Clinical trial NCT04007991
Conditions: Tourette Syndrome
Sponsor: Emalex Biosciences Inc.
Start date: 2019-06-28; Completion date: 2021-09-23
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the effect of ecopipam tablets in children and adolescents in the treatment of Tourette's Syndrome (TS). Half of the participants will receive ecopipam tablets, while the other half will receive matching placebo tablets

Detailed description:
Multicenter, placebo-controlled, double-blind, randomized, parallel-group, Phase 2b study in pediatric subjects (aged greater than equal to 6 to less than 18 years of age) with TS. Following a 28-day Screening period and Baseline visit, eligible subjects will be randomized 1:1 to receive either ecopipam hydrochloride (HCl) or matching placebo for a 12 week treatment period. Doses will be titrated up and down from target dose of 2 mg/kg/day. Follow Up visit will be conducted after the last dose of study medication.

Arms: arm 1: Ecopipam HCl 12.5-, 50-, 75- and 100-mg tablets; 2 mg/kg/day target dose; oral administration daily in evenings arm 2: Matching Placebo tablets taken orally in the evening
Interventions: intervention 1: Ecopipam intervention 2: Placebo
Intervention descriptions: intervention 1: Ecopipam HCI tablets administered PO to establish 2 mg/kg/day intervention 2: Matching Placebo

Protocol documents:
Prot_000.pdf: 
ECOPIPAM (EBS-101) 
EBS-101-CL-001 
 
IND Number: 
 
 
109746 
EudraCT Number:  
2019-000281-37 
Protocol Title:  
A Multicenter, Placebo-Controlled, Double-Blind, 
Randomized, Parallel-Group, Phase 2b Study to 
Evaluate the Efficacy and Safety of Ecopipam Tablets in 
Children and Adolescent Subjects with Tourette’s 
Syndrome 
 
Indication Studied:  
Children and Adolescent Subjects with Tourette’s Syndrome 
 
Protocol Version/Date: 6.0, Amendment 5, 13 April 2020 
 
Sponsor Address: 
Emalex Biosciences, Inc. 
300 North Wabash Avenue, Suite 3500 
Chicago, IL, 60611  
 
 
The program will be completed according to the guidelines of Good Clinical Practice. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study subjects 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki. 
 
Confidentiality Statement 
The information in this document contains trade and commercial information that is privileged or 
confidential and may not be disclosed unless such disclosure is required by federal or state law or 
regulations. In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you which is 
indicated as privileged or confidential. 
 


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 2 of 95 
1. 
PROTOCOL AMENDMENT CHANGES 
In addition to the changes summarized in this section, minor editorial and formatting changes 
were made to enhance clarity and readability.  
 
Section:  Title Page 
Existing Text 
1033 Skokie Boulevard, Suite 600  
Northbrook, IL 60062  
Revised Text 
300 North Wabash Avenue, Suite 3500 
Chicago, IL, 60611  
Rationale for Amendment 
Updated to reflect new location of Emalex Biosciences, Inc.  
 
Section:  Investigator’s Agreement  
Existing Text 
EBS-101-CL-101 
Revised Text 
EBS-101-CL-001 
Rationale for Amendment 
Correction of typographical error 
 
Section:  Table 1:  Emergency Contact Information   
Existing Text 
Role in Study 
Name 
Contact Information 
Clinical Study Leader 
 
 
  
Revised Text 
Role in Study 
Name 
Contact Information 
Clinical Study Leader 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 3 of 95 
Rationale for Amendment 
Updating telephone information at new location for Emalex Biosciences personnel.   
 
Section: Synopsis/Studied period (years)  
Existing Text 
Estimated date last subject completed: Q2 2020 
Revised Text 
Estimated date last subject completed: Q2 2022 
Rationale for Amendment 
Timeline extended according to delays incurred during the COVID-19 pandemic.   
 
Sections: Synopsis/Methodology and 7.1 Study Design 
Existing Text 
After the screening period, subjects will return to the clinic at Baseline and 4, 6, 8 and 12 weeks 
after Randomization. Subjects will have telephone visits on Weeks 2 and 10 to assess adverse 
events and other safety parameters. Efficacy assessments will be conducted at weeks 4, 6, 8 and 
12. Safety assessments will be conducted at these visits as well. A Follow Up visit will be 
conducted in the clinic 7 and 14 days after the last dose of study medication. Subjects will also 
be contacted 30 days after the last dose of study medication to determine any adverse events. At 
study completion or early termination, subjects will be tapered off study drug as outlined in the 
protocol.  
Revised Text 
After the screening period, subjects will return to the clinic at Baseline and 4, 6, 8 and 12 weeks 
after Randomization.  Study Visits at Weeks 4, 6, 8 and 12 after randomization may be 
completed in locations other than clinic and/or safety and efficacy assessments required at these 
visits will be made available for remote administration due to restrictions as a consequence of the 
COVID-19 pandemic or other qualifying event.  Subjects will have telephone visits on Weeks 2 
and 10 to assess adverse events and other safety parameters.  Efficacy assessments will be 
conducted at Weeks 4, 6, 8 and 12.  Safety assessments will be conducted at these visits as well.  
A Follow Up visit will be conducted in the clinic 7 and 14 days after the last dose of study 
medication.  The follow up visits on Day 7 and 14 after the last dose of study medication may be 
completed in locations other than clinic and/or safety and efficacy assessments required at these 
visits will be made available for remote administration due to restrictions as a consequence of the 
COVID-19 pandemic or other qualifying event.  Subjects will also be contacted 30 days after the 
last dose of study medication to determine any adverse events.  At study completion or early 
termination, subjects will be tapered off study drug as outlined in the protocol.  


