AEs, AEs that are 
associated with the COVID-19 pandemic (as determined by the investigator), and AEs 
that are not associated with the COVID-19 pandemic. AEs associated with the 
COVID-19 pandemic will be listed separately. 
11.6.1.2 Vital Signs  
Descriptive statistics for vital signs (ie, blood pressure, pulse rate, temperature, 
respiration rate, height, weight, BMI, height percentile, weight percentile, and BMI 
percentile) and changes from baseline values at each visit and at end of study will be 
presented by treatment group. Height, weight, and BMI z-scores will be calculated 
based on CDC growth charts. 
Vital sign values will be PCS if they meet both the observed-value criteria and the 
change from baseline-value criteria. The criteria for PCS vital sign values will be 
detailed in the SAP. The percentages will be calculated relative to the number of 
subjects with baseline values and at least one postbaseline assessment. The numerator 
will be the total number of subjects with available baseline values and at least one PCS 
postbaseline value. A supportive listing of subjects with PCS postbaseline values will be 
provided, including the subject identification (SID) number, study center number, and 
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baseline and postbaseline values. A listing of all AEs for subjects with PCS vital sign 
values will also be provided. 
11.6.1.3 Electrocardiograms  
Descriptive statistics for ECG parameters (ie, ventricular heart rate, RR interval, PR 
interval, QRS interval, QT interval, and QTc interval) and changes from baseline values 
at each assessment time point will be presented by treatment group. The QTc interval is 
calculated using both the Bazett (QTcB = QT/(RR)½) and Fridericia (QTcF = 
QT/(RR)⅓) corrections. The number and percentage of subjects with PCS postbaseline 
ECG values will be tabulated by treatment group. The criteria for PCS ECG values will 
be detailed in the SAP. The percentages will be calculated relative to the number of 
subjects with available non-PCS baseline values and at least one postbaseline 
assessment. The numerator will be the total number of subjects with available non-PCS 
baseline values and at least one PCS postbaseline value. A supportive listing of subjects 
with PCS postbaseline values will be provided, including the SID number, study center 
number, and baseline and postbaseline values. A listing of all AEs for subjects with 
PCS ECG values will also be provided. 
A listing of subjects with postbaseline clinically significant ECG abnormalities, as 
reported by the investigator or by the central cardiologist, will also be provided. 
The number and percentage of subjects with an increase >30 msec but ≤60 msec, and 
with an increase >60 msec in QTcB or QTcF will be tabulated. A supportive listing of 
subjects with postbaseline QTcB or QTcF increases >30 msec will be provided, 
including the SID number, study center, and all QTcB and QTcF values (including 
changes from baseline). A listing of all AEs for subjects with postbaseline QTcB or 
QTcF increases >30 msec will also be provided.  
11.6.1.4 Clinical Laboratory Evaluations  
Descriptive statistics for clinical laboratory values (in SI units) and changes from the 
baseline values at each assessment time point will be presented by treatment group for 
each clinical laboratory parameter. The number and percentage of subjects with PCS 
postbaseline clinical laboratory values will be tabulated by treatment group. The criteria 
for PCS laboratory values will be detailed in the SAP. The percentages will be 
calculated relative to the number of subjects with available non-PCS baseline values and 
at least one postbaseline assessment. The numerator will be the total number of subjects 
with available non-PCS baseline values and at least one PCS postbaseline value. A 
supportive listing of subjects with PCS postbaseline values will be provided, including 
the SID number, study center number, and baseline and postbaseline values. A listing of 
all AEs for subjects with PCS laboratory values will also be provided.  
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11.6.1.5 Columbia-Suicide Severity Rating Scale 
For the C-SSRS, the number and percentage of subjects with suicidal ideation or 
suicidal behavior as recorded on the C-SSRS scale will be presented by treatment group. 
The distribution of responses for most severe suicidal ideation and suicidal behavior 
during the lifetime history, the double-blind treatment period and the down taper period 
will also be presented by treatment group for the Safety Population. Supportive listings 
will be provided and will include the SID number, treatment group, visit number, 
lifetime history, and postbaseline values for each patient. Intensity of ideation, suicidal 
behavior type, and lethality of suicidal behavior will also be included in these listings. 
11.7 Pharmacokinetic and Exposure-Response Evaluation 
Escitalopram and S-demethylcitalopram plasma concentrations will be listed. 
Escitalopram concentrations will be analyzed using a nonlinear mixed effects approach. 
Population PK parameters, inter-subject, and residual variability will be determined. 
The effect of covariates on the escitalopram PK will also be investigated. The 
exposure/dose-response relationship between efficacy parameters and plasma exposure 
and potentially safety parameters and plasma exposure will be explored using a 
nonlinear mixed effects approach. The analysis results will be provided in a separate 
report. 
11.8 Interim Analyses 
A blinded interim analysis will be conducted when 75% of randomized subjects have 
either completed or discontinued the study to obtain an estimate of the pooled standard 
deviation on change from baseline in the PARS score to Week 8 of the double-blind 
treatment period. If the estimated pooled standard deviation is larger than the assumed 
pooled standard deviation in the sample size calculation due to assumption deviation as 
well as COVID-19 remote visits (see Section 11.9), sample sizes in placebo and 
escitalopram treatment groups may be increased to ensure an adequate power. However, 
due to the difficulties in recruiting pediatric subjects with GAD, the number of subjects 
in each treatment arm will be capped at 160.  
11.9 Determination of Sample Size 
The sample size estimate was constructed using a simulation approach as described in 
Lu K. (2012)18.  
The primary efficacy parameter will be the change from baseline to Week 8 of the 
double-blind treatment period in PARS total score. To detect an effect size (treatment 
group difference of 2.30 units relative to pooled standard deviation of 5.7919) of 0.39, a 
sample size of 128 subjects in the escitalopram treatment group and 128 subjects in the 
placebo group will provide 85% power based on an MMRM model using simulation 
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method. The simulation assumed a correlation of 0.7 between the repeated measures, 
and a common dropout rate of 14%, based on historical data of escitalopram in pediatric 
subjects. 
11.10 Protocol Deviations 
Deviations from the protocol will be documented on an ongoing basis based on 
monitoring reports (eg, failure of eligibility criteria). Protocol deviations may also be 
identified by data management checks or statistical programming (eg, study treatment 
compliance, duration of study treatment, study completion, prohibited medications 
based on drug codes).  
12 QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 Audit and Inspection 
Study centers and study documentation may be subject to Quality Assurance audit 
during the course of the study by the sponsor or its nominated representative. In 
addition, inspections may be conducted by regulatory authorities at their discretion. 
12.2 Monitoring 
Data for each subject will be recorded on an eCRF. Data collection must be completed 
for each subject who signs an ICF/assent and is administered study drug. 
In accordance with cGCP and ICH guidelines, the study monitor will carry out source 
document verification at regular intervals to ensure that the data collected in the eCRF 
are accurate and reliable.  
The investigator must permit the monitor, the IRB, the sponsor’s internal auditors, and 
representatives from regulatory authorities direct access to all study-related documents 
and pertinent hospital or medical records for confirmation of data contained within the 
eCRFs. 
12.3 Data Management and Coding 
Syneos Health will be responsible for activities associated with the data management of 
this study. This will include setting up a relevant database and data transfer 
mechanisms, along with appropriate validation of data and resolution of queries. Data 
generated within this clinical study will be handled according to the relevant standard 
operating procedures of the data management and biostatistics departments of Syneos 
Health. 
Study centers will enter data directly into an electronic data capture (EDC) system by 
completing the eCRF via a secure internet connection. Data entered into the eCRF must 
be verifiable against source documents at the study center. Data to be recorded directly 
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on the eCRF will be identified and the eCRF will be considered the source document. 
Any changes to the data entered into the EDC system will be recorded in the audit trail 
and will be FDA CFR 21 Part 11 compliant. 
Medical coding will use MedDRA for concomitant diseases and AEs and WHO Drug 
for medications. 
Missing or inconsistent data will be queried in writing to the investigator for 
clarification. Subsequent modifications to the database will be documented. 
12.4 Quality Management and Risk Evaluation 
Details are provided in Section 8.2.2. 
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13 RECORDS AND SUPPLIES 
13.1 Drug Accountability 
On receipt of the study drug (including rescue medication, if relevant), the investigator 
(or deputy) will conduct an inventory of the supplies and verify that study drug supplies 
are received intact and in the correct amounts before completing a supplies receipt. The 
investigator will retain a copy of this receipt at the study center and maintain the 
original receipt in the site investigator file. The monitor may check the study supplies at 
each study center at any time during the study. 
It is the responsibility of the study monitor to ensure that the investigator (or deputy) 
has correctly documented the amount of the study drug received, dispensed, and 
returned on the dispensing log that will be provided. A full drug accountability log will 
be maintained at the study center at all times. In addition, sites will be provided a 
separate Investigational Product Curbside Pickup and Shipment Tracking Form to 
document pertinent study drug dispensing information each time a new shipment of 
study drug is shipped directly to a subject’s residence, dispensed curbside at the site, or 
delivered to a subject’s residence via site personnel. Sites will be instructed to submit 
this form to Syneos Health any time study drug is dispensed using these methods. The 
study monitor will arrange collection of unused study drug returned by the subject. All 
used and unused bottles will be returned to the sponsor. The study monitor will also 
perform an inventory of study drug at the close-out visit to the study center. All 
discrepancies must be accounted for and documented. 
13.2 Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement between 
Syneos Health and the sponsor. 
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14 ETHICS 
14.1 Institutional Review Board 
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the subjects, and any other relevant study documentation will be 
submitted to the appropriate IRB. Written approval of the study and all relevant study 
information must be obtained before the study center can be initiated or the study drug 
is released to the investigator. Any necessary extensions or renewals of IRB approval 
must be obtained for changes to the study such as amendments to the protocol, the ICF 
or other study documentation. The written approval of the IRB together with the 
approved ICF must be filed in the study files. 
The investigator will report promptly to the IRB any new information that may 
adversely affect the safety of the subjects or the conduct of the study. The investigator 
will submit written summaries of the study status to the IRB as required. On completion 
of the study, the IRB will be notified that the study has ended. 
14.2 Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and 
approval before the beginning of the study. On completion of the study, the regulatory 
authorities will be notified that the study has ended. 
14.3 Ethical Conduct of the Study 
The investigators and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, cGCP, ICH 
guidelines, and the applicable national and local laws and regulatory requirements. 
14.4 Informed Consent 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s) and must adhere to cGCP. 
The investigator is responsible for ensuring that no subject undergoes any study-related 
examination or activity before that subject has given written informed consent to 
participate in the study. 
The investigator or designated personnel will inform the subject and their parent/legal 
representative of the objectives, methods, anticipated benefits and potential risks and 
inconveniences of the study. The subject and their parent/legal representative should be 
given every opportunity to ask for clarification of any points s/he does not understand 
and, if necessary, ask for more information. At the end of the interview, the subject and 
their parent/legal representative will be given ample time to consider the study. Subjects 
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and their parent/legal representative will be required to sign and date the ICF/assent. 
There will be a separate ICF/assent for the PK part of the study. After signatures are 
obtained, the ICF/assent will be kept and archived by the investigator in the 
investigator’s study file. A signed and dated copy of the ICF/assent will be provided to 
the subject and their parent/legal representative. 
It should be emphasized that the subject may refuse to enter the study or to withdraw 
from the study at any time, without consequences for their further care or penalty or loss 
of benefits to which the subject is otherwise entitled. Subjects who refuse to give or who 
withdraw written informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the subject’s willingness 
to continue participation in the study, a new ICF/assent will be approved by the IRBs 
(and regulatory authorities, if required). The study subjects and their parent/legal 
representative will be informed about this new information and reconsent will be 
obtained. 
14.5 Subject Confidentiality 
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the 
IRBs approving this research, and the United States FDA, as well as that of any other 
applicable agency(ies), will be granted direct access to the study subjects’ original 
medical records for verification of clinical study procedures and/or data, without 
violating the confidentiality of the subjects to the extent permitted by the law and 
regulations. In any presentations of the results of this study or in publications, the 
subjects’ identity will remain confidential. 
All personal data collected and processed for the purposes of this study should be 
managed by the investigator and his/her staff with adequate precautions to ensure 
confidentiality of those data, and in accordance with the Health Insurance Portability 
and Accountability Act20, applicable to national and/or local laws and regulations on 
personal data protection. 
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15 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced. After completion of the study 
(end of study defined as the date of the last visit of the last subject), all documents and 
data relating to the study will be kept in an orderly manner by the investigator in a 
secure study file. This file will be available for inspection by the sponsor or its 
representatives. Essential documents should be retained for 2 years after the final 
marketing approval in an ICH region or for at least 2 years since the discontinuation of 
clinical development of the investigational product. It is the responsibility of the 
sponsor to inform the study center when these documents no longer need to be retained. 
The investigator must contact the sponsor before destroying any study-related 
documentation. In addition, all subject medical records and other source documentation 
will be kept for the maximum time permitted by the hospital, institution, or medical 
practice. 
The sponsor must review and approve any results of the study or abstracts for 
professional meetings prepared by the investigator(s). Published data must not 
compromise the objectives of the study. Data from individual study centers in 
multicenter studies must not be published separately. 
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16 REFERENCES
Wehry AM, Beesdo-Baum K, Hennelly MM, Connolly SD, Strawn JR. Assessment and 
treatment of anxiety disorders in children and adolescents. Curr Psychiatry Rep. 
2015;17:52. 
Merikangas KR, He JP, Burstein M, et al. Lifetime prevalence of mental disorders in U.S. 
adolescents: results from the National Comorbidity Survey Replication-Adolescent 
Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010;49(10):980-9. 
Woodward LJ, Fergusson DM. Life course outcomes of young people with anxiety 
disorders in adolescence. J Am Acad Child Adolesc Psychiatry 2001;40:1086–93. 
Zimmermann P, Wittchen HU, Hofler M, Pfister H, Kessler RC, Lieb R. Primary anxiety 
disorders and the development of subsequent alcohol use disorders: A 4-year community 
study of adolescents and young adults. Psychol Med. 2003; 33:1211–22. 
Rynn M, Puliafico A, Heleniak C, Rikhi P, Ghalib K, Vidair H. Advances in 
pharmacotherapy for pediatric anxiety disorders. Depress Anxiety 2011;28:76–87. 
Chavira DA, Stein MB, Bailey K, Stein MT. Child anxiety in primary care: prevalent but 
untreated. Depress Anxiety 2004;20:155–164. 
Strawn JR, Sakolsky DJ, Rynn MA. Psychopharmacologic treatment of children and 
adolescents with anxiety disorders. Child Adolesc Psychiatr Clin North Am. 
2012;21:527-539. 
Lexapro [package insert]. Madison (NJ): Allergan USA, Inc; 2019. 
Khan A, Kolts RL, Rapaport MH. Krishnan KRR, Brodhead AR, Brown WA. Magnitude 
of placebo response and drug-placebo differences across psychiatric disorders. Psychol 
Med. 2005;35:743-749. 
The Pediatric Anxiety Rating Scale (PARS): development and psychometric properties. J 
Am Acad Child Adolesc Psychiatry. 2002;41;1061-1069. 
Verhulst FC, van der Ende J. Assessment scales in child and adolescent psychiatry. 1st 
ed. CRC Press; July 7, 2006;51-54. 
Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: 
US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug 
Abuse, and Mental Health Administration; 1976. 
Busner J, Targum SD. The clinical global impressions scale: applying a research tool in 
clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37. 
Shaffer D, Gould MS, Brasic J, et al. A children's global assessment scale (CGAS).
Archives of General Psychiatry. 1983;40:1228-1231 
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Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164:1035-43. 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997;53:989-987. 
ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials. Step 2;16 June 2017. 
Lu K. Sample size calculations with multiplicity adjustment for longitudinal clinical trials 
with missing data. Stat Med. 2012;31:19-28. 
Strawn JR, Prakash A, Zhang Q, Pangallo BA, Stroud CE, Cai N, Findling RL. A 
randomized, placebo-controlled study of duloxetine for the treatment of children and 
adolescents with generalized anxiety disorder. J Am Acad Child Adolesc Psychiatry. 
2015;54(4):283-93. 
US Department of Health and Human Services. The Health Insurance Portability and 
Accountability Act (HIPAA) of 1996 (P.L.104-191) [HIPAA].  
http://aspe hhs.gov/admnsimp/pl104191 htm. Effective August 21, 1996. 
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CONFIDENTIAL 
17 APPENDICES 
 
 
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17.1 Prohibited Medications 
Drugs Allowed (Y) and Drugs Not Allowed (N) as Concomitant Medications 
Drug Class 
Episodic Use 
(p.r.n) 
Chronic Use 
Restrictions 
Analgesics 
Y 
Y 
Non-narcotic analgesics only 
Anesthetics 
General 
Local 
N 
Y 
N 
N 
 
Anorexics 
N 
N 
 
Antacids 
Y 
Y 
 
Antiacne 
Y 
Y 
Topical agents only; Accutane 
(isotretinoin) is not allowed. 
Antianginal Agents 
N 
N 
 
Antiarrhythmics 
N 
N 
 
Antibiotics 
Y 
(Calla) 
  Zyvox (linezolid) is prohibited 
Anticoagulants 
N 
Y 
Only aspirin (maximum 
325 mg/day) is allowed as chronic 
anti-platelet treatment. 
Anticonvulsants 
N 
N 
 
Antidepressants 
N 
N 
 
Antidiarrheal 
Preparations 
 
Y 
 
N 
Only Imodium (loperamide hydrochloride), 
Pepto-Bismol, and kaolin preparations are 
allowed. 
Antifungal Agents 
Systemic 
Topical 
 
N
Y 
 
N
Y 
 
 
  Antihistamines 
 
Y 
 
(Calla) 
Only Allegra (fexofenadine), Claritin 
(loratadine), Clarinex (desloratadine), and 
Zyrtec (cetirizine) are allowed. See 
Cough and Cold Preparations for 
combination products. 
Antihypertensives 
N 
 
Yb 
Diupres (reserpine), Catapres (clonidine), 
Minipress (prazosin), Inderal 
(propranolol), Wytensin (guanabenz), 
Tenex (guanfacine), and Aldomet 
(methyldopa) are not allowed. 
Anti-impotence 
Medications 
(Calla) 
N 
 
Anti-inflammatory Drugs 
Y 
Yc 
Indocin (indomethacin) and systemic 
corticosteroids are not allowed. 
Migraine 
(Calla) 
N 
Ergotamine or ergot derivatives are not 
allowed. Calla for use of triptans. 
Antinauseants 
Y 
N 
Only phosphoric acid preparations 
(Emetrol, Emecheck), 
Pepto-Bismol and cola syrup are 
allowed. 
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Drugs Allowed (Y) and Drugs Not Allowed (N) as Concomitant Medications 
Drug Class 
Episodic Use 
(p.r.n) 
Chronic Use 
Restrictions 
Antineoplastics 
N 
N 
 
Antiobesity 
N 
Yc 
Only Xenical (orlistat) is allowed 
Anti-Psoriatic Treatments 
Y 
Y 
Soriatane (acitretin) is not allowed 
Antipsychotics 
N 
N 
 
Antiviral Agents 
Y 
Yb 
Only Zovirax, Valtrex, and Famvir are 
allowed 
Anxiolytics 
N 
N 
 
Biotin  
N 
N 
Biotin supplement > 2.5 mg total per day is 
not allowed. 
Biotin supplement ≤ 2.5 mg total per day is 
allowed. 
 