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 4 of 95 
Rationale for Amendment 
Alternate remote monitoring procedures implemented for safety purposes in response to the 
COVID-19 pandemic.   
 
Sections: Synopsis/Inclusion Criteria and 8.1 Inclusion Criteria  
Existing Text 
11) The subject has received an adequate trial of non-pharmacological therapy without adequate 
response prior to study enrollment as documented by the Investigator. 
Revised Text 
11) For subjects enrolled outside of the United States and Canada, the subject has received an 
adequate trial of non-pharmacological therapy without adequate response prior to study 
enrollment as documented by the Investigator. 
Rationale for Amendment 
The variability of access to formalized psychological treatment for TS in the US and Canada for 
patients in different regions creates an irregularity.  However, the severity of illness will continue 
to be assessed by the YGTSS.   
 
Section: Synopsis/Exclusion Criteria   
Existing Text 
19) Subjects receiving anti-depressant, anti-anxiety or anti-ADHD medications unless the dosage 
has been stable for a minimum of 2 weeks prior to Screening and not prescribed to relieve the 
neurological symptoms related to TS. 
Revised Text 
19) Subjects receiving anti-depressant, anti-anxiety or anti-ADHD medications unless the dosage 
has been stable for a minimum of 4 weeks prior to Screening and not prescribed to relieve the 
neurological symptoms related to TS. 
Rationale for Amendment 
Correction made to the inclusion criteria in the synopsis to match the corresponding item in 
Section 8.1 Inclusion Criteria.   
 
Sections: Synopsis/Exclusion Criteria and 8.2 Exclusion Criteria  
Existing Text 
22) Subjects who have initiated new behavioral therapies to treat TS fewer than 10 weeks prior to 
Baseline visit.   


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 5 of 95 
Revised Text 
22) Subjects who have initiated new behavioral therapies fewer than 10 weeks prior to Baseline 
visit.   
Rationale for Amendment 
The impact of behavioral treatment for any indication may lead to improvement of TS 
symptoms.   
 
Sections: Synopsis/Exclusion Criteria and 8.2 Exclusion Criteria  
Existing Text 
14) Subjects with a history of seizures (excluding febrile seizures that occurred >2 years prior to 
Screening). 
Revised Text 
14) Subjects with a history of seizures (excluding febrile seizures that occurred <2 years prior to 
Screening). 
Rationale for Amendment 
Significant typographical error corrected.   
 
Sections: Synopsis/Exclusion Criteria and 8.2 Exclusion Criteria  
Existing Text 
None 
Revised Text 
25) Any subject who in the opinion of the investigator is not a suitable candidate for the study. 
Rationale for Amendment 
In addition to formalized exclusion criteria this criterion is to provide investigators the ability to 
ensure that subjects who may not be suitable for the study can be excluded. 
 
Section: Synopsis/Safety  
Existing Text 
Safety will be assessed by monitoring and recording all adverse events (AEs) and Serious 
Adverse Events (SAEs) (all Visits), regular monitoring of hematology, blood chemistry, and 
urine values (Screening, Baseline, Week 12 and 7 and 14 day Follow Up visits).  HbA1c will be 
measured at the baseline and completion/early termination visits.  Regular measurement of vital 
signs and the performance of a physical examination and an ECG will occur at Screening, 
Baseline and Weeks 4, 6, 8 and 12 and 7 and 14 day Follow Up visits. An additional assessment 
will include the Columbia-Suicide Severity Rating Scale (C-SSRS) (all Visits except 30 day 
Follow up visit). Additional safety outcomes (Baseline and Weeks 4, 6, 8 and 12) will include 


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 6 of 95 
the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), 
the Swanson, Nolan and Pelham (SNAP-IV) questionnaire, the Children's Yale-Brown 
Obsessive Compulsive Scale (CY-BOCS), the Children's Depression Rating Scale-Revised 
(CDRS-R), the Giles de la Tourette Syndrome – Quality of Life Scale for Children and 
Adolescents (C&A-GTS-QOL) and the Pediatric Anxiety Rating Scale (PARS).  
Revised Text 
Study Visits at Weeks 4, 6, 8 and 12 after randomization may be completed in locations other 
than clinic and/or safety assessments required at these visits will be made available for remote 
administration due to restrictions as a consequence of the COVID-19 pandemic or other qualifying 
event.  Safety will be assessed by monitoring and recording all adverse events (AEs) and Serious 
Adverse Events (SAEs) (all Visits), regular monitoring of hematology, blood chemistry, and 
urine values (Screening, Baseline, Week 12 and 7 and 14 day Follow Up visits).  HbA1c will be 
measured at the baseline and completion/early termination visits.  Regular measurement of vital 
signs and the performance of a physical examination and an ECG will occur at Screening, 
Baseline and Weeks 4, 6, 8 and 12 and 7 and 14 day Follow Up visits.  An additional assessment 
will include the Columbia-Suicide Severity Rating Scale (C-SSRS) (all Visits except 30 day 
Follow up visit).  Additional safety outcomes (Baseline and Weeks 4, 6, 8 and 12) will include 
the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), 
the Swanson, Nolan and Pelham (SNAP-IV) questionnaire, the Children's Yale-Brown 
Obsessive Compulsive Scale (CY-BOCS), the Children's Depression Rating Scale-Revised 
(CDRS-R), the Giles de la Tourette Syndrome – Quality of Life Scale for Children and 
Adolescents (C&A-GTS-QOL) and the Pediatric Anxiety Rating Scale (PARS).  Subjects will be 
monitored for signs of abuse, and withdrawal or dependence.  
Rationale for Amendment 
Alternate remote monitoring procedures implemented for safety purposes in response to the 
COVID-19 pandemic.   
To provide investigators guidance to monitor subjects for signs of abuse, and withdrawal or 
dependence.   
 
Sections: Synopsis/PK and 11.3 Pharmacokinetics Parameters 
Existing Text 
Blood samples will be collected to measure concentrations of ecopipam and/or its major (active) 
metabolites at Weeks 4 and 12.  
Revised Text 
Blood samples will be collected to measure concentrations of ecopipam and/or its major (active) 
metabolites at Weeks 4 and 12.  If visits at Weeks 4 and 12 are not conducted at a site due to 
restrictions as a consequence of the COVID-19 pandemic or other qualifying event, collection of 
PK sampling is optional.   


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 7 of 95 
Rationale for Amendment 
Alternate remote monitoring procedures implemented for safety purposes in response to the 
COVID-19 pandemic.   
 
Sections:  Synopsis/Statistical Methods and 13 Statistics  
Existing Text 
None 
Revised Text 
Additional analyses may need to be conducted for data not collected at sites and/or collected via 
remote administration due to restrictions as a consequence of the COVID-19 pandemic or other 
qualifying event, details of these additional analyses will be specified in the SAP.  
Rationale for Amendment 
Alternate procedures noted in response to the COVID-19 pandemic.   
 
Section:  List of Abbreviations and Definition of Terms  
Existing Text 
CNS  
 
 
 
Central nervous system  
C-SSRS 
 
 
 
Columbia Suicide Severity Rating Scale  
Revised Text 
CNS   
 
 
 
Central nervous system  
COVID-19 
 
 
SARS-CoV-2 (coronavirus) 
Rationale for Amendment 
New abbreviation and definition added; incorrect/duplicate abbreviation and definition removed.   
 
Section:  5.2.2.1 Safety in Humans / Study PSY302 
Existing Text 
A total of 149 TEAEs were reported in 35 of the 40 treated subjects (87.50%). There was one 
serious TEAE during placebo treatment and one TEAE resulting in dose withdrawn permanently 
during ecopipam treatment.  
Revised Text 
A total of 149 TEAEs were reported in 35 of the 40 treated subjects (87.50%).  There was one 
serious TEAE during placebo treatment and one TEAE resulting in dose withdrawn permanently 
during ecopipam treatment.  More patients on placebo had severe adverse events (7.5%) 
compared to ecopipam (5%). 


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
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Page 8 of 95 
Rationale for Amendment 
Updated information included.   
 
Section:  5.3.1 Assessment of Risk  
Existing Text 
Of the total human exposures, 540 adults have participated in studies to investigate the safety, 
tolerability, pharmacodynamics and pharmacokinetics of ecopipam after single and multiple 
administration. In addition, a total of 2058 adult subjects have received treatment with ecopipam 
in therapeutic studies, including 1667 with obesity, 279 with cocaine addiction, 56 with 
schizophrenia, schizoaffective disorder and schizophreniform disorder, 28 with pathological 
gambling, 1 adult with LND, 18 adults with TS, 40 children/adolescents with TS and 9 adults 
with stuttering. 
Revised Text 
Of the 2651 human subjects that have been exposed to ecopipam, 540 adults have participated in 
studies to investigate the safety, tolerability, pharmacodynamics and pharmacokinetics of 
ecopipam after single and multiple dose administration.  Of the 2651 human subjects that have 
been exposed to ecopipam, a total of 2058 adult subjects have received treatment with ecopipam 
in therapeutic studies, including 1667 with obesity, 279 with cocaine addiction, 56 with 
schizophrenia, schizoaffective disorder and schizophreniform disorder, 28 with pathological 
gambling, 1 adult with LND, 18 adults with TS, 40 children/adolescents with TS and 9 adults 
with stuttering. 
Rationale for Amendment 
Updated information included.   
 
Section:  5.3.3 Methods to Minimize Risks 
Existing Text 
• All subjects will be evaluated for safety every two weeks while receiving study 
medication, with 4 evaluations conducted in person and 2 being phone assessments. 
Revised Text 
• All subjects will be evaluated for safety every two weeks while receiving study 
medication, with 4 evaluations conducted at the site and 2 via telephone assessments. 
Rationale for Amendment 
Clarifying language added.   
 


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 9 of 95 
Section:  7.5 Criteria for Study Discontinuation  
Existing Text 
A subject may elect to discontinue from the study at any time for safety or personal reasons.  All 
subjects who discontinue from the study are to complete the early study discontinuation 
procedures. 
Revised Text 
A subject may elect to discontinue from the study at any time for safety or personal reasons.  All 
subjects who discontinue from the study should complete the early study discontinuation 
procedures. 
Rationale for Amendment 
Clarifying language added.   