Cough/Cold Preparations 
 
Y 
 
(Calla) 
Use of cough and cold preparations 
containing pseudoephedrine are not 
permitted. Decongestants containing 
narcotics are not permitted. See 
Antihistamines. 
Diuretics 
Y 
Yb 
Episodic use of diuretics is restricted to 
treatment of premenstrual symptoms. 
H2 Blockers/Proton pump 
inhibitors 
Y 
Yb 
Tagamet (cimetidine) is not allowed. 
 
Hormones 
 
N 
 
Y 
Only thyroid hormone replacement, oral 
contraceptives, patch contraceptives, 
estrogen and progesterone replacement 
therapy are allowed. Hormone therapy 
(including oral contraceptives for female 
subjects) should not be initiated or 
discontinued within the 3 months prior to 
screening. 
Hormone Suppressants 
N 
Yb 
Only Proscar (finasteride) is allowed. 
Hypoglycemic Agents 
Y 
Y 
 
 
Hypolipidemics 
 
N 
 
Yb 
Only Mevacor (lovastatin), Zocor 
(simvastatin), Pravachol (pravastatin), 
Lipitor (atorvastatin), and Lescol 
(fluvastatin) are allowed. 
Insulin 
N 
N 
 
Laxatives 
Y 
Yc 
Only fiber-based products and Colace 
(docusate sodium) are allowed. 
Muscle Relaxants 
N 
N 
 
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Drugs Allowed (Y) and Drugs Not Allowed (N) as Concomitant Medications 
Drug Class 
Episodic Use 
(p.r.n) 
Chronic Use 
Restrictions 
Psychotropic drugs not 
otherwise specified 
(including herbal products) 
 
N 
 
N 
No drugs with psychomotor effects or with 
anxiolytic, stimulant, antipsychotic, or 
sedative properties are allowed. 
 
Sedatives/Hypnotics 
 
Y 
 
N 
Only Ambien (zolpidem) or Sonata 
(zaleplon) (no more than 3 times per week), 
at a maximum dose of 10 mg/day, is 
permitted if required for sleep. 
Steroids 
 - Systemic  
 - Topical  
 - Inhalant 
 
N  
Y  
Y 
 
N  
Y  
Y 
 
Vaccines 
Y 
N/A 
 
Abbreviations:  N = No; N/A = not applicable; p.r.n. = pro re nata; Y = yes. 
a Call the medical director to discuss.  
b If being taken for at least 6 months before study and dose is stabilized.  
c If being taken before admission to the study. 
 
 
 
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17.2 Investigator Signature Page 
Protocol Title: 
A Randomized, Multicenter, Double-Blind, Flexibly-dosed, Efficacy and 
Safety Study of Escitalopram in the Treatment of Children and 
Adolescents With Generalized Anxiety Disorder 
Protocol Number: 
SCT-MD-60 
Confidentiality and cGCP Compliance Statement 
I, the undersigned, have reviewed this protocol, including appendices, and I will 
conduct the study as described in compliance with this protocol, cGCP, and relevant 
ICH guidelines. 
Once the protocol has been approved by the IRB, I will not modify this protocol without 
obtaining prior approval of Allergan and of the IRB. I will submit the protocol 
amendments and/or any ICF modifications to Allergan and IRB, and approval will be 
obtained before any amendments are implemented. 
I understand that all information obtained during the conduct of the study with regard to 
the subjects’ state of health will be regarded as confidential. No subjects’ names will be 
disclosed. All subjects will be identified by assigned numbers on all eCRFs, laboratory 
samples, or source documents forwarded to the sponsor. Clinical information may be 
reviewed by the sponsor or its agents or regulatory agencies. Agreement must be 
obtained from the subject before disclosure of subject information to a third party. 
Information developed in this clinical study may be disclosed by Allergan, to other 
clinical investigators, regulatory agencies, or other health authority or government 
agencies as required. 
 
 
 
Investigator Signature 
 
Date 
 
 
 
Printed Name 
 
 
 
 
 
Institution 
 
 
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17.3 Telehealth  
For remote study visits subject data are collected via telephone or telehealth video calls 
using the technology provider. 
Overall Design 
In order to support the subject’s education, engagement and activity completion in the 
study, subjects will participate by using their own mobile telephone. If the subject’s 
own mobile telephone model and/or operating system does not meet the minimum 
technology requirements, if the subject does not have a device or chooses not to do 
video conferencing then regular telephone contact will be allowed. Sites should remain 
consistent with either methods for each subject. 
If the subject decides to use their own mobile device, the subject will be provided with a 
study-specific mobile application (app) to support reminders/notifications, activity 
completion, etc. This mobile app will be downloaded by the subject on their own mobile 
telephone from the Apple (iOS device) or Google Play Store (Android device) upon 
their receipt of a study-specific email with download hyperlink and unique study access 
code. 
The study-specific mobile application (app) will support the subject to complete 
study-specific activities such as: 
• Receive notifications for an ad-hoc telehealth call. 
• Conducting Telehealth Virtual Visits with the investigator and/or authorized site 
representative. 
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17.4 Protocol Amendment Summary 
Protocol version 2.0 dated 15 Mar 2019 is being amended to create protocol version 3.0 
dated 30 June 2020. This amended version of the protocol supersedes protocol version 2.0. 
This amendment is in reaction to the COVID-19 pandemic and it implements processes to 
mitigate COVID-19 risks and ensure subject and data quality. 
These changes and their rationale are described in detail in the following table. 
Minor consistency and administrative changes have also been made. 
 
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Table 2 
Protocol SCT-MD-60 Amendment 2.0 dated 30 June 2020 Table of Changes 
Location in 
Amended 
Protocol 
Original Text (Final Protocol Version 2.0 
dated 15 Mar 2019) 
Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
Title page 
Syneos Health 
3201 Beechleaf Court 
Suite 600 
Raleigh, NC 27604-1547 
United States 
Syneos Health 
1030 Sync Street 
Morrisville, NC 27560 
United States 
Address of contract research 
organization updated 
1 Protocol 
approval 
signatures 
, MD PhD 
Vice President, Clinical Development CNS 
Allergan 
5 Giralda Farms 
Madison, NJ 07940 
United States 
 
 
Associate Vice President, Clinical 
Pharmacology 
Allergan 
5 Giralda Farms 
Madison, NJ 07940 
United States 
, MS MD 
Vice President, Neuroscience Development 
AbbVie 
 
1 North Waukegan Road 
North Chicago, IL 60064 
United States 
 
, PhD DABT 
Vice President, Non-Clinical and Translational 
Sciences 
AbbVie 
2525 Dupont Drive 
Irvine, CA 92612 
United States 
Sponsor signatories updated 
2 Study personnel Allergan 
2525 Dupont Drive 
Irvine, CA 92612 
United States 
 
, PhD 
Director, Biostatistics 
AbbVie 
2525 Dupont Drive 
Irvine, CA 92612 
United States 
 
 PhD 
Director, Biostatistics 
 
In May 2020, AbbVie completed its acquisition 
of Allergan. Allergan remains sponsor of this 
Updates to account for changes in 
sponsor personnel and for acquisition 
of Allergan by AbbVie.  
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Location in 
Amended 
Protocol 
Original Text (Final Protocol Version 2.0 
dated 15 Mar 2019) 
Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
study. AbbVie is used for the addressess of 
sponsor signatories and sponsor personnel. 
2 Study personnel Syneos Health 
3201 Beechleaf Court 
Suite 600 
Raleigh, NC 27604-1547 
United States 
Syneos Health 
1030 Sync Street 
Morrisville, NC 27560 
United States 
Address of medical director from 
contract research organization 
updated 
3 Synopsis 
 
Study design 
During the coronavirus disease 2019 (COVID-
19) pandemic, remote study visits are possible to 
avoid missing efficacy data but not preferred 
over clinic visits.  
Addition of visit conduct options in 
response to COVID-19 pandemic 
3 Synopsis 
Study duration 
The study design incorporates a 1 to 2 week 
screening period, … 
Study duration 
The study design incorporates an up to 3-week 
screening period, …  
Screening window extended to allow 
for more time for safety results and 
medical records 
3 Synopsis 
Key inclusion criteria 
• Subject must be in general good health, 
weigh at least 20 kg and be within the 3rd to 
97th percentile for gender specific body 
mass index (BMI)-for-age from the World 
Health Organization growth charts at the 
Screening and Baseline Visits. 
Key inclusion criteria 
• Subject must be in general good health, 
weigh at least 20 kg and be within the 3rd to 
97th percentile for gender specific body mass 
index (BMI)-for-age from the Centers for 
Disease Control and Prevention growth 
charts at the Screening and Baseline Visits. 
Change from WHO (global) to CDC 
(US-specific) criteria to be more 
reflective of subject population in the 
US 
3 Synopsis 
Key exclusion criteria 
• Current diagnosis of major depressive 
disorder, attention-deficit/hyperactivity 
disorder, or lifetime diagnosis of bipolar 
disorder, psychotic depression, 
schizophrenia or other psychotic disorder, 
feeding and/or eating disorder, 
obsessive-compulsive disorder, conduct 
disorder, oppositional defiant disorder, post-
Key exclusion criteria 
• Current diagnosis of a major depressive 
episode, or lifetime diagnosis of 
attention-deficit/hyperactivity disorder, 
bipolar disorder, psychotic depression, 
schizophrenia or other psychotic disorder, 
feeding and/or eating disorder, 
obsessive-compulsive disorder, conduct 
disorder, oppositional defiant disorder, post-
Clarification of exclusion criteria 
 
 
 
 
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Location in 
Amended 
Protocol 
Original Text (Final Protocol Version 2.0 
dated 15 Mar 2019) 
Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
traumatic stress disorder, panic disorder, or 
pervasive development disorder. 
• Subject answers “yes” to “Suicidal 
Ideation” item 3 (active suicidal ideation 
with any methods, not plan, without intent 
to act), item 4 (active suicidal ideation with 
some intent to act, without specific plan) or 
item 5 (active suicidal ideation with specific 
plan and intent) and/or a lifetime history of 
suicidal behavior, as assessed by the 
Columbia-Suicide Severity Rating Scale 
(C-SSRS). 
traumatic stress disorder, panic disorder, or 
pervasive development disorder. 
• Subject answers “yes” to “Suicidal Ideation” 
item 3 (active suicidal ideation with any 
methods, not plan, without intent to act), item 
4 (active suicidal ideation with some intent to 
act, without specific plan) or item 5 (active 
suicidal ideation with specific plan and 
intent) within the past 6 months and/or a 
lifetime history of suicidal behavior, as 
assessed by the Columbia-Suicide Severity 
Rating Scale (C-SSRS). 
3 Synopsis 
 
Secondary Endpoints 
… 
• COVID-19 impact assessment score at each 
visit. 
Assessment of COVID-19 impact 
3 Synopsis 
Efficacy assessments 
The efficacy assessments include the PARS 
severity score for GAD, CGI-S, and the CGAS. 
Efficacy assessments 
The efficacy assessments include the PARS 
severity score for GAD, CGI-S, the CGAS, and a 
global COVID-19 impact assessment.  
Addition of COVID-19 specific 
assessment 
3 Synopsis 
Statistical Analysis 
… The change from baseline in CGI-S and 
CGAS will be analyzed using the same 
methodology described for the primary efficacy 
endpoint.  
Statistical Analysis 
… The change from baseline in CGI-S and 
CGAS will be analyzed using the same 
methodology described for the primary efficacy 
endpoint. The COVID-19 impact assessment 
score will be summarized at each visit. 
Addition of COVID-19 specific 
assessment 
5 List of 
Abbreviations 
 
ALT alanine aminotransferase 
AST aspartate aminotransferase 
CDC Centers for Disease Control and Prevention 
Abbreviations updated 
 
 
 
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Location in 
Amended 
Protocol 
Original Text (Final Protocol Version 2.0 
dated 15 Mar 2019) 
Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
COVID-19 coronavirus disease 2019 
ULN upper limit normal 
 
DSMB Data Safety Monitoring Board 
MAOI monoamine oxidase inhibitor 
PP per protocol 
 
Correction, deletion of abbreviations 
not used 
8.1 8.1 Overall 
Study Design and 
Plan: Description 
The study design incorporates a 1 to 2 week 
screening period,… 
The study design incorporates an up to 3-week 
screening period,… 
The coronavirus disease 2019 (COVID-19) 
pandemic (and any other naming conventions 
used) developed after this study began and this 
protocol has been amended to account for study 
procedures that need to be modified in 
association with adhering to local safety 
guidelines or regulations.  
During the COVID-19 pandemic, remote study 
visits, in which data are collected via telephone 
or videoconference, are possible but not 
preferred. Nearly all scheduled safety 
assessments, with exception of the Columbia-
Suicide Severity Rating Scale (C-SSRS), are not 
possible by remote visit and must be collected in 
person via clinic visits. To accommodate 
changes sites may need to implement during the 
pandemic, Section 8.1.2 outlines the conduct of 
study assessments during in-clinic visits, which 
is the preferred method of conducting the study, 
while study assessments for remote visits are 
included in Section 8.1.3. 
Screening window extended to allow 
for more time for safety results and 
medical records 
Explanation of COVID-19 specific 
study processes 
8.1.1 Study 
Design 
 
Changing the screening period from 2 to 3 weeks 
in study flow chart (Figure 1). 
Screening window extended to allow 
for more time for safety results and 
medical records 
 
 
 
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Location in 
Amended 
Protocol 
Original Text (Final Protocol Version 2.0 
dated 15 Mar 2019) 
Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
8.1.2 Schedule of 
Assessments 
Screening period Day -14 to -1 
Screening period Day -21 to -1 
 
Screening window extended to allow 
for more time for safety results and 
medical records 
 
 
Global COVID-19 impact assessment added for 
Visits 1, 2, 3, 4, 5, 6, 7/ET including footnote g: 
To be completed last after all other study assessments 
Addition of COVID-19 specific 
process in line with Section 8.2.2.1 
 
b If a site becomes aware of any adverse events after 
study completion (occurring outside of a defined 
study visit, including any contact up to 30 days after 
study completion),… 
b If a site becomes aware of any adverse events after 
study completion (occurring outside of a defined study 
visit, including any contact up to 30 days after 
receiving the last dose of study drug), … 
Harmonization of language for 
follow-up of adverse events in line 
with 10.1.2.2 
 
c Visit window ± 3 days after Visit 2 (Baseline). 
c Visit window ± 3 days. Refer to Section 8.2.2.1, 
Table 1 for visit windows for safety assessments 
(physical examination, BMI, vital signs, ECG, urine 
drug screen, clinical chemistry including thyroid, 
hematology, urinalysis, pregnancy test) and/or PK 
assessments missed due to remote visits.    
Correction and clarification 
 
i Subjects should take their first dose of study drug 
on site.   
j Subjects should take their first dose of study drug in 
clinic.   
Clarification 
 
 
 
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Location in 
Amended 
Protocol 
Original Text (Final Protocol Version 2.0 
dated 15 Mar 2019) 
Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
8.1.3 Schedule of 
Assessments for 
Remote Visits 
 
Schedule of Assessments added for visits that 
can be done remotely 
 
Introduction of optional remote visits 
in reaction to the impact of COVID-
19 pandemic and to ensure subject 
safety and data quality 
8.2.2.1 COVID-19 
Specific Processes 
 
8.2.2.1 COVID-19 Specific Processes 
To promote subject safety and data quality 
during the COVID-19 pandemic, the following 
processes will be implemented: 
• Exclusion of subjects whose anxiety is 
significantly impacted by COVID-19 as 
assessed by investigator (see Section 8.3.3). 
• Global COVID-19 impact assessment (see 
Section 10.1.1.4). 
• Visit conduct options allowing remote visits 
as outlined below: 
During remote study visits data are collected 
via telephone or videoconference (see 
Appendix 17.3). 
Any clinical assessment (including physical 
examination, vital signs, urine or blood tests) 
necessary as part of evaluation of a reported 
Introduction of COVID specific 
processes and visit conduct options in 
reaction to COVID-19 pandemic and 
to ensure subject safety and data 
quality 
 
 
 
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Location in 
Amended 
Protocol 
Original Text (Final Protocol Version 2.0 
dated 15 Mar 2019) 
Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
adverse event (AE) must be performed 
immediately. If the study site is closed or the 
subject is unable to travel to the study site, 
alternate arrangements for in person clinical 
assessment should be secured. 
Option 1: In-Clinic Visits  
This is the preferred option. All study visits are 
performed as in-clinic visits with all assessments 
outlined in the Schedule of Assessments in 
Section 8.1.2.  
Option 2: Remote Visits (except Screening for 
all subjects and Baseline Visit for female 
subjects of childbearing potential)  
This option is only to be used if local guidance 
and regulations are preventing the site or subject 
from completing an in-clinic visit. Screening 
must take place as an in-clinic visit with all 
assessments outlined in the Schedule of 
Assessments in Section 8.1.2. The Baseline Visit 
must take place as an in clinic visit for all female 
subjects of childbearing potential with all 
assessments outlined in the Schedule of 
Assessments in Section 8.1.2 (including 
pregnancy test). All other visits can be completed 
remotely with the assessments outlined in 
Section 8.1.3. 
Table 1 outlines allowed visit windows if a 
subject comes into the clinic to complete 
physical examination, body mass index (BMI), 
vital signs, electrocardiogram (ECG), urine drug 
screen, safety lab (clinical chemistry including 
 
 
 
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(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
thyroid, hematology, urinalysis), pregnancy test 
and/or PK.    
All attempts should be made to collect all safety 
assessments within 6 weeks of the Visit 7 date, if 
logistically possible. 
If a subject is able to switch from remote visits to 
in clinic visits, the investigator should contact the 
study monitor for guidance. 
 
8.3.1 Number of 
Planned Subjects 
… Based on this, the sample size may be 
increased to ensure an adequate power. …. 
 
 
 
Re-screening of subjects who do not meet the 
entry criteria is not allowed. Re-screening may 
be performed for logistical reasons (eg, 
scheduling of visits), but a subject can only be 
re-screened once. 
… Based on this, the sample size may be 
increased to ensure an adequate power due to 
variance assumption deviation as well as 
increased variance due to COVID-19 remote 
visits…. 
Re-screening of subjects who do not meet the 
entry criteria is not allowed, except for the 
reasons outlined in Section 8.3.4. A subject can 
only be re-screened once. 
Updates on re-screening in reaction 
to the COVID-19 pandemic 
8.3.2 Inclusion 
Criteria 
14. Subject weighs at least 20 kg and is within 
the 3rd to 97th percentile for gender specific 
body mass index (BMI)-for-age from the World 
14. Subject weighs at least 20 kg and is within 
the 3rd to 97th percentile for gender specific 
BMI-for-age from the Centers for Disease 
Changed from WHO (global) to CDC 
(US-specific) criteria to be more 
 
 
 
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Location in 
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Protocol 
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dated 15 Mar 2019) 
Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
Health Organization (WHO) growth charts at 
the Screening and Baseline Visits. 
Control and Prevention (CDC) growth charts at 
the Screening and Baseline Visits. 
 
reflective of subject population in the 
US 
8.3.3 Exclusion 
Criteria 
1. Current diagnosis of MDD, 
attention-deficit/hyperactivity disorder, or 
lifetime diagnosis of bipolar disorder, psychotic 
depression, schizophrenia or other psychotic 
disorder, feeding and/or eating disorder, 
obsessive-compulsive disorder, conduct 
disorder, oppositional defiant disorder, post-
traumatic stress disorder, panic disorder, or 
pervasive development disorder. 
1. Current diagnosis of a major depressive 
episode, or lifetime diagnosis of attention 
deficit/hyperactivity disorder, bipolar disorder, 
psychotic depression, schizophrenia or other 
psychotic disorder, feeding and/or eating 
disorder, obsessive-compulsive disorder, conduct 
disorder, oppositional defiant disorder, post-
traumatic stress disorder, panic disorder, or 
pervasive development disorder. 
Clarification of exclusion criterion 
 
7. Subject answers “yes” to “Suicidal Ideation” 
item 3 (active suicidal ideation with any 
methods, not plan, without intent to act), item 4 
(active suicidal ideation with some intent to act, 
without specific plan) or item 5 (active suicidal 
ideation with specific plan and intent) and/or a 
lifetime history of suicidal behavior, as assessed 
by the C-SSRS. 
7. Subject answers “yes” to “Suicidal Ideation” 
item 3 (active suicidal ideation with any 
methods, not plan, without intent to act), item 4 
(active suicidal ideation with some intent to act, 
without specific plan) or item 5 (active suicidal 
ideation with specific plan and intent) within the 
past 6 months and/or a lifetime history of 
suicidal behavior, as assessed by the C-SSRS. 
Clarification of exclusion criterion 
 
23. Unlikely to comply with study requirements 
or unsuitable for any reason, based on 
investigator judgement. 
23. Unlikely to comply with study requirements 
or unsuitable for any reason, including any 
indication the subject may be significantly 
impacted by the COVID-19 (or associated virus) 
pandemic, based on investigator judgement. 
Addition of precautions for screening 
in response to COVID-19 pandemic 
 
 
25. Family members or individuals living in the 
same household as the study subject. 
Addition to avoid data bias 
 
 
 
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Rationale for Change 
8.3.4 Re-screening  
8.3.4 Re-screening 
Re-screening is allowed only under the following 
exceptional circumstances. Note a subject can 
only be re-screened once. 
• Logistical reasons (eg, scheduling of visits). 
• Subjects who have not yet completed 
washout of fluoxetine at screening can be re-
screened once washout is completed. The 
medical monitor is to be contacted in these 
cases.  
• For subjects who failed screening according 
to the BMI criteria based on WHO growth 
charts. 
• Screen failures due to a recruitment hold. 
Subjects can be re-screened once the 
recruitment hold is lifted. 
Addition of rescreen criteria in line 
with other amendment changes  
8.3.5 Removal of 
Subjects From the 
Study 
 
• Due to the COVID-19 pandemic 
COVID-19 specific update 
8.4.6 Selection 
and Timing of 
Dose for Each 
Subject 
… 
Subjects will receive their first dose of study 
drug on site on Day 1. Subjects will then self-
administer the investigational product on an 
outpatient basis once a day. Subjects should be 
instructed to administer investigational product 
at approximately the same time each day 
including on days when clinic visits occur. 
Subjects may take investigational product with 
or without food. To allow for PK sampling, 
subjects receiving study drug in the morning 
For in-clinic visits according to Option 1 in 
Section 8.2.2.1: 
Subjects will receive their first dose of study 
drug on site on Day 1. Subjects will then self-
administer the investigational product on an 
outpatient basis once a day. Subjects should be 
instructed to administer investigational product 
at approximately the same time each day 
including on days when clinic visits occur. 
Subjects may take the investigational product 
with or without food. To allow for PK sampling 
Addition of text on remote visits in 
line with Section 8.2.2.1 
 
 
 
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(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
will be instructed to withhold taking the 
morning dose on the day of the Week 4 Visit 
(Visit 5) and to bring their study drug to the 
visit. Subjects receiving study drug in the 
evening should take their dose in the evening 
before the visit. 
during in clinic visits, subjects receiving study 
drug in the morning will be instructed to 
withhold taking the morning dose on the day of 
the Week 4 Visit (Visit 5) and to bring their 
study drug to the visit. Subjects receiving study 
drug in the evening should take their dose in the 
evening before the visit. 
For remote visits according to Option 2 in 
Section 8.2.2.1:  
Subjects will receive and take their first dose of 
study drug on Day 1 via curbside (preferred) or 
they will receive it by courier and take it at 
home. Subjects will then self-administer the 
investigational product on an outpatient basis 
once a day. Subjects should be instructed to 
administer investigational product at 
approximately the same time each day including 
on days when remote visits are scheduled. 
Subjects may take the investigational product 
with or without food. 
8.4.8.1 Prohibited 
Medication/ 
Therapy 
 
Subjects must stop all antidepressant treatment 
(except for fluoxetine) at least 14 days prior to 
randomization. Antidepressant treatment 
includes SSRIs, serotonin-norepinephrine 
reuptake inhibitors (SNRIs), bupropion, and 
tricyclic antidepressants. 
Subjects must stop fluoxetine at least 28 days 
prior to randomization. If the subject is taking 
fluoxetine at the time of screening, the subject 
may need to be screen failed and then re-
screened once the washout is complete. Please 
Clarification of washout of 
antidepressant treatments 
 
 
 
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Location in 
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Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
contact the medical monitor for guidance (see 
Section 8.3.4). 
9.1.1 Screening 
Visit 
 
• Complete global COVID-19 impact 
assessment. 
Addition of global COVID-19 impact 
assessment in line with 
Section 8.2.2.1 
9.1.2 Baseline 
Visit 
 
• Complete global COVID-19 impact 
assessment. 
Addition of global COVID-19 impact 
assessment in line with 
Section 8.2.2.1 
 
Subjects should take their first dose of study 
drug on site on Day 1 
Subjects should take their first dose of study drug 
in clinic on Day 1. 
Clarification 
 
 
Refer to Section 8.1.3 for procedures and 
assessments if Visit 2 is done remotely. For 
remote visits, subjects will receive and take their 
first dose of study drug via curbside (preferred) 
or they will receive it by courier and take it at 
home. 
Addition of language for remote 
visits.  
9.2.1 Week 1 
(Visit 3) 
 
• Complete global COVID-19 impact 
assessment. 
Addition of global COVID-19 impact 
assessment in line with 
Section 8.2.2.1 
 
 
Refer to Section 8.1.3 for assessments if Visit 3 
is done remotely. Study drug will be delivered to 
subjects via curbside (preferred) or courier. 
Addition of language for remote 
visits. 
9.2.2 Week 2 
(Visit 4) 
 
• Complete global COVID-19 impact 
assessment. 
Addition of global COVID-19 impact 
assessment in line with 
Section 8.2.2.1 
 
 
Refer to Section 8.1.3 for assessments if Visit 4 
is done remotely. Study drug will be delivered to 
subjects via curbside (preferred) or courier. 
Addition of language for remote 
visits. 
 
 
 
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Rationale for Change 
9.2.3 Week 4 
(Visit 5) 
 
• Complete global COVID-19 impact 
assessment. 
Addition of global COVID-19 impact 
assessment in line with 
Section 8.2.2.1 
 
 
Refer to Section 8.1.3 for assessments and to 
Table 1 for assessment windows if Visit 5 is 
done remotely. Study drug will be delivered to 
subjects via curbside (preferred) or courier. 
Addition of language for remote 
visits. 
9.2.4 Week 6 
(Visit 6) 
 
• Complete global COVID-19 impact 
assessment. 
Addition of global COVID-19 impact 
assessment in line with 
Section 8.2.2.1 
 
 
Refer to Section 8.1.3 for assessments if Visit 6 
is done remotely. Study drug will be delivered to 
subjects via curbside (preferred) or courier. 
Addition of language for remote 
visits. 
9.2.5 Week 8 
(Visit 7) 
 
• Complete global COVID-19 impact 
assessment. 
Addition of global COVID-19 impact 
assessment in line with 
Section 8.2.2.1 
 
 
Refer to Section 8.1.3 for assessments and to 
Table 1 for assessment windows if Visit 7 is 
done remotely. Study drug will be delivered to 
subjects via curbside (preferred) or courier. All 
attempts should be made to collect safety labs 
within 6 weeks of the Visit 7 date. 
Addition of language for remote 
visits. 
9.3.1 Week 9 
(Visit 8) 
 
Refer to Section 8.1.3 for assessments and to 
Table 1 for assessment windows if Visit 8 is 
done remotely. 
Addition of language for remote 
visits. 
9.7 End of Study 
 
9.7 End of Study  
A subject will have fulfilled the requirements for 
study completion when the subject has 
completed all study periods, including the last 
scheduled follow-up telephone contact at Week 
Clarification and definition of end of 
study 
 
 
 
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Location in 
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(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
10 as indicated in the Schedule of Assessments 
in Section 8.1.2. 
The end of the study will be the last subject’s last 
scheduled follow-up telephone contact at Week 
10 as indicated in the Schedule of Assessments 
in Section 8.1.2. 
10 Efficacy, 
Safety, and 
Pharmacokinetic 
Assessments 
 
The modified Schedule of Assessments in 
conjunction with the COVID-19 pandemic is in 
Section 8.1.3 and the options for conducting 
remote visits are outlined in Section 8.2.2.1. For 
any efficacy or safety assessment data that are 
collected during a remote visit, the appropriately 
trained study center staff may conduct the 
assessment by telephone or videoconference. 
Sites should remain consistent with the method 
used for each subject. 
Explanation  
10.1.1.4 Global 
COVID-19 Impact 
Assessment 
 
10.1.1.4 Global COVID-19 Impact Assessment 
A global COVID-19 impact assessment will be 
used to evaluate the impact of the coronavirus 
disease pandemic on the severity of the subject’s 
GAD during the last 1 week. The rating will 
include scores from 0 (not applicable, subject not 
enrolled in the trial during the pandemic) to 7 
(extreme impact). Raters will also evaluate 
whether the impact was an improvement or 
worsening of the subject’s GAD. The global 
COVID-19 impact assessment will be completed 
last after all study assessments by appropriately 
qualified study center staff and the scores 
recorded on the eCRF. Every effort should be 
Addition of coronavirus disease 
specific process in line with Section 
8.2.2.1 
 
 
 
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Location in 
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Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
made to ensure that the assessments are 
completed by the same assessor at each visit. 
10.1.2.2 Adverse 
Events 
Follow-up of Adverse Events 
All investigators should follow up subjects with 
AEs until the event is resolved or until, in the 
opinion of the investigator, the event is 
stabilized or determined to be chronic. Details 
of AE resolution must be documented in the 
eCRF. 
Subjects should be followed up for 30 days after 
receiving the last dose of study drug, and any 
AEs that occur during this time should be 
reported according to the procedures outlined 
above. 
Follow-up of Adverse Events 
All investigators should follow up subjects with 
AEs until the event is resolved or until, in the 
opinion of the investigator, the event is stabilized 
or determined to be chronic. Details of AE 
resolution must be documented in the eCRF. 
 
Harmonization of language for 
follow-up of adverse events 
 
Documentation and Reporting of Adverse 
Events 
Documentation and Reporting of Adverse Events 
All AEs from the signing of the informed 
consent form (ICF) until 30 days after receiving 
the last dose of study drug will be collected 
according to the procedures outlined above at the 
timepoints specified in the Schedule of 
Assessments (Section 8.1.2/8.1.3), and as 
observed or reported spontaneously by study 
participants. 
 
10.1.2.2.1 Serious 
Adverse Events 
Any SAE must be reported by the investigator if 
it occurs during the clinical study or within 30 
days of receiving the study drug, whether or not 
the SAE is considered to be related to the 
investigational product. 
Any SAEs from the signing of the ICF until 30 
days after receiving the last dose of study drug 
will be collected according to the procedures 
outlined above at the timepoints specified in the 
Schedule of Assessments (Section 8.1.2/8.1.3), 
and as observed or reported spontaneously by 
study participants, whether or not the SAE is 
Harmonization of language for 
follow-up of adverse events 
 
 
 
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Rationale for Change 
considered to be related to the investigational 
product. 
10.1.2.2.2 
Reporting of 
Pregnancies 
Occurring During 
the Study 
Study site personnel must report every 
pregnancy from the time the subject signs the 
informed consent form (ICF) until 30 days 
following the last dose of investigational 
product. 
Study site personnel must report every pregnancy 
from the time the subject signs the ICF until 
30 days after receiving the last dose of study 
drug. 
Harmonization of language for 
follow-up of adverse events 
10.1.2.2.6 10. 
Potential Hy’s 
Law Cases 
 
10.1.2.2.6 Potential Hy’s Law Cases 
Criteria for potential Hy’s law cases are as 
follows: 
• Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥ 3 × upper limit of 
normal (ULN) AND 
• Total bilirubin ≥ 2 × ULN AND 
• Alkaline phosphatase < 2 × ULN 
Study site personnel must report every subject 
who meets these criteria. Typically, all 3 analytes 
will be obtained from the same sample, but they 
may come from multiple samples taken within a 
24-hour period. This requirement applies from 
the time the subject signs the ICF for the study 
until 30 days after receiving the last dose of 
study drug. 
A laboratory alert for potential Hy’s laws cases 
will be in place, and the laboratory must notify 
investigators and the sponsor immediately when 
the above criteria have been met. A potential 
Hy’s law case must be reported to the sponsor on 
an SAE form as soon as possible (within 24 
hours of learning of the potential Hy’s law case) 
to the SAE/pregnancy fax number, even if no AE 
Addition for subject safety 
 
 
 
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Rationale for Change 
has occurred. The eCRF for potential Hy’s law 
cases must be completed within 7 calendar days. 
Every effort to determine the cause of the liver 
enzyme abnormalities must be made, and close 
monitoring should be initiated in conjunction 
with the Study Medical Monitor and in 
accordance with the FDA Guidance for Industry, 
Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation, July 2009. The patient 
should return to the study site and be evaluated 
as soon as possible, preferably within 48 hours 
from the time the investigator becomes aware of 
the abnormal results. This evaluation should 
include laboratory tests, detailed history, and 
physical examination. 
10.1.3.1 Study 
Drug 
Concentration 
Measurements 
 
For subjects who cannot go the site for scheduled 
visits due to the COVID 19 pandemic, PK 
sample collection can occur at the times 
specified in Section 8.2.2.1, Table 1. 
Addition to align with changes in 
Section 8.2.2.1 
11.2 Disposition 
 
Subjects whose disposition status was impacted 
by the COVID-19 pandemic will also be 
summarized. 
Update to consider COVID-19 
impact in disposition data  
 
Screen failures (ie, subjects who were screened 
but not included in the Randomized Population) 
and the associated reasons for failure will be 
tabulated overall. Subjects completing the 
Week 8 assessment will be considered 
completers.  
Screen failures (ie, subjects who were screened 
but not included in the Randomized Population) 
and the associated reasons for failure will be 
tabulated overall. 
 