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 10 of 95 
Section: Table 2 Schedule of Assessments 
 
Existing Text 
Assessment 
Screeninga 
Baseline 
Titration 
Treatment 
Completion/ 
Early 
Termination 
7 Day  
Follow-up 
14 Day 
Follow-up 
30 day  
Follow-up* 
Study Week 
Up to -4 
0 
2* 
4 
6 
8 
10* 
12 
13/14 
14/15 
16/17 
Study Days 
Up to -28 
0 
14+3 
28+3 
42+3 
56+3 
70+3 
84+3 
7 Days  
Post Last 
Dose +3 
14 Days 
Post Last 
Dose +3 
30 Days  
Post Last 
Dose +3 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric/medicat
ion History  
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Exam/Vital Signsb 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
ECG 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Laboratory tests 
(Hematology and 
Chemistry)c 
X 
X 
 
 
 
 
 
X 
X 
X c 
 
Urine Drug Screen 
X 
X 
 
 
 
 
 
X 
 
 
 
Urine Pregnancy Test 
X 
X 
 
 
 
 
 
X 
 
 
 
DSM-5 Criteria for TS 
X 
 
 
 
 
 
 
 
 
 
 
Yale Global Tic Severity 
Scale 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
Clinical Global Impression - 
Tourette’s Syndrome of 
Severity 
 
X 
 
X 
X 
X 
 
X 
 
 
 


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 11 of 95 
Assessment 
Screeninga 
Baseline 
Titration 
Treatment 
Completion/ 
Early 
Termination 
7 Day  
Follow-up 
14 Day 
Follow-up 
30 day  
Follow-up* 
Study Week 
Up to -4 
0 
2* 
4 
6 
8 
10* 
12 
13/14 
14/15 
16/17 
Study Days 
Up to -28 
0 
14+3 
28+3 
42+3 
56+3 
70+3 
84+3 
7 Days  
Post Last 
Dose +3 
14 Days 
Post Last 
Dose +3 
30 Days  
Post Last 
Dose +3 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Clinical Global Impression - 
Tourette’s Syndrome of 
Improvement 
 
 
 
X 
X 
X 
 
X 
 
 
 
Caregiver Global 
Impression of Change 
 
 
 
X 
X 
X 
 
X 
 
 
 
Columbia Suicide Severity 
Rating Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abnormal Involuntary 
Movementd 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Barnes Akathisia Rating 
Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Swanson, Nolan, and 
Pelham Questionnaire 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Children’s Yale-Brown 
Obsessive Compulsive Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Children’s Depression 
Rating Scale - Revised 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Gilles de la Tourette 
Syndrome Quality of Life 
Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Pediatric Anxiety Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
PK Blood Drawse 
 
 
 
X 
 
 
 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
Concomitant Medications 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 12 of 95 
Assessment 
Screeninga 
Baseline 
Titration 
Treatment 
Completion/ 
Early 
Termination 
7 Day  
Follow-up 
14 Day 
Follow-up 
30 day  
Follow-up* 
Study Week 
Up to -4 
0 
2* 
4 
6 
8 
10* 
12 
13/14 
14/15 
16/17 
Study Days 
Up to -28 
0 
14+3 
28+3 
42+3 
56+3 
70+3 
84+3 
7 Days  
Post Last 
Dose +3 
14 Days 
Post Last 
Dose +3 
30 Days  
Post Last 
Dose +3 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Dispense Study Drug 
 
X 
 
X 
X 
X 
 
Xf 
 
 
 
Collect Unused Study 
Drug/Assess drug 
compliance 
 
 
 
X 
X 
X 
 
X 
X 
 
 
Abbreviations: AE = adverse event; BP = blood pressure; ECG = electrocardiogram; HR = heart rate; PK = pharmacokinetic(s) 
a 
Informed consent must be performed prior to any screening procedures.  All screening procedures are to occur after washout of any applicable medications.  
Rescreening is allowed.  
b 
Vital signs will include, pulse, BP, orthostatic BP (done 5 minutes after being supine and then 3 minutes after standing), height and weight. 
c 
Subjects should be in a fasting state (8 hours) for laboratory tests. HbA1c will be measured at the baseline and completion/early termination visits. 
d 
Every attempt should be made to perform this assessment at the same time at each visit. 
e 
At Week 4 Study dose should not be taken until after predose blood draw at the site. PK draws should be predose, between 0.5 and 1.5 hours after study drug 
administration, and between 2 and 4 hours after study drug administration. Both Week 4 and Week 12, visits should be scheduled for the morning. At Week 
12, blood sample will be collected in the afternoon at the end of the visit.  
f 
Study drug will be dispensed for dose down titration. 
* Weeks 2 and 10 will be telephone visits. If there are any abnormal findings, the subject will be brought to the site for full assessment. A telephone call will be 
made to the subject 30 days after the last dose to assess any adverse events that may have occurred. 
 