 
 
Protocol deviations that occur due to COVID-19 
will be summarized and listed separately. 
 
 
 
 
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(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
11.5.1.1 Primary 
Efficacy Analysis 
 
Sensitivity analyses will be conducted on the 
primary efficacy endpoint to assess the missing 
at random assumption of the MMRM model and 
the impact of COVID-19 using remote home 
assessment. Details will be provided in the SAP. 
Addition to consider COVID-19 
impact in efficacy data 
11.5.1.1.1 
Estimand for the 
Primary Efficacy 
Analysis 
The second will be a sensitivity analysis using a 
pattern-mixture model. The commonly applied 
“copy reference” method may be employed.  
The second will be a sensitivity analysis using a 
pattern-mixture model.  
Correction 
11.5.1.2 
Secondary 
Efficacy 
Parameters 
 
• COVID-19 impact assessment score at each 
visit. 
Additional secondary endpoint for 
assessment of COVID-19 impact 
11.5.1.2.4 
COVID-19 Impact 
Assessment Score 
at each Visit 
 
11.5.1.2.4 COVID-19 Impact Assessment Score 
at each Visit 
The COVID-19 impact assessment score will be 
summarized at each visit. 
Addition to align with additional 
secondary endpoint 
11.6 Safety 
Analysis 
 
Safety data collected outside of planned visit 
windows but within allowance limits (up to 
1 week late for Visits 7 and 8) will be included in 
the summary tables. Safety data collected outside 
of planned visit windows and outside of the 
allowance limits (>1 week to 6 weeks late for 
Visits 7 and 8) will be listed, but will not be 
included in the summary tables. Subgroup 
analyses may be performed to assess the impact 
of COVID-19 on the safety analyses. 
Addition to align with changes in 
Section 8.2.2.1 
11.6.1.1 Adverse 
Events 
 
Each AE summary described above will be 
presented as all AEs, AEs that are associated 
with the COVID-19 pandemic (as determined by 
Addition to consider COVID-19 
impact in summary of safety data 
 
 
 
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Rationale for Change 
the investigator), and AEs that are not associated 
with the COVID-19 pandemic. AEs associated 
with the COVID-19 pandemic will be listed 
separately. 
11.8 Interim 
Analyses 
If the estimated pooled standard deviation is 
larger than the assumed pooled standard 
deviation in the sample size calculation (see 
Section 11.9), sample sizes in placebo and 
escitalopram treatment groups may be increased 
to ensure an adequate power. 
If the estimated pooled standard deviation is 
larger than the assumed pooled standard 
deviation in the sample size calculation due to 
assumption deviation as well as COVID-19 
remote visits (see Section 11.9), sample sizes in 
placebo and escitalopram treatment groups may 
be increased to ensure an adequate power. 
Additional language to account for 
remote visits 
13.1 Drug 
Accountability 
 
In addition, sites will be provided a separate 
Investigational Product Curbside Pickup and 
Shipment Tracking Form to document pertinent 
study drug dispensing information each time a 
new shipment of study drug is shipped directly to 
a subject’s residence, dispensed curbside at the 
site, or delivered to a subject’s residence via site 
personnel. Sites will be instructed to submit this 
form to Syneos Health any time study drug is 
dispensed using these methods. 
Additional language for remote visits.  
17.1 Clinical 
Global Impression 
of Severity 
1. Normal—not at all ill, symptoms of disorder 
not present past 7 days  
2. Borderline mentally ill—subtle or suspected 
pathology  
3. Mildly ill—clearly established symptoms 
with minimal, if any, distress or difficulty in 
social and occupational function  
4. Moderately ill—overt symptoms causing 
noticeable, but modest, functional 
 
Deleted for consistency as no other 
assessments are included in the 
protocol appendix. 
 
 
 
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Rationale for Change 
impairment or distress; symptom level may 
warrant medication  
5. Markedly ill—intrusive symptoms that 
distinctly impair social/occupational 
function or cause intrusive levels of distress  
6. Severely ill—disruptive pathology, behavior 
and function are frequently influenced by 
symptoms, may require assistance from 
others  
7. Among the most extremely ill patients—
pathology drastically interferes in many life 
functions; may be hospitalized 
17.1 Prohibited 
Medication 
Hormones  
Only thyroid hormone replacement, oral 
contraceptives, patch contraceptives, estrogen and 
progesterone replacement therapy are allowed. 
Hormones 
Reference to footnote b removed  
Hormone therapy (including oral contraceptives 
for female subjects) should not be initiated or 
discontinued within the 3 months prior to 
screening. 
Update to align with changes in 
Section 8.4.8.1 for washout of 
antidepressant medication. 
17.3 Telehealth  
 
17.3 Telehealth  
For remote study visits subject data are collected 
via telephone or telehealth video calls using the 
technology provider. 
Overall Design 
In order to support the subject’s education, 
engagement and activity completion in the study, 
subjects will participate by using their own 
mobile telephone. If the subject’s own mobile 
telephone model and/or operating system does 
not meet the minimum technology requirements, 
if the subject does not have a device or chooses 
not to do video conferencing then regular 
Addition of information on data 
collection via telephone or video calls 
for remote visits.  
 
 
 
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Allergan 
30 June 2020 
SCT-MD-60 
Version 3.0 Final 
Page 99 of 99 
 
 
CONFIDENTIAL 
Location in 
Amended 
Protocol 
Original Text (Final Protocol Version 2.0 
dated 15 Mar 2019) 
Revised Text in Amended Protocol 
(Protocol Version 3.0 dated 30 June 2020) 
Rationale for Change 
telephone contact will be allowed. Sites should 
remain consistent with either methods for each 
subject. 
If the subject decides to use their own mobile 
device, the subject will be provided with a study-
specific mobile application (app) to support 
reminders/notifications, activity completion, etc. 
This mobile app will be downloaded by the 
subject on their own mobile telephone from the 
Apple (iOS device) or Google Play Store 
(Android device) upon their receipt of a study-
specific email with download hyperlink and 
unique study access code. 
The study-specific mobile application (app) will 
support the subject to complete study-specific 
activities such as: 
• Receive notifications for an ad-hoc telehealth 
call. 
• Conducting Telehealth Virtual Visits with the 
investigator and/or authorized site representative. 
 
 
 
 
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SAP_001.pdf: 
SAP SCT-MD-60 
Allergan                                                                                                                                 Page 1 of 53 
FINAL 
 
22 Jul 2021 
TITLE PAGE 
 
SCT-MD-60 
A Randomized, Multicenter, Double-Blind, Flexibly-dosed, Efficacy and 
Safety Study of Escitalopram in the Treatment of Children and 
Adolescents With Generalized Anxiety Disorder 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Version 4.0: 22 JUL 2021 
 
 
Confidentiality Statement 
This document is the property of Allergan, and may not in full or part be passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory 
authority without the express written permission of Allergan.  
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NCT03924323


SAP SCT-MD-60 
Allergan                                                                                                                                 Page 2 of 53 
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22 Jul 2021 
1.0 
OVERALL TABLE OF CONETENTS 
1.0 
OVERALL TABLE OF CONETENTS ............................................................................................ 2 
1.1 
List of In-Text Tables ......................................................................................................... 4 
1.2 
List of In-Text Figures ........................................................................................................ 5 
2.0 
LIST OF ABBREVIATIONS ........................................................................................................... 6 
3.0 
INTRODUCTION ............................................................................................................................ 8 
3.1 
Study Design ..................................................................................................................... 10 
3.2 
Schedule of Assessments .................................................................................................. 11 
3.3 
Schedule of Assessments that can be done Remotely ....................................................... 13 
4.0 
STUDY OBJECTIVES ................................................................................................................... 15 
4.1 
Primary Objective ............................................................................................................. 15 
4.2 
Secondary Objective ......................................................................................................... 15 
4.3 
Exploratory Objective ....................................................................................................... 15 
5.0 
SUBJECT POPULATIONS............................................................................................................ 16 
5.1 
Screened Population ......................................................................................................... 16 
5.2 
Randomized Population .................................................................................................... 16 
5.3 
Safety Population .............................................................................................................. 16 
5.4 
Modified Intent-to-Treat (mITT) Population .................................................................... 16 
5.5 
Pharmacokinetic Population ............................................................................................. 16 
6.0 
SUBJECT DISPOSITION .............................................................................................................. 17 
7.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................................ 19 
7.1 
Demographics ................................................................................................................... 19 
7.2 
Medical History ................................................................................................................ 19 
7.3 
Concomitant Medication................................................................................................... 19 
8.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................................ 21 
8.1 
Extent of Exposure ........................................................................................................... 21 
8.2 
Measurement of Treatment Compliance ........................................................................... 21 
9.0 
EFFICACY ANALYSES ............................................................................................................... 23 
9.1 
Primary Efficacy Parameter .............................................................................................. 23 
9.1.1 
Primary Objective Estimand ............................................................................... 23 
9.1.2 
Analysis of Primary Parameter ........................................................................... 24 
9.2 
Secondary Efficacy Parameters ........................................................................................ 26 
9.2.1 
Analysis of Response Rate on PARS ................................................................. 27 
9.2.2 
Analysis of Remission Rate on the PARS .......................................................... 27 
9.2.3 
Summary of PARS Severity Score at each Visit ................................................ 27 
9.2.4 
Analysis of Change on the CGI-S from Baseline and Remission Rate of 
CGI-S ................................................................................................................. 27 
9.2.5 
Summary of CGI-S Score at each Visit .............................................................. 28 
9.2.6 
Analysis of Change on the CGAS from Baseline and Remission Rate of 
CGAS ................................................................................................................. 28 
9.2.7 
Summary of CGAS Score at each Visit .............................................................. 28 
9.2.8 
Analysis of COVID-19 impact assessment score ............................................... 28 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 3 of 53 
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10.0 
SAFETY ANALYSES .................................................................................................................... 30 
10.1 
Adverse Events ................................................................................................................. 30 
10.2 
Clinical Laboratory Parameters ........................................................................................ 32 
10.3 
Vital Signs ........................................................................................................................ 34 
10.4 
Electrocardiogram ............................................................................................................. 35 
10.5 
Columbia-Suicide Severity Rating Scale .......................................................................... 36 
11.0 
PHARMACOKINETIC ANALYSIS ............................................................................................. 37 
12.0 
HEALTH OUTCOMES ANALYSES ............................................................................................ 38 
13.0 
BLINDED INTERIM ANALYSIS ................................................................................................. 39 
14.0 
DETERMINATION OF SAMPLE SIZE ....................................................................................... 40 
15.0 
STATISTICAL SOFTWARE ......................................................................................................... 41 
16.0 
DATA HANDLING CONVENTIONS .......................................................................................... 42 
16.1 
Visit Time Windows ......................................................................................................... 42 
16.2 
Age-and-Gender-Correlated Values for Weight AND Height .......................................... 43 
16.3 
Repeated or Unscheduled Assessments of Safety Parameters .......................................... 44 
16.4 
Missing Date of the Last Dose of Investigational Product................................................ 44 
16.5 
Missing Severity Assessment for Adverse Events ............................................................ 44 
16.6 
Missing Causal Relationship to Investigational Product for Adverse Events ................... 45 
16.7 
Missing Date Information for Adverse Events ................................................................. 45 
16.8 
Missing Date Information for Prior or Concomitant Medications .................................... 46 
16.8.1 
Incomplete Start Date ......................................................................................... 46 
16.8.2 
Incomplete Stop Date ......................................................................................... 47 
16.9 
Character Values of Clinical Laboratory Parameters ........................................................ 48 
17.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .......................................................... 50 
18.0 
REFERENCES ............................................................................................................................... 51 
19.0 
APPENDICES ................................................................................................................................ 52 
APPENDIX I 
PATTERN-MIXTURE MODEL DETAILS ...................................................... 52 
 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 4 of 53 
FINAL 
 
22 Jul 2021 
1.1 
LIST OF IN-TEXT TABLES 
Table 11.2–1. 
Criteria for Potentially Clinically Significant Laboratory Values 32 
Table 11.3–1. 
Criteria for Potentially Clinically Significant Vital Signs ............ 34 
Table 11.4–1. 
Criteria for Potentially Clinically Significant Electrocardiographic 
Parameters 
35 
Table 17.1–1. 
Visit Time Windows ..................................................................... 42 
Table 17.1–2. 
Visit Time Windows for the Double-Blind Down-Taper Period .. 42 
Table 17.9–1. 
Examples of Coding Special Character Values for Clinical 
Laboratory Parameters ...................................................................................................... 49 
 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 5 of 53 
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22 Jul 2021 
1.2 
LIST OF IN-TEXT FIGURES 
Figure 4–1. 
Study Design ............................................................................................. 10 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 6 of 53 
FINAL 
 
22 Jul 2021 
2.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC4 
anatomic therapeutic class 4 
BMI 
body mass index 
CDC 
Center for Disease Control 
CGAS 
Children’s Global Assessment Scale 
CGI-S 
Clinical Global Impression - Severity 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
electrocardiogram, electrocardiographic 
eCRF 
electronic case report form 
ET 
end of treatment 
GAD 
generalized anxiety disorder 
LOCF 
last observation carried forward 
MCH 
mean cell hemoglobin 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
MMRM 
mixed-effects model for repeated measures 
MMRM-CAT 
categorical mixed effects model for repeated measures 
NEAE 
newly emergent adverse event 
OC 
observed cases 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 7 of 53 
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22 Jul 2021 
PARS 
pediatric anxiety rating scale 
PCS 
potentially clinically significant 
PK 
pharmacokinetic 
PT 
preferred term 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using the Bazett formula  
QTcF 
QT interval corrected for heart rate using the Fridericia formula  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
Standard Error 
SI 
Le Système International d’Unités (International System of Units) 
SID 
subject identification 
SOC 
System Organ Class 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal laboratory reference range 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 8 of 53 
FINAL 
 
22 Jul 2021 
3.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses of the efficacy and safety data as outlined and/or specified in the 
protocol of Study SCT-MD-60. Specifications of tables, figures, and data listings are 
contained in a separate document.  
This is a randomized, multicenter, double-blind, flexibly-dosed, placebo-controlled 
parallel group study of escitalopram in the treatment of children (aged 7 through 11 
years) and adolescents (aged 12 through 17 years) with generalized anxiety disorder 
(GAD). 
The study design incorporates an up to 3 week screening period, an 8-week double-blind, 
acute treatment period, and a 1-week double-blind down taper period with a follow-up 
telephone contact 1 week after the end of the double-blind down taper period. 
Approximately 430 subjects will be screened and a total of approximately 256 subjects 
are planned to be randomized in a 1:1 ratio to either escitalopram or placebo. The 
randomization schedule will be stratified by age at randomization (grouped as 7-11 years 
vs. 12–17 years) and sex, and blocked. The sample size may be increased based on the 
outcome of a blinded interim analysis but the number of subjects in each treatment arm 
will be capped at 160. 
Subjects will begin with a 10 mg/day dose of escitalopram (taken orally) or matching 
placebo for the first 2 weeks of double-blind treatment. At the end of Week 2, subjects 
who can tolerate the current dose of 10 mg/day may have a dose escalation to 20 mg/day 
of escitalopram or matching placebo. Dose escalation will be at the investigator’s 
discretion taking into account the Clinical Global Impression of Severity (CGI-S) score. 
Subjects who remain on the 10 mg/day dose of escitalopram or matching placebo will be 
evaluated again at Week 4 for a possible dose escalation to 20 mg/day at the 
investigator’s discretion. Dose escalations cannot be made at any other time during the 
study. The dose may be decreased from 20 mg/day to 10 mg/day following discussion 
with the medical director if the subject does not tolerate the 20 mg/day dose. At the end 
of the treatment period or at early withdrawal, subjects will enter a 1-week double-blind 
down taper period. 
For subjects receiving escitalopram 10 mg/day, the doses given during the double-blind 
down taper period will be as follows: 
 Week 9: Subjects will receive placebo. 
For subjects receiving escitalopram 20 mg/day, the doses given during the double-blind 
down taper period will be as follows: 
 Week 9: Subjects will receive 10 mg/day. 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 9 of 53 
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Subjects randomized to the placebo arm will receive matching placebo during the double-
blind acute treatment period. Subjects evaluated at the end of Week 2 and Week 4 and 
tolerating 10 mg/day matching placebo may be indicated for dose escalation by the 
investigator but in a blinded fashion will continue to receive matching placebo. Subjects 
receiving placebo will follow a similar down tapering schedule at the end of the double-
blind acute treatment period. 
A follow-up telephone contact will take place 1 week after the end of the double-blind 
down taper period. 
A blinded interim analysis will be conducted when 75% of randomized subjects have 
either completed or discontinued the study in order to check the assumptions in the 
sample size calculation. Based on this, the sample size may be increased to ensure an 
adequate power. However, due to the difficulties in recruiting pediatric subjects with 
GAD, the number of subjects in each treatment arm will be capped at 160.  
The study design is shown in Figure 1. 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 10 of 53 
FINAL 
 
22 Jul 2021 
3.1 
STUDY DESIGN 
Figure 1. 
Flow Chart of the Study 
 
 
 
 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 11 of 53 
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22 Jul 2021 
3.2 
SCHEDULE OF ASSESSMENTS 
Period 
Screening 
Period 
Double-blind Acute Treatment Period 
 