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
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Page 13 of 95 
Revised Text  
 
Assessment 
Screeninga 
Baseline 
Titration 
Treatment 
Completion/ 
Early 
Termination 
7 Day  
Follow-up 
14 Day 
Follow-up 
30 day  
Follow-up* 
Study Week 
Up to -4 
0 
2* 
4g 
6g 
8g 
10* 
12g 
13/14g 
14/15g 
16/17 
Study Days 
Up to -28 
0 
14+3 
28+3 
42+3 
56+3 
70+3 
84+3 
7 Days  
Post Last 
Dose +3 
14 Days 
Post Last 
Dose +3 
30 Days  
Post Last 
Dose +3 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric/medicat
ion History  
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Exam/Vital Signsb 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
ECG 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Laboratory tests 
(Hematology and 
Chemistry)c 
X 
X 
 
 
 
 
 
X 
X 
X c 
 
Urine Drug Screen 
X 
X 
 
 
 
 
 
X 
 
 
 
Urine Pregnancy Test 
X 
X 
 
 
 
 
 
X 
 
X 
 
DSM-5 Criteria for TS 
X 
 
 
 
 
 
 
 
 
 
 
Yale Global Tic Severity 
Scale 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
Clinical Global Impression - 
Tourette’s Syndrome of 
Severity 
 
X 
 
X 
X 
X 
 
X 
 
 
 


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 14 of 95 
Assessment 
Screeninga 
Baseline 
Titration 
Treatment 
Completion/ 
Early 
Termination 
7 Day  
Follow-up 
14 Day 
Follow-up 
30 day  
Follow-up* 
Study Week 
Up to -4 
0 
2* 
4g 
6g 
8g 
10* 
12g 
13/14g 
14/15g 
16/17 
Study Days 
Up to -28 
0 
14+3 
28+3 
42+3 
56+3 
70+3 
84+3 
7 Days  
Post Last 
Dose +3 
14 Days 
Post Last 
Dose +3 
30 Days  
Post Last 
Dose +3 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Clinical Global Impression - 
Tourette’s Syndrome of 
Improvement 
 
 
 
X 
X 
X 
 
X 
 
 
 
Caregiver Global 
Impression of Change 
 
 
 
X 
X 
X 
 
X 
 
 
 
Columbia Suicide Severity 
Rating Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abnormal Involuntary 
Movementd 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Barnes Akathisia Rating 
Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Swanson, Nolan, and 
Pelham Questionnaire 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Children’s Yale-Brown 
Obsessive Compulsive Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Children’s Depression 
Rating Scale - Revised 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Gilles de la Tourette 
Syndrome Quality of Life 
Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Pediatric Anxiety Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
PK Blood Drawse,h 
 
 
 
X 
 
 
 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
Concomitant Medications 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 


Emalex Biosciences, Inc. 
Protocol EBS-101-CL-001 
Ecopipam 
Version 6.0, Amendment 5, 13 April 2020 
 
Confidential 
Page 15 of 95 
Assessment 
Screeninga 
Baseline 
Titration 
Treatment 
Completion/ 
Early 
Termination 
7 Day  
Follow-up 
14 Day 
Follow-up 
30 day  
Follow-up* 
Study Week 
Up to -4 
0 
2* 
4g 
6g 
8g 
10* 
12g 
13/14g 
14/15g 
16/17 
Study Days 
Up to -28 
0 
14+3 
28+3 
42+3 
56+3 
70+3 
84+3 
7 Days  
Post Last 
Dose +3 
14 Days 
Post Last 
Dose +3 
30 Days  
Post Last 
Dose +3 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Dispense Study Drug 
 
X 
 
X 
X 
X 
 
Xf 
 
 
 
Collect Unused Study 
Drug/Assess drug 
compliance 
 
 
 
X 
X 
X 
 
X 
X 
 
 
Abbreviations: AE = adverse event; BP = blood pressure; ECG = electrocardiogram; HR = heart rate; PK = pharmacokinetic(s) 
a 
Informed consent must be performed prior to any screening procedures.  All screening procedures are to occur after washout of any applicable medications.  
Rescreening is allowed after approval by the Medical Advisor.     
b 
Vital signs will include, pulse, BP, orthostatic BP (done 5 minutes after being supine and then 3 minutes after standing), height and weight. 
c 
Subjects should be in a fasting state (8 hours) for laboratory tests. HbA1c will be measured at the baseline and completion/early termination visits. 
d 
Every attempt should be made to perform this assessment at the same time at each visit. 
e 
At Week 4 Study dose should not be taken until after predose blood draw at the site. PK draws should be predose, between 0.5 and 1.5 hours after study drug 
administration, and between 2 and 4 hours after study drug administration. Both Week 4 and Week 12, visits should be scheduled for the morning. At Week 
12, blood sample will be collected in the afternoon at the end of the visit.  
f 
Study drug will be dispensed for dose down titration. 
* Weeks 2 and 10 will be telephone visits. If there are any abnormal findings, the subject will be brought to the site for full assessment. A telephone call will be 
made to the subject 30 days after the last dose to assess any adverse events that may have occurred. 
g 
Assessments for these visits may be completed in locations other than study clinic and/or safety and efficacy assessments required at these visits will be made 
available for remote administration due to restrictions as a consequence of the COVID-19 pandemic or other qualifying event .   
h 
If visits at Weeks 4 and 12 are completed in locations other than study clinic due to restrictions as a consequence of the COVID-19 pandemic or other 
qualifying event then collection of labs for PK assessments are optional 
 
Rationale for Amendment 
Alternate remote monitoring procedures implemented for safety purposes in response to the COVID-19 pandemic.  Note added to 
indicate that Day 14 Follow Up Visit laboratory results may serve as baseline labs for Study EBS-101-OL-001 to eliminate potential 
duplicate sampling.  Urine pregnancy test added to Day 14 follow up visit to ensure adequate testing of subjects entering into the EBS-
101-OL-001 study within 14 days.  Clarification regarding approval required for rescreening added.  


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Version 6.0, Amendment 5, 13 April 2020 
 
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Section: 8.3 Subject Withdrawal, Removal and Replacement Criteria  
Existing Text 
Any subject with a CDI assessment indicative of the onset of a new depressive episode at any 
visit can be discontinued from study participation at the discretion of the Investigator.  
Revised Text 
Any subject with a CDRS-R assessment indicative of the onset of a new depressive episode at 
any visit can be discontinued from study participation at the discretion of the Investigator.  
Rationale for Amendment 
Correction of incorrect scale reference.   
 
Section: 10.7 Study Drug Accountability  
Existing Text 
None 
Revised Text 
Due to the COVID-19 pandemic, in some cases direct to patient shipments may be necessary.  In 
this case, study medication may be transported to the subject by a third party vendor who has 
systems in place to protect blinding, patient privacy, and data integrity. 
Rationale for Amendment 
Modifications implemented as a result of COVID-19 pandemic. 
 
Section: 11 Assessment of Efficacy  
Existing Text 
None. 
Revised Text 
Assessments may be completed in locations other than study clinic and/or via remote 
administration due to restrictions as a consequence of the COVID-19 pandemic or other 
qualifying event. 
Rationale for Amendment 
Alternate remote monitoring procedures implemented for safety purposes in response to the 
COVID-19 pandemic.    
 
Sections: Synopsis/Criteria for Evaluation and 11.2 Secondary Efficacy Assessments  
Existing Text 
Other Secondary efficacy endpoints include: 


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• Change in Clinician Global Impression Tourette Syndrome of Improvement (CGI-TS-I) 
from Baseline to Week 12 
• Change in YGTSS-Global Score (GS) from Baseline to Week 12 
• Change in Caregiver Global Impression of Change (CaGI-C) from Baseline to Week 12 
Revised Text 
Other Secondary efficacy endpoints include: 
• Change in Clinician Global Impression Tourette Syndrome of Improvement (CGI-TS-I) 
from Week 4 to Week 12 
• Change in YGTSS-Global Score (GS) from Baseline to Week 12 
• Change in Caregiver Global Impression of Change (CaGI-C) from Week 4 to Week 12 
Rationale for Amendment 
Efficacy endpoints for Change in Clinician Global Impression Tourette Syndrome of 
Improvement (CGI-TS-I) and Caregiver Global Impression of Change (CaGI-C) corrected to 
begin at Week 4 with the first administration of these scales.   
 
Section: 12 Assessment of Safety  
Existing Text 
None 
Revised Text 
Assessments may be completed in locations other than study clinic due to restrictions as a 
consequence of the COVID-19 pandemic or other qualifying event. 
Rationale for Amendment 
Alternate remote monitoring procedures implemented for safety purposes in response to the 
COVID-19 pandemic.    
 
Section: 12.1.3 Other Safety Parameters  
Existing Text 
None  
Revised Text 
Subjects must be monitored for signs of study drug abuse, and withdrawal or dependence and if 
detected must be recorded as AEs. 
Rationale for Amendment 
To provide investigators guidance to monitor subjects for signs of abuse, and withdrawal or 
dependence.    


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Version 6.0, Amendment 5, 13 April 2020 
 
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Section: 13.1 Analysis Population   
Existing Text 
The list of subjects or observations to be excluded from the PP Population, along with the reason 
for exclusion, will be finalized prior to database unblinding.  
Revised Text 
The list of subjects or observations to be excluded from the PP Population, along with the reason 
for exclusion, will be finalized prior to database unblinding.  Protocol deviations that occur due 
to the COVID-19 pandemic related issues will be categorized separately as applicable.    
Rationale for Amendment 
Plan for protocol deviations related to the COVID-19 pandemic specified.   
 


PPD
PPD
PPD
PPD


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for Ecopipam.  I have read the protocol 
EBS-101-CL-001 and agree to conduct the study as outlined.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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Version 6.0, Amendment 5, 13 April 2020 
 
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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Clinical Study Leader 
 
 
 
Drug Safety Physician 
 
 
 