Double-blind 
Down Taper 
Period 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7/ETa 
8b 
Telephone 
Contact 
Day/Week 
Day -21 to -1 
Baseline 
Day 1 
Week 1c 
Week 2c 
Week 4c 
Week 6c 
Week 8/ETc 
Week 9c 
Week 10c 
Subject Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
Parent Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Psychiatric History  
X 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
MINI Kid 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
X 
 
 
Body Mass Index (BMI) 
X 
 
 
 
X 
 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Vital Signsd 
X 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
X 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
X 
 
 
Screen for HBsAg, HCVAb, HIV 
X 
 
 
 
 
 
 
 
 
Clinical Chemistry including Thyroid 
Xe 
 
 
 
 
 
X 
 
 
Hematology 
X 
 
 
 
 
 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
 
Pregnancy Testf 
X 
X 
 
 
 
 
X 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGAS 
X 
X 
X 
X 
X 
X 
X 
 
 
PARS  
X 
X 
 
X 
 
 
X 
 
 
CGI-S  
X 
X 
 
X 
 
 
X 
 
 
Global COVID-19 Impact 
Assessmentg 
X 
X 
X 
X 
X 
X 
X 
 
 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 12 of 53 
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22 Jul 2021 
Evaluate for Dose Escalationh 
 
 
 
X 
X 
 
 
 
 
PK Blood Samplesi 
 
 
 
 
X 
 
X 
 
 
Dispense Study Drug 
 
Xj 
X 
X 
X 
X 
X 
 
 
Study Drug Accountability  
 
 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
◄-------------------------------------------------------------------------------------------------------------------------► 
Concomitant Medications 
◄-------------------------------------------------------------------------------------------------------------------------------------------► 
Abbreviations: BMI = body mass index; CGAS = Children’s Global Assessment Scale; CGI-S = Clinical Global Assessment of Severity; COVID-19 = coronavirus 
disease 2019; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ET = End of Treatment; HBsAg = hepatitis B surface antigen; HCVAb = 
hepatitis C virus antibody; HIV = human immunodeficiency virus; MINI Kid = Mini-International Neuropsychiatric Interview for Children and Adolescents; PARS = 
Pediatric Anxiety Rating Scale; PK = pharmacokinetic.  
a End of Treatment or Early Withdrawal.  
b If a site becomes aware of any adverse events after study completion (occurring outside of a defined study visit, including any contact up to 30 days after study 
completion), all adverse events reported by the patient or patient representative or observed or otherwise identified by the investigator or other study personnel must be 
documented.  
c Visit window ± 3 days. Refer to Section 8.2.2.1, Table 1 of the protocol for visit windows for safety assessments (physical examination, BMI, vital signs, ECG, urine 
drug screen, clinical chemistry including thyroid, hematology, urinalysis, pregnancy test) and/or PK assessments missed due to remote visits. 
d Vital signs (blood pressure, pulse rate, temperature, and respiration rate) will be recorded at every visit. Height and weight will be recorded at Visit 1 (Screening), Visit 
5 (Week 4), and Visit 7 (Week 8/ET) only.  
e Fasting blood sample.  
fA serum pregnancy test will be performed at Visit 1 (Screening); a urine pregnancy test will be performed at Visit 2 (Baseline) and Visit 7 (Week 8/ET) for females of 
childbearing potential.  
g To be completed last after all other study assessments. 
h Subjects who can tolerate the current dose of 10 mg/day may have a dose escalation to 20 mg/day at the investigator’s discretion taking into account the CGI-S score.  
i For PK blood sampling for assented/consented subjects at Visit 5 (Week 4) and Visit 7 (Week 8/ET), 2 blood samples per subject will be collected at each of these visits 
for escitalopram and S-demethylcitalopram analysis at the following times: Visit 5 (Week 4): for subjects receiving dose in the morning, at 0 h (predose) and ≥ 1 h 
postdose and for subjects receiving dose in the evening, 2 samples at random times during the visit (i.e., postdose from the dose received the previous evening), collected 
at least 2 hours apart from each other; and Visit 7 (Week 8/ET): 2 samples at random times during the visit (i.e., postdose from the dose received in the morning or the 
previous evening), collected at least 2 hours apart from each other.  
j Subjects should take their first dose of study drug in clinic.    
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 13 of 53 
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22 Jul 2021 
3.3 
SCHEDULE OF ASSESSMENTS THAT CAN BE DONE REMOTELY 
Period 
Double-blind Acute Treatment Period 
 
Double-blind 
Down Taper 
Period 
Follow-up 
Visit 
2 
3 
4 
5 
6 
7/ETa 
8b 
Telephone 
Contact 
Day/Week 
Baseline 
Day 1 
Week 1c 
Week 2c 
Week 4c 
Week 6c 
Week 8/ETc 
Week 9c 
Week 10c 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
 
CGAS 
X 
X 
X 
X 
X 
X 
 
 
PARS  
X 
 
X 
 
 
X 
 
 
CGI-S  
X 
 
X 
 
 
X 
 
 
Global COVID-19 Impact 
Assessmentd 
X 
X 
X 
X 
X 
X 
X 
 
Evaluate for Dose Escalatione 
 
 
X 
X 
 
 
 
 
Dispense Study Drugf 
Xg 
X 
X 
X 
X 
X 
 
 
Study Drug Accountability  
 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
◄-------------------------------------------------------------------------------------------------------------------------► 
Concomitant Medications 
Abbreviations: CGAS = Children’s Global Assessment Scale; CGI-S = Clinical Global Assessment of Severity; COVID-19 = coronavirus disease 2019; C-SSRS = 
Columbia-Suicide Severity Rating Scale; ET = End of Treatment; PARS = Pediatric Anxiety Rating Scale; PK = pharmacokinetic.  
Notes for Remote Study Visits: 
• The Baseline Visit can be remote but it is not preferred. For all female subjects of childbearing potential, the Baseline Visit must take place as an in-clinic visit with all 
assessments outlined in Section 8.1.2 of the protocol. 
• Subject data are collected via telephone or telehealth video calls using a technology provider. Sites should remain consistent with either method (video or telephone) for 
each subject. 
• In-clinic safety and PK assessments missed due to remote visits may be collected per Section 8.2.2.1, Table 1 of the protocol. 
a End of Treatment or Early Withdrawal.  
b If a site becomes aware of any adverse events after study completion (occurring outside of a defined study visit, including any contact up to 30 days after study 
completion), all adverse events reported by the patient or patient representative or observed or otherwise identified by the investigator or other study personnel must be 
documented.  
c Visit window ± 3 days. 
d To be completed last after all other study assessments. 
e Subjects who can tolerate the current dose of 10 mg/day may have a dose escalation to 20 mg/day at the investigator’s discretion taking into account the CGI-S score.  
f For remote visits study drug will be sent to subjects via curbside (preferred) or courier.  
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 14 of 53 
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g In case of a remote Baseline Visit, subjects will receive and take their first dose of study drug via curbside (preferred) or they will receive it by courier and take it at 
home.    
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 15 of 53 
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22 Jul 2021 
4.0 
STUDY OBJECTIVES 
4.1 
PRIMARY OBJECTIVE  
The primary objective of this study is to assess the safety and efficacy of escitalopram 
relative to placebo in the acute treatment of children (aged 7 through 11 years) and 
adolescents (aged 12 through 17 years) who meet criteria for GAD as defined in the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).  
4.2 
SECONDARY OBJECTIVE  
The secondary objective of this study is to characterize the pharmacokinetic (PK) profile 
of escitalopram in the pediatric population (aged 7 through 17 years).  
4.3 
EXPLORATORY OBJECTIVE  
The exploratory objective of this study is to assess the exposure/dose-response 
relationship. 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 16 of 53 
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5.0 
SUBJECT POPULATIONS 
Five populations will be considered in the statistical analysis of the study. 
5.1 
SCREENED POPULATION  
The Screened Population will consist of all subjects who underwent a Screening Visit and 
received a subject number, and signed the informed consent form.  
5.2 
RANDOMIZED POPULATION  
The Randomized Population will consist of all subjects in the Screened Population who were 
randomized to a treatment group in the study. Randomized treatment will be utilized for the 
summaries of Randomized Population by treatment. 
5.3 
SAFETY POPULATION  
The Safety Population will consist of all subjects in the Randomized Population who took at 
least one dose of study medication. Actual treatment received based on the treatment received 
the most during the double-blind acute treatment period (>50% of doses) will be utilized for 
the summaries of Safety Population by treatment. If placebo and escitalopram are received an 
equal number of times, escitalopram will be considered the actual treatment received. 
5.4 
MODIFIED INTENT-TO-TREAT (MITT) POPULATION  
The mITT Population is defined as all subjects who were randomized and received at least 
one dose of study medication, and have both baseline and at least one post-baseline primary 
efficacy measure [ie, Pediatric Anxiety Rating Scale (PARS) severity score]. The mITT 
population will be used for all of the efficacy analyses. Randomized treatment will be utilized 
for the summaries of mITT Population by treatment.  
5.5 
PHARMACOKINETIC POPULATION  
The Pharmacokinetic Population is defined as all subjects in the Safety Population with at 
least one evaluable plasma concentration of escitalopram or S-demethylcitalopram. 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 17 of 53 
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6.0 
SUBJECT DISPOSITION 
The number of subjects in 3 of the study populations (Randomized, Safety, and mITT) 
will be summarized by treatment group and study center; the Screened Population will be 
summarized overall only by study center. 
Screen-failure subjects (i.e., subjects screened but not randomized) and the associated 
reasons for failure to randomize will be tabulated overall for the Screened Population. 
Subjects who are randomized but not in the Safety Population will be listed. 
Subjects completing the Week 8 assessment of double-blind acute treatment period will be 
considered completers. The number and percentage of subjects who complete the double-
blind acute treatment period and of subjects who prematurely discontinue during the 
same period will be presented for each treatment group and overall for the Safety 
Population. 
The reasons for premature discontinuation from the double-blind acute treatment period 
as recorded on the disposition pages of the electronic case report forms will be 
summarized (number and percentage) by treatment group for the Safety Population. All 
subjects who prematurely discontinue during the double-blind acute treatment period will 
be listed by discontinuation reason for the Safety Population. 
The number and percentage of subjects impacted by the COVID-19 pandemic will be 
summarized by treatment group and overall for the Screened Population.  The summary 
will also include the extent of the impact, including: 
• discontinuations related to COVID-19 during screening, double-blind acute treatment 
period, and down-taper period 
• visits missed due to COVID-19 
• video/phone visits conducted in place of on-site visits due to COVID-19  
• assessments missed due to COVID-19 (this will only include assessments missed that 
were not permitted to be missed during off-site visits) 
• significant protocol deviations related to COVID-19 
• study drug disruption due to COVID-19 
• TEAEs of coronavirus infection or positive coronavirus test 
The number and percentage of subjects with missing or remote visits and with missing 
assessments due to COVID-19 will be summarized by treatment group and overall for 
each visit: 
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The number and percentage of subjects with significant protocol deviations will be 
summarized overall and by treatment group for the Randomized Population. Deviations 
related to the following categories will be included: 
• inclusion or exclusion criteria 
• withdrawal criteria 
• treatment or dose 
• concomitant medications 
These and any additional significant protocol deviations will be reviewed and 
documented before database lock and unblinding of treatment codes. 
Significant protocol deviations that occur due to COVID-19 will be summarized 
separately. All protocol deviations that occur due to COVID-19 will be listed. 
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SAP SCT-MD-60 
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7.0 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
7.1 
DEMOGRAPHICS 
Demographic parameters (age, age group [7-11 vs. 12-17 years], sex, race, ethnicity, 
weight, height, BMI, BMI z-score group [≥ 2, < 2]) and other baseline characteristics will 
be summarized descriptively by treatment group and overall for the Safety and mITT 
populations, respectively.  
Continuous variables will be summarized by number of subjects and mean, SD, median, 
minimum, and maximum values. Categorical variables will be summarized by number 
and percentage of subjects. 
7.2 
MEDICAL HISTORY 
Medical history will be classified by system organ class and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA), version 22.0 or newer. The 
number and percentage of subjects in each system organ class (SOC) and preferred term 
(PT) will be summarized by treatment group for the Safety Population.  
Psychiatric history and result from MINI Kid will also be summarized descriptively by 
treatment group for the Safety Population. 
Listings of medical history, psychiatric history and results from MINI Kid will be 
presented 
7.3 
CONCOMITANT MEDICATION 
The World Health Organization Drug Dictionary, version Global B3, Mar 2019 or newer, 
will be used to classify prior and concomitant medications by therapeutic class and drug 
name. 
Prior medication is defined as any recorded medication taken before the date of the first 
dose of double-blind investigational product. Concomitant medication is defined as any 
medication taken on or after the date of the first dose of double-blind investigational 
product through the last study visit, including the follow-up call. The imputation of 
incomplete and missing start/stop date of medication are specified in the section 17. 
Both prior and concomitant medications use will be coded by PT and Anatomic 
Therapeutic Class 4 (ATC4). The use of prior and concomitant medications will be 
summarized by the number and percentage of subjects in each treatment group and 
overall for the Safety Population. Summaries will be ordered in alphabetical order of 
ATC4 and then, within an ATC4, in decreasing frequencies by PT in total column. If a 
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SAP SCT-MD-60 
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subject took a specific medication multiple times or took multiple medications within a 
specific therapeutic class, that subject would be counted only once for the coded drug 
name or therapeutic class. 
Summaries for concomitant medication use will be presented for the double-blind acute 
treatment period and the down-taper period, separately. Any concomitant medications 
which started after the date of the last dose of double-blind investigational product in the 
study will not be presented in the summary tables but will be included in the subject data 
listings. 
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SAP SCT-MD-60 
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8.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
EXTENT OF EXPOSURE 
Total exposure to double-blind investigational product for the Safety Population during the 
double-blind acute treatment period will be summarized, calculated as the number of days 
from the date of the first dose of double-blind investigational product taken to the date of the 
last dose taken through the Week 8 End of Treatment or Early Withdrawal visit, inclusive. 
Descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented by treatment group. Similarly, the treatment duration in the down taper period, 
defined as the first dose in the down taper period to the last dose in the down taper period, 
inclusive, will be summarized. The total duration of double-blind investigational product 
exposure, defined as the sum of the treatment duration through Week 8 and the duration in 
the down taper period will be summarized.   
The number and percentage of subjects who had their dosage escalated at Week 2 from 
10 mg/day to 20 mg/day will be summarized by treatment group. The denominator will 
be the number of subjects who had study medication dispensed at Week 2. Similarly, the 
number and percentage of subjects who had their dosage escalated at Week 4 from 10 
mg/day to 20 mg/day will be summarized by treatment group. The number of subjects 
who required a dose reduction from 20 mg/day to 10 mg/day will be summarized by 
treatment group. The number of days from first date of escalation to 20 mg/day to the 
dose reduction will be summarized using descriptive statistics. 
The mean daily dose of investigational product between visits and overall during double-
blinded acute treatment period will be summarized by treatment group for the Safety 
Population. The calculation is as below: 
Mean daily dose = (Total dose taken during the interval) / (Total number of days in the 
interval). 
Total number of days = Stop date of study drug – start date of study drug + 1. 
The total dose, start date, and stop date will be based on the eCRF Study Drug 
Administration page. 
8.2 
MEASUREMENT OF TREATMENT COMPLIANCE 
Dosing compliance for a specified period is defined as the total number of capsules 
actually taken by a subject during that period divided by the number of capsules 
prescribed to be taken for the same period multiplied by 100.The total number of 
capsules actually taken during a specific time period is calculated based on the study 
medication record. The number of capsules prescribed to be taken for a specific treatment 
period will be calculated by multiplying the number of days in that period by the number 
of capsules to be taken per day. 
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SAP SCT-MD-60 
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Descriptive statistics for investigational product compliance will be presented by 
treatment group for each period between 2 consecutive visits, as well as for the entire 
double-blind acute treatment period, the period from first dose to the Week 8 End of 
Treatment or Early Withdrawal visit, and the down taper period. 
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SAP SCT-MD-60 
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9.0 
EFFICACY ANALYSES 
The efficacy analyses will be based on the mITT Population. Baseline for efficacy is 
defined as the last non-missing efficacy assessment before the first dose of double-blind 
investigational product. All statistical tests will be 2-sided hypothesis tests performed at 
the 5% level of significance for main effects. All confidence intervals will be 2-sided 
95% confidence intervals, unless stated otherwise. 
For efficacy analyses in which study center is a factor, a small center will be defined as a 
center with fewer than 2 subjects in any treatment group in the mITT Population. Small 
centers will be pooled to form pseudo-centers so that each treatment group includes at 
least 2 mITT subjects within the center. Pooling will be done (within each country first) 
using the following algorithm: 
Based on the number of mITT subjects, small centers will be ordered from the largest to 
the smallest, and centers of the same size will be ordered from the largest center code to 
the smallest center code. The pooling process starts with the largest small center from the 
top, which will be pooled with the smallest from the bottom until a non-small pseudo 
center is formed. The process will be repeated using the small centers left out after the 
first pass. If any centers are left out at the end of the process, they will be pooled with the 
smallest pseudo center. If there is more than 1 smallest pseudo center, the pseudo center 
with the smallest center code will be selected. In case that the pseudo center formed by 
pooling all small centers is still a small center, it will be pooled with the smallest non-
small center. If there is more than 1 smallest non-small center, the one with the smallest 
center code will be selected.   
These pseudo-centers will be used for all efficacy analyses when the model is adjusted 
for study center.  
By-visit analyses based on the mixed-effects model for repeated measures (MMRM) 
using the observed case (OC) approach will be performed for all continuous efficacy 
parameters with multiple post-baseline measurements.  
9.1 
PRIMARY EFFICACY PARAMETER 
9.1.1 
Primary Objective Estimand 
The estimand used to address the primary objective “To determine efficacy of 
escitalopram relative to placebo in the acute treatment of children (aged 7 through 11 
years) and adolescents (aged 12 through 17 years) who meet criteria for GAD as defined 
in the Diagnostic and Statistical Manual of Mental Disorders”  is defined by the 
following: 
 Population:  
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SAP SCT-MD-60 
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o The target population is children (aged 7 through 11 years) and 
adolescents (aged 12 through 17 years) with GAD and who satisfy the 
inclusion and exclusion criteria as specified in the protocol.  
o The analysis population is mITT population defined in section 5.4. 
 Variable:  
o Change from baseline to Week 8 in PARS severity. The PARS severity 
score is derived by summing 5 of 7 severity/impairment/interference items 
(2, 3, 5, 6, and 7). 
 Intercurrent events:  
o To evaluate the efficacy at Week 8 in the mITT population, participants 
are assumed to adhere to the assigned treatment for the duration of the 
study. As a result, data after the discontinuation from the study treatment 
due to all reasons will not be included in the primary analysis and they 
will be assumed as missing at random. 
o For the sensitivity analyses of primary parameter, the LOCF approach and 
pattern-mixture model approach will be utilized to impute the missing 
value. The details are provided in Section 10.1.2. 
 Population-level summary:   
o The change from baseline of PARS severity score at Week 8 in subjects 
treated with escitalopram compared to the change from baseline of PARS 
severity score at Week 8 in subjects treated with placebo 
9.1.2 
Analysis of Primary Parameter 
The primary efficacy parameter is the change from baseline to Week 8 in PARS severity. 
The PARS severity score for GAD is assessed for all symptoms identified in the 
generalized anxiety section of the PARS symptom checklist. The PARS severity score for 
GAD will be derived by summing 5 of 7 severity/impairment/interference items (2, 3, 5, 
6, and 7). If any of the items is missing, the severity score will be considered missing. 
The primary analysis will be performed using an MMRM with treatment group, age 
group strata (7-11 vs. 12-17 years), sex, pooled study center, visit, and treatment group-
by-visit interaction as the fixed effects and the baseline value and baseline value-by-visit 
interaction as the covariates.  An unstructured covariance matrix will be used to model 
the covariance of within-subject scores. The Kenward-Roger approximation 
(Kenward and Roger, 1997) will be used to estimate denominator degrees of freedom. If 
the model convergence for the unstructured covariance matrix fails, then the Fisher scoring 
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SAP SCT-MD-60 
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algorithm will be used to provide better initial values of the covariance parameters. In the 
event that the model still does not converge after using those initial values, simplified 
covariance structures will be used to fit the model in the following order until the model 
converges: (1) ante-dependence, (2) heterogeneous autoregressive, (3) Toeplitz, and (4) 
compound symmetry. If a structured covariance is used, then a robust sandwich estimator 
will be used for estimating the variance of the treatment effect estimate. 
This analysis will only use the observed cases of post-baseline scores without imputation 
of missing values. The significance test for the difference in means at Week 8 will be based 
on least squares (LS) means using a 2-sided α of 0.05. Differences between treatments at the 
other post-baseline visits will also be estimated based on LS means. 
The primary analysis will treat measurements after study withdrawal as missing in the 
MMRM modeling, leading to an estimate of the treatment effect while on treatment. Two 
sensitivity analyses, last observation carried forward (LOCF) and pattern-mixture model, 
will be performed on the primary efficacy parameter to assess the impact of the missing 
at random assumption of MMRM. 
For the LOCF approach, only the postbaseline PARS severity score for GAD will be 
imputed; individual item scores will not be carried forward to derive the PARS severity 
score. Baseline total score will be carried forward only for the missing scores 
immediately after baseline. If all the postbaseline values are missing, the baseline value 
will not be carried forward. The LOCF approach is based on an analysis-of-covariance 
(ANCOVA) model including treatment group and pooled study center as factors and 
baseline PARS severity score as a covariate 
Another sensitivity analysis using a pattern-mixture model approach based on non-future 
dependent missing value restrictions (Kenward et al., 2003) will be performed to assess 
the robustness of the primary MMRM results to the possible violation of the missing-at-
random assumption. The details of this sensitivity analysis are as follows: 
The pattern for the pattern-mixture model will be defined by the subject’s last visit with 
an observed value. The observed PARS severity score at a visit is assumed to have a 
linear relationship with the subject’s prior measurements. The missing values will be 
imputed under the assumption that the distribution of the missing observations differs 
from that of the observed only by a shift parameter value ∆. The dataset with missing 
values imputed will be analyzed using an analysis of covariance (ANCOVA) model with 
treatment group and pooled study center as factors and baseline PARS severity score as a 
covariate for between–treatment group comparisons at Week 8. The imputation of 
missing values and the analysis will be performed multiple times and the inference of this 
sensitivity analysis will be based on the combined estimates using the standard multiple 
imputation technique. The shift parameter values ∆ for the multiple imputation will start 
at 0 and increase by 1 to 6 or until a tipping point is reached (ie, the p-value switches 
from <= 0.05 to > 0.05), whichever is higher.  
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SAP SCT-MD-60 
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More details of the proposed pattern-mixture model approach (e.g., the models for the 
pattern-specific identifiable densities and the unidentified conditional distributions, the 
shift parameter Δ, and the multiple imputation algorithm) are provided in Appendix I to 
this SAP.  
To examine the consistency of the primary efficacy results across study centers, the 
treatment differences versus placebo treatment groups (mean ± SE) in the change from 
baseline to Week 8 in PARS severity score, both OC and LOCF, will be graphed by 
pooled study center.  
The comparison of escitalopram vs. placebo will be performed to assess study assay 
sensitivity. 
To assess the impact of COVID-19 on the primary efficacy parameter: 
 The primary analysis will be repeated for subjects that were not significantly 
impacted by COVID-19 (Global COVID-19 Impact Assessment score of 4 or 
higher, regardless of direction of impact; see section 9.2.5).  
 A sensitivity analysis will be conducted by treating remote visits as missing, and 
analyzing the remaining data using the primary MMRM model.  
 A sensitivity analysis will be conducted by repeating the primary analysis and 
adding the following to the model: an indicator of whether data was collected 
before or on and after the start of the pandemic (17 March 2020) and the indicator 
by treatment interaction. 
 A subgroup analysis will be conducted by repeating the primary analysis for 
randomized patients before or on and after the start of the COVID-19 pandemic 
(17 March 2020). 
The subject-level PARS scores will be listed 
9.2 
SECONDARY EFFICACY PARAMETERS 
The secondary efficacy endpoints are as follows: 
 