24-Hour emergency contact 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Version 6.0, Amendment 5, 13 April 2020 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Emalex Biosciences, Inc. 
Name of Investigational Product: 
Ecopipam Tablets 
Protocol Number: EBS-101-CL-001 
Title of Study:  
A Multicenter, Placebo-Controlled, Double-Blind, Randomized, Parallel-Group, Phase 2b Study to 
Evaluate the Efficacy and Safety of Ecopipam Tablets in Children and Adolescent Subjects with 
Tourette’s Syndrome 
Study center(s): Approximately 60 sites in the United States, Canada, and the European Union  
Principal Investigator: TBD 
Investigators: TBD 
Studied period (years):  
Estimated date first subject enrolled: Q2 2019 
Estimated date last subject completed: Q2 2022 
Phase of development:  
2b 
Objectives:  
Primary: 
The primary objective of this study is to evaluate the efficacy of ecopipam tablets in pediatric subjects 
(aged > 6 to <18 years) with Tourette’s Syndrome (TS). 
Secondary: 
The secondary objectives of this study are to evaluate the safety of ecopipam tablets in pediatric 
subjects (aged > 6 to <18 years) with TS and characterize the pharmacokinetics (PK) of ecopipam. 
Exploratory: 
To evaluate the PK/pharmacodynamic relationship between plasma levels of ecopipam and treatment 
effect if possible. 
Methodology:  
This is a multicenter, placebo-controlled, double-blind, randomized, parallel-group, Phase 2b study in 
pediatric subjects (aged >6 to <18 years) with TS.  Following a 28-day Screening period and Baseline 
visit, eligible subjects will be randomized 1:1 to receive either a target steady-state dose of 
2 mg/kg/day ecopipam HCl or matching placebo for a 4-week Titration period followed by an 8-week 
Treatment period.  Following titration, subjects who weigh 18 kg to <23 kg will receive a 37.5-mg 
active dose (or placebo), subjects who weigh >23 kg to <34 kg will receive a 50-mg active dose (or 
placebo), subjects who weigh >34 kg to <44 kg will receive a 75-mg active dose (or placebo), 
subjects who weigh >44 kg to <68 kg will receive a 100-mg active dose (or placebo), subjects who 
weigh >68 kg to <83 kg will receive a 150-mg active dose (or placebo), and subjects who weigh 
>83 kg will receive a 200-mg active dose (or placebo). 
After the screening period, subjects will return to the clinic at Baseline and 4, 6, 8 and 12 weeks after 
Randomization.  Study Visits at Weeks 4, 6, 8 and 12 after randomization may be completed in 
locations other than clinic and/or safety and efficacy assessments required at these visits will be made 
available for remote administration due to restrictions as a consequence of the COVID-19 pandemic 
or other qualifying event.  Subjects will have telephone visits on Weeks 2 and 10 to assess adverse 


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events and other safety parameters.  Efficacy assessments will be conducted at Weeks 4, 6, 8 and 12.  
Safety assessments will be conducted at these visits as well.  A Follow Up visit will be conducted in 
the clinic 7 and 14 days after the last dose of study medication.  The follow up visits on Day 7 and 14 
after the last dose of study medication may be completed in locations other than clinic and/or safety 
and efficacy assessments required at these visits will be made available for remote administration due 
to restrictions as a consequence of the COVID-19 pandemic or other qualifying event.  Subjects will 
also be contacted 30 days after the last dose of study medication to determine any adverse events.  At 
study completion or early termination, subjects will be tapered off study drug as outlined in the 
protocol.  
An interim analysis will be conducted by an independent data safety monitoring board (DSMB) when 
50% of the total subjects complete the study.  The DSMB will determine the probability of a 
successful study (conditional power).  If this probability is too small and does meet pre-specified 
criteria, the DSMB could recommend stopping the study for futility.  If the probability of a successful 
study is reasonable, the DSMB can recommend continuing the study as planned.  The DSMB can also 
recommend the continuation of the study with a sample size adjustment based on conditional power.   
Sample Size Justification: 
A sample size of 75 subjects per group will provide >80% power to detect difference between groups 
of 3 points on change from baseline the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-
TTS), with standard deviation = 6.1 and alpha = 0.05, assuming 10% drop out.  
Number of subjects (planned):  
75 per arm; 150 total 
Diagnosis and main criteria for inclusion:  
Inclusion Criteria: 
1) Subject’s parent or legal guardian must sign a written informed consent.  
2) Subject must sign a written informed assent according to the requirements of the 
site’s IRB/EC. 
3) Subjects must be ≥6 to <18 years of age at time of screening. 
4) Subjects must weigh ≥18 kg (39.6 lbs). 
5) Subjects must have TS based on Diagnostic and Statistical Manual for Mental 
Disorders – 5th Edition (DSM-5 diagnostic criteria) for TS.  
6) Subjects must exhibit both motor and vocal tics that cause impairment with normal 
routines. 
7) Subjects must have a minimum score of 20 on the YGTSS-TTS at Screening and at 
Baseline visits with tic symptoms in the investigator’s judgment causing: 
a. Subjective discomfort (e.g., pain or injury) 
b. Sustained social problems (e.g., social isolation or bullying) 
c. Social and emotional problems 
d. Functional interference (e.g., impairment of academic achievements) 
8) Subjects may not be taking any medications used to treat motor or vocal tics for at 
least 14 days prior to Baseline. 
9) Adolescent females of childbearing potential who are sexually active must be using 
highly effective contraception (i.e., oral contraceptives, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized male 
partner) and agree to continue use of highly effective contraception for the duration 