Response rate on the PARS at acute treatment endpoint (Week 8)  
 
Remission rate on the PARS at acute treatment endpoint (Week 8) 
 
Change on the CGI-S from baseline to acute treatment endpoint (Week 8)  
 
Remission rate on CGI-S at acute treatment endpoint (Week 8) 
 
Change on the CGAS from baseline to acute treatment endpoint (Week 8)  
 
Remission rate on the CGAS at acute treatment endpoint (Week 8) 
 
COVID-19 impact assessment score at each visit. 
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SAP SCT-MD-60 
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Inferential testing for the secondary endpoints will be reported with nominal p-values. No 
adjustments for multiplicity will be made. All confidence intervals will be 2-sided 95% 
confidence intervals, unless stated otherwise 
9.2.1 
Analysis of Response Rate on PARS 
The response rate on the PARS at acute treatment endpoint (Week 8) is defined as 50% 
reduction on PARS severity score for GAD (using 5 PARS items: 2, 3, 5, 6, and 7) from 
baseline. The response rate of the PARS will be analyzed using a repeated measures 
model for categorical outcomes. Modeling will be completed using a categorical MMRM 
(MMRM-CAT) approach, in which a pseudo-likelihood-based repeated measures 
analysis will be used and implemented in SAS procedure GLIMMIX. A binary 
distribution with logit link will be used for the dependent variable. Classification 
variables for treatment, age group, sex, visit (as a categorical variable), treatment-by-age 
group interaction, treatment-by-sex interaction, treatment by visit interaction, treatment-
by-age group-by-sex interaction, and baseline score as a covariate will be considered in 
the modeling. If the GLMM does not converge, a logistic regression model with 
treatment group and baseline score as explanatory variables will be used. For the logistic 
regression analysis, postbaseline missing data will be imputed using the LOCF approach. 
9.2.2 
Analysis of Remission Rate on the PARS 
Remission rate on the PARS at acute treatment endpoint (Week 8) is defined as PARS 
severity score for GAD <8 (using 6 PARS items: 2, 3, 4, 5, 6, and 7). The analysis of 
remission rate will be conducted using the same methodology as the response rate on the 
PARS. 
9.2.3 
Summary of PARS Severity Score at each Visit 
Observed values and change from baseline in the PARS severity score will be 
summarized by treatment at each visit. 
9.2.4 
Analysis of Change on the CGI-S from Baseline and Remission 
Rate of CGI-S 
The CGI-S is a 7-point scale developed for use in clinical trials to provide an assessment 
of the clinician's view of the patient's global functioning. The change from baseline in 
CGI-S will be analyzed using the same methodology described for the primary efficacy 
parameter. The subject-level CGI-S score will be listed. 
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SAP SCT-MD-60 
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The remission rate of CGI-S at acute treatment endpoint (Week 8) is defined as 
percentage of subjects having a CGI-S score ≤2 at endpoint. The remission rate will be 
analyzed using the same methodology described for the analysis of the response rate on 
the PARS. 
9.2.5 
Summary of CGI-S Score at each Visit 
Observed values and change from baseline in the CGI-S score will be summarized by 
treatment at each visit. 
9.2.6 
Analysis of Change on the CGAS from Baseline and Remission 
Rate of CGAS 
The CGAS is a 100-point scale range from 1 to 100 used as a measure of global 
functioning and impairment. The change in the CGAS will be analyzed using the same 
methodology described for the primary efficacy parameter.  
Remission rate on the CGAS at acute treatment endpoint (Week 8) is defined as CGAS 
>70. The analysis of the remission rate for the CGAS will use the same methodology 
described for the analysis of the response rate on the PARS. 
9.2.7 
Summary of CGAS Score at each Visit 
Observed values and change from baseline in the CGAS score will be summarized by 
treatment at each visit. 
9.2.8 
Analysis of COVID-19 impact assessment score 
The global COVID-19 impact assessment will be used to evaluate the impact of the 
coronavirus disease pandemic on the severity of the subject’s GAD during the last 1 
week. The rating will include scores from 0 (not applicable, subject not enrolled in the 
trial during the pandemic) to 7 (extreme impact). Raters will also evaluate whether the 
impact was an improvement or worsening of the subject’s GAD.  
Subjects with scores from 4 (moderate impact) to 7 (extreme impact) at any visit other 
than the Screening Visit will be considered to have been significantly impacted, 
regardless of the direction of impact. 
Number and percentage of subjects with each score on the global COVID-19 impact 
assessment will be summarized descriptively at each visit by treatment group for the 
mITT population, including subjects that were significantly impacted. For each score 
from 2 to 7, the number and percentage of subjects who improved or worsened will also 
be summarized. 
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SAP SCT-MD-60 
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SAP SCT-MD-60 
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10.0 
SAFETY ANALYSES 
The safety analysis will be performed for the double-blind acute treatment period and the 
double-blind down-taper period separately, using the Safety Population unless stated 
otherwise.  
The safety parameters include adverse events (AEs), clinical laboratory parameters, vital 
signs, electrocardiographic (ECG) parameters, and suicide risk assessment using the 
Columbia-Suicide Severity Rating Scale (C-SSRS). For each safety parameter, the 
last non-missing safety assessment before the first dose of double-blind investigational 
product will be used as baseline. Continuous variables will be summarized by number of 
subjects and mean, SD, median, minimum, and maximum values. Categorical variables 
will be summarized by number and percentage of subjects. 
Safety data collected outside of planned visit windows but within allowance limits (up to 
1 week late for Visits 7 and 8) will be included in the summary tables. Safety data 
collected outside of planned visit windows and outside of the allowance limits (>1 week 
to 6 weeks late for Visits 7 and 8) will be listed, but will not be included in the summary 
tables. Subgroup analyses may be performed to assess the impact of COVID-19 on the 
safety analyses; details are listed in each safety section. 
10.1 
ADVERSE EVENTS 
Adverse events will be coded by SOC and PT using the MedDRA version 22.0 or newer. 
An AE (classified by PT) that occurs during the double-blind acute treatment period, 
during the down-taper period, or within 30 days after the date of the last dose of double-
blind investigational product will be considered a treatment-emergent adverse event 
(TEAE) if it was not present before the date of the first dose of double-blind 
investigational product, or was present before the date of the first dose of double-blind 
investigational product and increased in severity during the double-blind acute treatment 
period or during the down-taper period, respectively.  
If more than 1 AE was reported before the date of the first dose of double-blind 
investigational product and coded to the same preferred term, the AE with the greatest 
severity will be used as the benchmark for comparison with the AEs occurring during the 
double-blind acute treatment period or during the down-taper period that were also coded 
to that preferred term. An AE that occurs more than 30 days after the date of the last dose 
of double-blind investigational product in the study will not be counted as a TEAE but 
will be included in the listings. 
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SAP SCT-MD-60 
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An AE occurring during the down-taper period or safety follow-up period will be 
considered a newly emergent AE (NEAE) if it is not present before the start of the down-
taper period or was present before the start of the down-taper period but increased in 
severity during the down-taper period. All NEAEs will be summarized by SOC, PT, and 
treatment group. 
The number and percentage of subjects in each treatment group reporting TEAEs during 
the double-blind acute treatment period will be tabulated by SOC and PT; by SOC, PT, 
and severity; and by SOC, PT, and causal relationship to the investigational product. If 
more than one AE is coded to the same PT for the same subject, the subject will be 
counted only once for that PT using the most severe and most related occurrence for the 
summarization by severity and by causal relationship to the investigational product, 
respectively. Study-treatment-related TEAEs are defined as TEAEs with relationship to 
treatment categorized as Possible, Probable, Very, Like/Certain or missing. 
The distribution of TEAEs by severity and causal relationship to the investigational 
product will be summarized by treatment group. The incidence of common (≥ 2% of 
subjects in any treatment group) TEAEs during the double-blind acute treatment period 
will be summarized by PT and treatment group. 
A serious adverse event (SAE) that occurred between the date of the first dose of double-
blind investigational product and 30 days after the date of the last dose of double-blind 
investigational product in the study, inclusive, will be considered an on-therapy SAE. 
The incidence of SAEs and AEs leading to premature discontinuation of the study will 
also be summarized by study period (separately for double-blind acute treatment period 
and double-blind down taper period), SOC, PT, and treatment group.  
The above summaries will be sorted by decreasing frequency of SOC and by the 
decreasing frequency of PT within SOC for the escitalopram treatment group. If 
incidence for more than 1 term is identical, they will then be sorted alphabetically. In 
addition, the above summaries will be presented as all AEs, AEs that are associated with 
the COVID-19 pandemic (as determined by the investigator), and AEs that are not 
associated with the COVID-19 pandemic. AEs associated with the COVID-19 pandemic 
will be listed separately. 
Listings will be presented for subjects with SAEs, subjects with AEs leading to premature 
discontinuation, and subjects who died for the Screened Population. All subjects with 
SAEs, including those reported during the screening period or more than 30 days after the 
date of the last dose of the double-blind investigational product, and subjects 
discontinuing due to AEs before the start of double-blind investigational product will be 
included in these listings 
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SAP SCT-MD-60 
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10.2 
CLINICAL LABORATORY PARAMETERS 
Descriptive statistics for clinical laboratory values (in SI units) and changes from the 
baseline values at each assessment time point (including the end of the double-blind acute 
treatment period) will be presented by treatment group for the following laboratory 
parameters: 
Hematology: 
Hemoglobin, hematocrit, white blood cell count (total and 
differential), red blood cell count, platelet count, mean cell 
volume, mean cell hemoglobin (MCH), and MCH concentration. 
Chemistry: 
Creatinine, urea (or blood urea nitrogen), aspartate transferase, 
alanine transferase, gamma glutamyltransferase, alkaline 
phosphatase, lactate dehydrogenase, total bilirubin, albumin, total 
protein, sodium, potassium, chloride, glucose, uric acid, calcium, 
phosphorus, thyroid-stimulating hormone, T3, and T4. 
Urinalysis: 
pH, glucose, ketones, blood, protein, and microscopy.  
Clinical laboratory test values will be considered potentially clinically significant (PCS) 
if they meet either the lower-limit or higher-limit PCS criteria listed in Table 10.2–1. The 
number and percentage of subjects who have PCS post-baseline clinical laboratory values 
will be tabulated by treatment group. The percentages will be calculated relative to the 
number of subjects with available non-PCS baseline values and at least 1 postbaseline 
assessment. The numerator will be the total number of subjects with available non-PCS 
baseline values and at least 1 PCS post-baseline value. A supportive listing of subjects 
with PCS post-baseline values will be provided, including the subject identification (SID) 
number, study center number, and baseline and all post-baseline (including non-PCS) 
values.  
In addition, a listing of all AEs that occurred in subjects who had PCS post-baseline 
clinical laboratory values will be provided. 
Table 10.2–1. 
Criteria for Potentially Clinically Significant Laboratory Values 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
HEMATOLOGY 
Basophils  
%  
—  
> 6  
Eosinophils  
%  
—  
> 10  
Hematocrit  
1.0  
< 0.9 × LLN  
—  
Hemoglobin  
g/L  
< 0.9 × LLN  
—  
Lymphocytes  
%  
< 10  
> 60  
Monocytes  
%  
—  
> 20  
Neutrophils  
%  
< 30  
> 90  
Platelet count  
× 109/L  
≤ 75  
≥ 700  
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White blood cell count  
× 109/L  
≤ 2.5  
≥ 15  
CHEMISTRY  
 
 
 
Albumin  
g/L  
< 0.9 × LLN  
> 1.1 × ULN  
Alkaline phosphatase  
U/L  
—  
≥ 3 × ULN  
Alanine 
aminotransferase  
U/L  
—  
≥ 3 × ULN  
Aspartate 
aminotransferase  
U/L  
—  
≥ 3 × ULN  
Bicarbonate 
mmol/L 
< 0.9 × LLN  
> 1.1 × ULN  
Blood urea nitrogen   
mmol/L  
—  
> 1.2 × ULN  
Calcium  
mmol/L  
< 0.9 × LLN  
> 1.1 × ULN  
Chloride  
mmol/L  
< 0.9 × LLN  
> 1.1 × ULN  
Cholesterol, total  
mmol/L  
—  
> 200mg/dL  
Creatinine  
µmol/L  
—  
> 1.3 × ULN  
Glucose  
mmol/L  
< 0.8 × LLN  
> 1.4 × ULN  
high-density 
lipoprotein 
mmol/L 
< 40 mg/dL 
— 
Low-density lipoprotein 
mmol/L 
— 
> 130 mg/dL 
Magnesium 
mmol/L 
< 0.9 × LLN  
> 1.1 × ULN  
Phosphate 
mmol/L 
< 0.9 × LLN  
> 1.1 × ULN  
Potassium  
mmol/L  
< 1.0 × LLN  
> 1.0 × ULN  
Sodium  
mmol/L  
< 1.0 × LLN  
> 1.0 × ULN  
Total bilirubin  
µmol/L  
—  
> 1.5 × ULN  
Total protein  
g/L  
< 0.9 × LLN  
> 1.1 × ULN  
Triglyceride 
mmol/L 
— 
> 100 mg/dL (ages 7-10), 
>130 mg/dL (ages 11-17) 
URINALYSIS  
 
 
 
Protein  
g/L  
—  
at least two +  
Glucose  
mmol/L  
—  
at least two +  
LLN = lower limit of normal value provided by the laboratory; SI = Le Système International d'Unités (International 
System of Units); ULN = upper limit of normal value provided by the laboratory. 
 
Shift tables from baseline to the end of double-blind acute treatment period for clinical 
laboratory parameters will be presented by treatment group for the following categories: 
low, normal, and high. 
Potential Hy’s Law criteria is defined by a postbaseline elevation of alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3× ULN (ULN = upper 
limit of normal laboratory reference range), along with total bilirubin (TBL) ≥ 2× ULN 
and a non-elevated alkaline phosphatase (ALP) < 2× ULN, all based on blood draws 
collected within a 24-hour period. The number and percentage of subjects who meet the 
following criteria of clinical interest during the double-blind acute treatment period will 
be tabulated by treatment group. A supportive list will also be provided.  
 ALT: ≥ 3× ULN, ≥ 5× ULN, ≥ 10× ULN, ≥ 20× ULN 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 34 of 53 
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 AST: ≥ 3× ULN, ≥ 5× ULN, ≥ 10× ULN, ≥ 20× ULN 
 ALT or AST: ≥ 3× ULN, ≥ 5× ULN, ≥ 10× ULN, ≥ 20× ULN 
 TBL: ≥ 1.5 x ULN, 2 × ULN 
 ALP: < 2 × ULN 
 Concurrent elevations:  
○ ALT or AST ≥ 3× ULN with TBL ≥ 1.5× ULN;  
○ ALT or AST ≥ 3× ULN with TBL ≥ 2× ULN;  
○ ALT or AST ≥ 3× ULN with TBL ≥ 2× ULN and ALP < 2× ULN. 
10.3 
VITAL SIGNS 
Descriptive statistics for vital signs (sitting systolic and diastolic blood pressure, pulse 
rate, respiration rate, temperature, height, weight, BMI, height percentile, weight 
percentile, and BMI percentile) and their changes from baseline values at each visit and 
at the end of study will be presented by treatment group. Height, weight and BMI z-
scores will be calculated based on Centers for Disease Control (CDC) growth charts. 
Only subjects with available baseline and at least 1 postbaseline assessment will be 
included in the summary. 
Vital sign values will be considered PCS if they meet both the observed-value criteria and 
the change-from-baseline criteria listed in Table 10.3–1. The number and percentage of 
subjects with PCS postbaseline values will be tabulated by treatment group separately. 
The percentages will be calculated relative to the number of subjects with available 
baseline and at least 1 postbaseline assessment. The numerator will be the total number of 
subjects with available baseline values and at least 1 PCS postbaseline value. A 
supportive listing of subjects with PCS postbaseline values will be provided, including 
the SID number, study center number, and baseline and all postbaseline (including non-
PCS) values. 
In addition, a listing of all AEs that occurred in subjects who had PCS postbaseline vital 
sign values will be provided. 
Table 10.3–1. 
Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Flag 
Criteriaa 
Observed Value 
Change From Baseline 
Age 7-11 
Age 12-17 
High 
≥ 125 
≥ 140 
Increase of ≥ 20 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 35 of 53 
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Sitting systolic blood 
pressure, mm Hg 
Low 
≤ 85 
≤ 90 
Decrease of ≥ 20 
Sitting diastolic blood 
pressure, mm Hg 
High 
≥ 90 
≥ 95 
Increase of ≥ 15 
Low 
≤ 40 
≤ 50 
Decrease of ≥ 15 
Sitting pulse rate, bpm 
High 
≥ 130 
≥ 110 
Increase of ≥ 15 
Low 
≤ 55 
≤ 45 
Decrease of ≥ 15 
Weight, kg 
High 
— 
— 
> 2 deviations above the age-gender 
mean weight 
Low 
— 
— 
> 2 deviations below the age-gender 
mean weight 
a A post-baseline value is considered potentially clinically significant if it meets both the observed-value 
and the change-from-baseline criteria. 
bpm = beats per minute kg = kilogram, mmHg = millimeters of mercury hemoglobin. 
10.4 
ELECTROCARDIOGRAM 
Descriptive statistics for ECG parameters (heart rate, PR interval, QRS interval, RR 
interval, QT interval, and QTc interval) at baseline and changes from baseline values at 
each assessment time point will be presented by treatment group. The QTc interval is 
calculated using both the Bazett (QTcB = QT/(RR)½) and Fridericia (QTcF = 
QT/(RR)⅓) corrections. Only subjects with available baseline and at least 1 postbaseline 
assessment will be included in the summary. 
Electrocardiographic parameter values are considered PCS if they meet or exceed the 
higher-limit PCS criteria listed in Table 10.4–1. The number and percentage of subjects 
with PCS postbaseline ECG values will be tabulated by treatment group. The percentages 
will be calculated relative to the number of subjects with available non-PCS baseline 
values and at least 1 postbaseline assessment. The numerator is the total number of 
subjects with available non-PCS baseline values and at least 1 PCS postbaseline value. A 
supportive listing of subjects with PCS postbaseline values will be provided, including 
the SID number, study center number, baseline, and all postbaseline (including non-PCS) 
values. 
Table 10.4–1. 
Criteria for Potentially Clinically Significant Electrocardiographic 
Parameters 
Parameter 
Unit 
Higher Limit 
QRS interval 
msec 
 150 
PR interval 
msec 
 250 
QTcB 
msec 
> 460 
QTcF 
msec 
> 450 
QTcB = QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½); QTcF = QT interval 
corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓). 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 36 of 53 
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In addition, a listing of all AEs that occurred in subjects who had postbaseline PCS ECG 
values will be provided. 
A listing of subjects with postbaseline clinically significant ECG abnormalities, as 
reported by the investigator or by the central cardiologist, will also be provided. 
The number and percentage of subjects with an increase > 30 msec but ≤ 60 msec, and 
with an increase > 60 msec in QTcB or QTcF will be tabulated. A supportive listing of 
subjects with postbaseline QTcB or QTcF increases > 30 msec will be provided, 
including the SID number, study center number, and all QTcB and QTcF values 
(including changes from baseline). A listing of all AEs for subjects with postbaseline 
QTcB or QTcF increases > 30 msec will also be provided. 
Shift tables from baseline to the end of double-blind acute treatment period in the 
Investigator’s overall interpretation of the ECG and the central reader’s overall 
interpretation will be presented separately by treatment group for the following 
categories: normal; abnormal, not clinically significant; abnormal, clinically significant. 
10.5 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
For the C-SSRS, the number and percentage of subjects with any suicidal ideation or 
suicidal behavior will be presented by treatment group, separately for the lifetime history, 
the double-blind acute treatment period and the double-blind down-taper period. The 
distribution of responses for the most severe suicidal ideation and suicidal behavior will 
be summarized by treatment group, separately for the lifetime history, the double-blind 
acute treatment period, and the double-blind down-taper period. Supportive listings will 
be provided and will include the SID number, treatment group, visit number, lifetime 
history, and postbaseline values for each subject. Intensity of ideation, suicidal behavior 
type, and lethality of suicidal behavior will also be included in these listings. 
 
 
 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 37 of 53 
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11.0 
PHARMACOKINETIC ANALYSIS 
PK analysis of Escitalopram will be conducted using a non-linear mixed-effect modeling 
approach. Population PK parameters, inter-subject, and residual variability will be 
determined. The effect of covariates on the escitalopram PK will also be investigated. 
From the developed population PK model (Pop-PK), PK parameters like volume of 
distribution and clearance will be estimated. Additional PK parameters including, but not 
limited to, area under the curve at steady-state (AUCSS) will be derived from the 
individual Bayes estimates from the pop-PK model.  
The relationship between efficacy parameters and plasma exposure using a nonlinear 
mixed effects approach will be explored. The relationship between safety parameters and 
plasma exposure may also be explored. 
A separate analysis plan will be created to detail this approach. 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 38 of 53 
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12.0 
HEALTH OUTCOMES ANALYSES 
Not applicable.  
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 39 of 53 
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13.0 
BLINDED INTERIM ANALYSIS 
A blinded interim analysis will be conducted when approximately 75% of randomized 
subjects have either completed the study or discontinued from the study. The blinded 
interim analysis is to obtain an estimate of the pooled standard deviation of the change 
from baseline in the PARS score to Week 8 of the double-blind acute treatment period. 
The sample size will be re-estimated using simulation in the same manner as the original 
sample size as described in Section 14 using the estimated pooled standard deviation and 
dropout rate from the blinded interim analysis. If the estimated pooled standard deviation 
is larger than the assumed pooled standard deviation due to assumption deviation as well 
as COVID-19 remote visits or dropout rate is increased, the sample size in placebo and 
escitalopram treatment groups may be increased to ensure an adequate power. However, 
due to the difficulties in recruiting pediatric subjects with GAD, the number of subjects in 
each treatment arm will be capped at 160.  
As the sample size re-estimation requires only the pooled standard deviation and dropout 
rate to be updated, all data and personnel will remain blinded for the interim analysis. 
Randomization code will not be released for the sample size re-estimation. There are no 
potential unblinding issues in the sample size re-estimation. As this is a blinded re-
estimation, there is no impact on the overall Type I error rate of the study. 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 40 of 53 
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14.0 
DETERMINATION OF SAMPLE SIZE 
The sample size estimate was constructed using a simulation approach as described in Lu 
K. (2012). 
The primary efficacy parameter is the change from baseline to Week 8 of the double-
blind acute treatment period in PARS total score. To detect an effect size (treatment 
group difference of 2.30 units relative to pooled standard deviation of 5.79) of 0.39, a 
sample size of 128 subjects in the escitalopram treatment group and 128 subjects in the 
placebo group will provide 85% power based on an MMRM model using simulation 
method. The simulation assumed a correlation of 0.7 between the repeated measures, and 
a common dropout rate of 14%, based on historical data of escitalopram in pediatric 
subjects.  
 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 41 of 53 
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15.0 
STATISTICAL SOFTWARE 
Statistical analyses will be performed using version 9.4 (or newer) of SAS. 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 42 of 53 
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16.0 
DATA HANDLING CONVENTIONS 
16.1 
VISIT TIME WINDOWS 
Table 16.1–1 and Table 16.1–2 present the visits assigned for efficacy and safety 
analyses and the corresponding ranges of treatment days (window) during which an 
actual visit may occur. 
Table 16.1–1. 
Visit Time Windows 
Derived Visit 
Scheduled Visit (Day)a 
Window 
Baselineb 
Week 0 (Day 1) 
Days ≤ 1 
Week 1 
Week 1 (Day 8) 
Days [2, 11] 
Week 2 
Week 2 (Day 15) 
Days [12, 21] 
Week 4 
Week 4 (Day 29) 
Days [22, 35] 
Week 6 
Week 6 (Day 43) 
Days [36, 49] 
Week 8 
Week 8 (Day 57) 
Days ≥ 50 days and within double-blind acute 
treatment period 
End 
of 
double-blind 
acute treatment periodc 
Final or termination visit during the double-blind acute treatment period 
a 
Relative to the date of the first dose of double-blind investigational product. Day 1 = the date of the first dose of 
double-blind investigational product.  
b 
The window for selecting baseline values is from 30 days before the first dose of double-blind investigational 
product to Day 1. 
c 
Presented in analysis tables for safety parameters, including but not limited to electrocardiograms, clinical 
laboratory values, vital signs, and C–SSRS. If repeated assessments occur at the end of double-blind acute 
treatment period visit or during any visit window, the algorithm in Section 16.3 will be used to determine which 
values are used in the analysis. 
 
Table 16.1–2. 
Visit Time Windows for the Double-Blind Down-Taper Period 
Derived Visit 
Scheduled Visit 
Window 
Week 9/Down-Taper 
Period 
Week 9 
Within the double-blind down-taper period 
(from 1 day after the end of double-blind acute 
treatment period to the end of the double-blind 
down-taper period) 
End of double-blind 
down-taper perioda 
Final or termination visit during the double-blind down-taper period 
a 
Presented in analysis tables for safety parameters collected during the double-blind down-taper period. If any 
assessments are repeated at the end-of-double-blind-down-taper-period visit or during any visit window, the 
algorithm in Section 16.3 will be used to determine which values are used in the analysis. 
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SAP SCT-MD-60 
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If the visit date is on or after the date of the first dose of double-blind investigational 
product, the study day is calculated by visit date – date of the first dose of double-blind 
investigational product + 1. If the visit date is before the date of the first dose of 
double-blind investigational product, the study day is calculated by visit date – date of the 
first dose of double-blind investigational product. Therefore, a negative day indicates a 
day before the start of the double-blind investigational product. 
If a subject has 2 or more visits within the same window, the last visit with a nonmissing 
value will be used for analysis. 
16.2 
AGE-AND-GENDER-CORRELATED VALUES FOR WEIGHT 
AND HEIGHT 
To adjust weight (kg) and height (cm) for sex and age, one needs to compare them to 
standard reference values for the same sex and age group, which are available in the 
United States Growth Charts and can be downloaded from: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm 
The z-score is calculated as below 
, if L ≠ 0 and 
, if 
, 
where X is the physical measurement (e.g. weight and height) and L, M and S are the 
values from the appropriate table corresponding to the age in months (or length/stature) 
and sex (1 = male; 2 = female). X must be in metric measurements (kilograms or meters). 
This is called LMS method (Cole TJ, 1990), and parameters L, M, and S are the Box-Cox 
transformation power, median, and standard deviation, respectively, in the reference data, 
which again are provided in the reference data tables. 
SL
M
X
z
L
1
)
/
(


S
M
X
z
)
/
ln(

0

L
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SAP SCT-MD-60 
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16.3 
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS 
If a subject has repeated assessments before the date of first dose of double-blind 
investigational product, the results from the final nonmissing assessment made before the 
date of the first dose of double-blind investigational product will be used as baseline. If 
end-of-double-blind-treatment period assessments are repeated or if unscheduled visits 
occur, the last nonmissing post-baseline assessment during the double-blind acute 
treatment period will be used as the end-of-double-blind-acute-treatment-period 
assessment for generating summary statistics. Likewise, if end of double-blind down-
taper period assessments are repeated or if unscheduled visits occur, the last non-missing 
assessment during the double-blind down-taper period will be used as the end-of-double-
blind-down-taper-period assessment for generating summary statistics.  
Similarly, if a subject has repeated assessments within a given visit window, the last non-
missing post-baseline assessment during the window will be used as the assessment for 
that visit window when generating summary statistics. 
However, all post-baseline assessments will be used to determine PCS values for 
laboratory parameters, vital signs and ECG parameters, and to determine most severe 
suicidal ideation and most severe suicidal behavior from C-SSRS. All assessments will 
be presented in the data listings. 
16.4 
MISSING DATE OF THE LAST DOSE OF 
INVESTIGATIONAL PRODUCT 
When the date of the last dose of investigational product in the study taken during the 
double-blind acute treatment period is missing for a subject in the Safety Population, all 
efforts should be made to obtain the date from the Investigator. If it is still missing after 
all efforts, then the last available dosing record date will be used as the last dose date. 
16.5 
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS 
If severity is missing for an AE that started before the date of the first dose of 
double-blind investigational product, an intensity of mild will be assigned. If severity is 
missing for an AE that started on or after the date of the first dose of double-blind 
investigational product, an intensity of severe will be assigned. The imputed values for 
severity assessment will be used for the incidence summary. The number of imputed 
severity value will be presented in the footnote of the incidence summary.  The imputed 
values will be shown as missing in the data listings.  
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 45 of 53 
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16.6 
MISSING CAUSAL RELATIONSHIP TO INVESTIGATIONAL 
PRODUCT FOR ADVERSE EVENTS 
If the causal relationship to the investigational product is missing for an AE that started 
on or after the date of the first dose of double-blind investigational product, a causality of 
Likely/Certain will be assigned. The imputed values for causal relationship to double-
blind treatment will be used for the incidence summary. The number of imputed severity 
value will be presented in the footnote of the incidence summary. The imputed values 
will be shown as missing in the data listings. 
16.7 
MISSING DATE INFORMATION FOR ADVERSE EVENTS 
The following imputation rules only apply to cases in which the start date for AEs is 
incomplete (i.e., partly missing). 
Missing month and day 
 If the year of the incomplete start date is the same as the year of the first dose of 
double-blind investigational product, the month and day of the first dose of 
double-blind investigational product will be assigned to the missing fields 
 If the year of the incomplete start date is before the year of the first dose of 
double-blind investigational product, December 31 will be assigned to the missing 
fields 
 If the year of the incomplete start date is after the year of the first dose of 
double-blind investigational product, January 1 will be assigned to the missing fields 
Missing month only 
 If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure 
Missing day only 
 If the month and year of the incomplete start date are the same as the month and year 
of the first dose of double-blind investigational product, the day of the first dose of 
double-blind investigational product will be assigned to the missing day 
 If either the year of the incomplete start date is before the year of the date of the 
first dose of double-blind investigational product or if both years are the same but the 
month of the incomplete start date is before the month of the date of the first dose of 
double-blind investigational product, the last day of the month will be assigned to the 
missing day 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 46 of 53 
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 If either the year of the incomplete start date is after the year of the date of the 
first dose of double-blind investigational product or if both years are the same but the 
month of the incomplete start date is after the month of the date of the first dose of 
double-blind investigational product, the first day of the month will be assigned to the 
missing day 
If the stop date is complete and the imputed start date as above is after the stop date, the 
start date will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, the following 
algorithm will be used to impute the start date: 
 If the stop date is after the date of the first dose of double-blind investigational 
product, the date of the first dose of double-blind investigational product will be 
assigned to the missing start date 
 If the stop date is before the date of the first dose of double-blind investigational 
product, the stop date will be assigned to the missing start date 
16.8 
MISSING DATE INFORMATION FOR PRIOR OR 
CONCOMITANT MEDICATIONS 
For prior or concomitant medications, including rescue medications, incomplete 
(i.e., partly missing) start dates and/or stop dates will be imputed. When the start date and 
the stop date are both incomplete for a subject, the start date will be imputed first. 
16.8.1 
Incomplete Start Date 
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication start date. If the stop date is complete 
(or imputed) and the imputed start date is after the stop date, the start date will be 
imputed using the stop date. 
Missing month and day 
 If the year of the incomplete start date is the same as the year of the first dose of 
double-blind investigational product, the month and day of the first dose of 
double-blind investigational product will be assigned to the missing fields 
 If the year of the incomplete start date is before the year of the first dose of 
double-blind investigational product, December 31 will be assigned to the missing 
fields 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 47 of 53 
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 If the year of the incomplete start date is after the year of the first dose of 
double-blind investigational product, January 1 will be assigned to the missing fields 
Missing month only 
 If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure 
Missing day only 
 If the month and year of the incomplete start date are the same as the month and year 
of the first dose of double-blind investigational product, the day of the first dose of 
double-blind investigational product will be assigned to the missing day 
 If either the year of the incomplete start date is before the year of the date of the 
first dose of double-blind investigational product or if both years are the same but the 
month of the incomplete start date is before the month of the date of the first dose of 
double-blind investigational product, the last day of the month will be assigned to the 
missing day 
 If either the year of the incomplete start date is after the year of the date of the 
first dose of double-blind investigational product or if both years are the same but the 
month of the incomplete start date is after the month of the date of the first dose of 
double-blind investigational product, the first day of the month will be assigned to the 
missing day 
16.8.2 
Incomplete Stop Date 
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication stop date. If the date of the last dose of 
double-blind investigational product is missing, impute it as described in Section 16.4. If 
the imputed stop date is before the start date (imputed or nonimputed start date), the 
imputed stop date will be equal to the start date. 
Missing month and day 
 If the year of the incomplete stop date is the same as the year of the last dose of 
double-blind investigational product, the month and day of the last dose of 
double-blind investigational product in the study will be assigned to the missing fields 
 If the year of the incomplete stop date is before the year of the last dose of 
double-blind investigational product, December 31 will be assigned to the 
missing fields 
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SAP SCT-MD-60 
Allergan                                                                                                                                 Page 48 of 53 
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 If the year of the incomplete stop date is after the year of the last dose of double-blind 
investigational product, January 1 will be assigned to the missing fields 
Missing month only 
 If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure 
Missing day only 
 If the month and year of the incomplete stop date are the same as the month and year 
of the last dose of double-blind investigational product, the day of the last dose of 
double-blind investigational product will be assigned to the missing day 
 If either the year of the incomplete stop date is before the year of the date of the 
last dose of double-blind investigational product or if both years are the same but the 
month of the incomplete stop date is before the month of the date of the last dose of 
double-blind investigational product, the last day of the month will be assigned to the 
missing day 
 If either the year of the incomplete stop date is after the year of the date of the 
last dose of double-blind investigational product or if both years are the same but the 
month of the incomplete stop date is after the month of the date of the last dose of 
double-blind investigational product, the first day of the month will be assigned to the 
missing day 
16.9 
CHARACTER VALUES OF CLINICAL LABORATORY 
PARAMETERS 
If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table because, for example, a character string is reported for a parameter of the 
numeric type, a coded value must be appropriately determined for use in the statistical 
analyses. The actual values, as reported in the database will be presented in the 
data listings. 
Table 16.9–1 shows examples of how some possible laboratory results should be coded 
for analysis. 
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SAP SCT-MD-60 
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Table 16.9–1. 
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters 
Laboratory Test, 
SI Unit 
Possible Laboratory Results 
Coded Value for Analysis 
CHEMISTRY 
ALT, U/L 
< 5 
5 
AST, U/L 
< 5 
5 
Bilirubin, total, μmol/L 
< 2 
2 
URINALYSIS 
Glucose, mmol/L 
< 2.775, Negative 
0 
[2.775, 5.55) 
1+ 
[5.55, 13.875) 
2+ 
[13.875, 27.75) 
3+ 
[27.75, 55.5) 
4+ 
≥ 55.5 
5+ 
ketones, mmol/L 
> 0.444, ≥ 0.444, >0, Trace 
Positive 
≤ 0, Negative 
Negative 
pH 
> 8.0, ≥ 8.0 
8.0 
≥ 8.5 
8.5 
Protein, g/L 
< 0, Negative 
Negative 
[0, 0.15), Trace 
0 
[0.15, 0.3) 
1+ 
[0.30, 1.0) 
2+ 
[1.0, 5.0) 
3+ 
>= 5.0 
4+ 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités 
(International System of Units). 
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SAP SCT-MD-60 
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17.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Only the following changes have been made to the protocol version 3.0: 30 Jun 2020. 
Per protocol section 11.3, demographic parameters to be summarized include weight z-
score and height z-score.  However, these will be listed but not summarized.  
No other changes have been made to the analyses specified in the protocol. 
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SAP SCT-MD-60 
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18.0 
REFERENCES 
Cole TJ. The LMS method for constructing normalized growth standards. Eur J Clin 
Nutr., 44: 45-60, 1990. 
Kenward MG, Molenberghs G, Thijs H. Pattern-mixture models with proper time 
dependence. Biometrika, 2003;90:53-71. 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics, 1997;53:983-997. 
Lu K. Sample size calculations with multiplicity adjustment for longitudinal clinical trials 
with missing data. Stat Med 2012;31:19-28. 
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SAP SCT-MD-60 
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19.0 
APPENDICES 
APPENDIX I 
PATTERN-MIXTURE MODEL DETAILS 
For repeated measures with the monotone missing mechanism, the pattern-mixture model 
with non-future dependent missing assumption, proposed by Kenward et al. (2003), 
provides a feasible solution to accommodate certain missing not at random (MNAR) 
mechanism. The methodology relies on constructing unidentifiable conditional densities 
using identifiable densities and borrows techniques from standard multiple imputation. 
1. Non-Future Dependent Missing Assumption 
Assume there are T designed visits in a longitudinal study and let 
)
,...,
2
,1
(
T
i
yi

 
represent subject’s measurement at Visit i. When the missing mechanism is monotone, 
the pattern of missing data can be defined by the number of measurements (L) actually 
observed from the subject. Let 
)
|
,...,
(
t
L
y
y
f
j
i

 denote the conditional density of  
yi ,... yj, given that the last observed measurement is at Visit t. Then the overall density 
function for Pattern t can be written as 
f (y1,..., yT | L = t) = f (y1,..., yt | L = t) f (yt+1 | y1 ,..., yt, L = t) 
(1)
 
× 
T 
 f (ys | y1 ,..., ys-1, L = t) 
Π 
s = t+2 
Note on the right hand side of (1) the first factor is clearly identifiable from the observed 
data, while the second and the beyond are not, due to lack of available data. The second 
factor 
)
,
,...,
|
(
1
1
t
L
y
y
y
f
t
t


 could be identifiable based on an assumed relationship 
between 
)
,
,...,
|
(
1
1
t
L
y
y
y
f
t
t


 and f (yt+1 | y1,...yt, L ≥ t + 1). The third and beyond 
factors 
)
,
,...,
|
(
1
1
t
L
y
y
y
f
s
s


(with all s ≥ t + 2) could be identifiable with the help of 
non-future dependent missing assumption. 
For longitudinal data with dropouts, non-future dependent missing (NFD) mechanism 
(Kenward et al., 2003) assumes that the unidentifiable conditional distributions of 
s
y  
(s ≥ t + 2), given earlier measurements, in Pattern t, is equal to the corresponding 
distribution in patterns L ≥ s – 1 :  
f (ys | y1,..., ys-1, L = t) = f (ys | y1,..., ys-1, L ≥ s – 1) 
(2) 
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SAP SCT-MD-60 
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The right hand side of (2) can further be partitioned into 
f (ys | y1,..., ys-1, L ≥ s – 1) = 
T 
ωs-1, j · f (ys | y1,..., ys-1, L = j) 
(3)
Σ 
j = s-1 
Where mixture probabilities ωs-1,j are: 
 ωs-1,j =  
αj f (y1,...,ys-1 | L = j) 
, and αj represents the fraction of  
(4) 
T 
αt f (y1,...,ys-1 | L = t) 
 
Σ 
 
t = s-1 
subjects from Pattern j. 
Each factor of the unidentifiable conditional distribution of
s
y  (s ≥ t + 2) on the right side 
of (1) can be expressed using the following: 
- 
)
1
,
,...,
|
(
1
1



s
L
y
y
y
f
s
s
, the unidentifiable conditional distribution of the 
first missing in pattern 
1

s
,  
- 
)
,
,...,
|
(
1
1
j
L
y
y
y
f
s
s


, the identifiable conditional distributions of
s
y given
1
1,...,

s
y
y
 
of pattern j (j ≥ s), and 
- αj, the fraction of subjects from pattern j (j ≥ s - 1).  
So under NFD, all the unidentifiable conditional distribution on the right side of (1) can 
be estimated and missing value could be therefore imputed based on the assumption for 
unidentifiable conditional distribution of the first missing. 
We re-formulate the partition in (3), for s ≥ t +2, as the following: 
f (ys | y1,..., ys-1, L = t) = δs-1 f (ys | y1,..., ys-1, L = s – 1) 
(5) 
+ (1 – δs-1) f (ys | y1,..., ys-1, L ≥ s) 
for s ≥ t +2 with 
1
,1
1



s
s
s
ω
δ
. 
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SAP SCT-MD-60 
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Therefore, under monotone missing and NFD assumption, the unidentifiable conditional 
densities for Visit s in Pattern t (s ≥ t +2) can be expressed as a mixture distribution of 
)
1
,
,...,
|
(
1
1



s
L
y
y
y
f
s
s
- the unidentifiable conditional distribution of the first missing 
measurement ys in Pattern
1

s
, and f (ys | y1,...,ys-1, L ≥ s) - the identifiable conditional 
distribution of ys from all the patterns with observed data at Visit s or beyond: 
f (ys | y1,..., ys-1, L ≥ s) =
T 
 λs-1,j f (ys | y1,..., ys-1, L = j) 
(6) 
Σ 
j = s 
where the mixture probability  
λs - 1, j = ωs-1,j /(1 – ωs - 1, s - 1) =  
αj f (y1,...,ys-1 | L = j) 
for j ≥ s, where αj is the fraction of  
(7) 
T 
αt f (y1,...,ys-1 | L = t) 
Σ 
 
t = s 
 
 
subjects from Pattern j. 
The conditional densities for the first missing are selected as: 
f (ys | y1,..., ys-1, L = s – 1) = f (ys – Δ | y1,..., ys-1, L ≥ s) for s = 2, ..., T,  (8) 
Note that the two distributions only differ by a shift (Δ) parameter. When Δ = 0, the 
missing value ys in Pattern s-1 is imputed based on the distribution of all observed data up 
to Visit s, as a result, leading to missing at random (MAR) missingness. When Δ ≠ 0, (8) 
will introduce a scenario of MNAR. The similar idea was also presented in the recent 
publication “The Prevention and Treatment of Missing Data in Clinical Trials” by the 
National Academies Press. The selection of the plausible values for the shift parameter 
(Δ) is discussed in Section 3 of this appendix. 
Note that per recommendation in Wang and Daniels (2011), only the observed data 
within pattern is assumed to be multivariate normal. The observed data distribution can 
be expressed in terms of the marginal distribution of baseline measurement and the 
conditional distributions of postbaseline measurements given earlier measurements. 
Assuming that these distributions are normal, the linear regression of each observation on 
prior observations will yield least-squares estimates of model parameters that can be 
utilized for independent posterior draws of model parameters for observed data. Multiple 
imputation approach will be used to estimate the overall mean at the final time point. 
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SAP SCT-MD-60 
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2. Imputation Procedure 
All the missing data will be imputed to create complete datasets, then statistical analysis 
can be performed using appropriate techniques such as ANCOVA. The imputation can 
accommodate MNAR missing data mechanisms, based on the theory discussed in the 
previous section.  
The model parameters for each dropout pattern, i.e., the mean, variance and proportions 
of observations in each pattern, are drawn from their posterior distributions prior to the 
imputation of missing data for a single imputation.  
The details of imputation within a pattern, say Pattern t, are as the following: 
Step 1. Impute the first missing value yt+1 for each subject in Pattern t (t = 1,..., T – 1):  
a. Compute estimates of mixture probabilities λs-1,j in (7) with s = t+1 given the 
posterior draw of proportions of observations in each pattern and the posterior draw 
of regression parameters for the observed data. 
b. Draw a random integer from {s, ..T} to index a component distribution on the right 
hand side of (6), using mixture probabilities obtained in a). Draw 
*
1

ty
 from the 
identified component normal distribution. Impute the missing yt+1 as  
*
1
1
~


t
t
y
y
 + Δ. 
Step 2. Impute the rest of the missing values of yt+2, yt+3, ..., yT for subjects in Pattern t: 
Starting with imputation for yt+2, first, similar to Step 1, draw 
*
2

ty
 from the normal 
mixture (6) based on the observed y1,...,yt and the already imputed 
1
~

ty
 for the subject. 
Then the missing yt+2 is imputed as 
*
2
2
~


t
t
y
y
 + Δ with probability δt+1 and as 
*
2
2
~


t
t
y
y
 with probability 1 – δt+1, where the mixture probability δt+1 = ωt+1,t+1 is 
obtained from (4) given the posterior draw of proportions of observations in each pattern 
and the posterior draw of regression parameters for the observed data. 
Missing values of yt+3 through yT can be imputed similarly as yt+2.  
To summarize, the imputations of yt+1 through yT is done recursively within each Pattern t 
(for all t = 1,...,T – 1) to create a complete dataset after imputation is done for all patterns 
with missing values.  
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SAP SCT-MD-60 
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The above imputation procedure is applied to all subjects in each missing data pattern to 
create a single imputed data set. Repeating the process of drawing parameters from the 
posterior distribution and imputing missing data given the posterior draw m times will 
yield m imputed data sets. The observed or imputed values at the final data point are 
averaged to obtain the overall mean estimate for each imputed data set, and the multiple 
imputation estimate is obtained by averaging the estimates across m imputations.  
In this sensitivity analysis, m is set to equal to 20. The value of m is discussed in the 
context of imputation efficiency in standard multiple imputation theory (Rubin, 1987, 
p. 114), and m = 20 would provide at least 96% of relative efficiency as compared with 
using an large number of imputations (SAS/STAT User’s Guide, p. 3796).  
3. Determination of the Shift Parameter Values 
The common shift parameter Δ is the difference between the mean of yt+1 among those 
who drop out at Visit t and those who remain beyond Visit t (1 ≤ t ≤ T – 1). The exact 
value of Δ is unknown and can’t be estimated from data because of missingness. The 
magnitude of Δ depends on the medical aspects of the trial. Using relevant historical data, 
one may select Δ as a proportion of the sample standard deviation or a proportion of 
observed treatment efficacy.  
References: 
Kenward MG, Molenberghs G, Thijs H. Pattern-mixture models with proper time 
dependence. Biometrika, 2003;90:53-71. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. J. Wiley & Sons, 
New York; 1987. 
SAS Institute Inc. SAS/STAT 9.2 User’s Guide, Second Edition. Cary, NC: SAS Institute 
Inc; 2009. 
Wang C, Daniels MJ. A note on MAR, identifying restrictions, model comparison, and 
sensitivity analysis in pattern mixture models with and without covariates for incomplete 
data. Biometrics, 2011; 67(3):810-818.  
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