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of their participation in the study.  They must also agree to use highly effective 
contraception for 30 days after their last dose of study drug.  
10) Sexually active male subjects must use a highly effective method of contraception 
during the study and agree to continue the use of highly effective contraception for at 
least 30 days after the last dose of study drug.  
11) For subjects enrolled outside of the United States and Canada, the subject has 
received an adequate trial of non-pharmacological therapy without adequate response 
prior to study enrollment as documented by the Investigator. 
Exclusion Criteria: 
1) Subjects with any unstable primary mood disorder (DSM-5 criteria) at Screening. 
2) Subjects who have unstable medical illness or clinically significant abnormalities on 
laboratory tests, or ECG at Screening as determined by the Principal Investigator.  
3) Subjects with a significant risk of committing suicide based on history, routine 
psychiatric status examination, investigator’s judgment, or who had an answer of 
‘‘yes’’ on any question other than 1–3 (currently or within the past 30 days) on the 
baseline/screening version of the Columbia Suicide Severity Rating Scale (C-SSRS). 
4) Subjects with a clinical presentation at Screening and/or history consistent with 
another neurologic condition that may have had accompanying abnormal movements 
(e.g., Huntington’s disease, Parkinson’s disease, Wilson’s disease, stroke, Restless 
Legs Syndrome). 
5) Female subjects who are currently pregnant or lactating or planning to become 
pregnant during the course of the study.   
6) Subjects who have moderate to severe renal insufficiency at Screening. 
7) Subjects who have hepatic impairment at Screening 
8) Subjects with current or recent (past 3 months) history of DSM-5 substance use 
disorder (with the exception of nicotine).  
9) Subjects with positive urine drug screen for cocaine, amphetamine, 
methamphetamine, benzodiazepines, barbiturates, phencyclidine (PCP), or opiates at 
Screening, except those receiving stable, prescribed treatment for attention 
deficit/hyperactivity disorder (ADHD) 
10) Subjects with a > 25% difference in the absolute change in YGTSS-TTS score 
between the Screening visit and the Baseline visit 
11) Subjects with a lifetime history of bipolar disorder type I or II, dementia, 
schizophrenia, or any other psychotic disorder. 
12) Subjects with a major depressive episode in the past 2 years.  
13) Subjects with a history of attempted suicide.  
14) Subjects with a history of seizures (excluding febrile seizures that occurred <2 years 
prior to Screening). 
15) Subjects with a history of neuroleptic malignant syndrome. 
16) Subjects with a myocardial infarction within 6 months.  
17) Subjects who have had previous treatment with ecopipam. 
18) Subjects who have had previous treatment with:  
o investigational medication within 1 month prior to Screening  
o depot neuroleptics within 3 months prior to Screening 
o oral neuroleptics within 4 weeks prior to Screening 
19) Subjects receiving anti-depressant, anti-anxiety or anti-ADHD medications unless the 
dosage has been stable for a minimum of 4 weeks prior to Screening and not 
prescribed to relieve the neurological symptoms related to TS. 


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20) Subjects who have a need for medications which would have unfavorable interactions 
with ecopipam, e.g., dopamine antagonists or agonists [including bupropion], 
tetrabenazine, monoamine oxidase inhibitors, or St. John’s Wort.  
21) Initiation or changes in behavioral therapies for TS during the course of the study 
(i.e., Habit Reversal Training or Comprehensive Behavioral Intervention for Tics) as 
well as deep brain stimulation. 
22) Subjects who have initiated new behavioral therapies  fewer than 10 weeks prior to 
Baseline visit 
23) Subjects unable to swallow tablets  
24) Subjects with a known hypersensitivity to ecopipam or any of its excipients. 
25) Any subject who in the opinion of the investigator is not a suitable candidate for the 
study. 
Investigational product, dosage and mode of administration:  
Ecopipam HCl 12.5-, 50-, 75- and 100-mg tablets; 2 mg/kg/day target dose; oral administration. 
Dosing will be stratified by the following weight bands to better achieve the 2 mg/kg/day target dose: 
≥18-≤23 kg, >23-≤34 kg, >34-≤44 kg, >44-≤68 kg, >68-≤83 kg, > 83 kg.  Dosing will be based on the 
subject’s weight at the Baseline and will not be adjusted if the subject’s weight changes at subsequent 
Visits.  
During the 4-week titration period, the following ecopipam HCl doses or matching placebo will be 
administered for each of the weight bands:  
• 
Those who weigh ≥18-≤23 kg will titrate from 12.5 mg daily to 37.5 mg daily: 12.5 mg 
during Week 1, 25 mg during Week 2, and 37.5 mg during Weeks 3 and 4. 
• 
Those who weigh >23-≤34 kg will titrate from 12.5 mg daily to 50 mg daily: 12.5 mg during 
Week 1, 25 mg during Week 2, 37.5 mg during Week 3 and 50 mg during Week 4. 
• 
Those who weigh >34-≤44 kg will titrate from 12.5 mg daily to 75 mg daily: 12.5 mg during 
week 1, 25 mg during week 2, 50 mg during Week 3 and 75 mg during Week 4. 
• 
Those who weigh >44-≤68 kg will titrate from 25 mg daily to 100 mg daily: 25 mg during 
Week 1, 50 mg during Week 2, 75 mg during Week 3 and 100 mg during Week 4. 
• 
Those who weigh >68-≤83 kg will titrate from 25 mg daily to 150 mg daily: 25 mg during 
Week 1, 50 mg during Week 2, 100 mg during Week 3 and 150 mg during Week 4. 
• 
Those who weigh >83 kg will titrate from 25 mg daily to 200 mg daily: 25 mg during 
Week 1, 50 mg during Week 2, 100 mg during Week 3, and 200 mg during Week 4. 
During the 8-week treatment phase, the following ecopipam HCl doses or matching placebo will be 
administered for each of the weight bands:  
• 
Those who weigh ≥18-≤23 kg will receive 37.5 mg daily. 
• 
Those who weigh >23-≤34 will receive 50 mg daily. 
• 
Those who weigh >34-≤44 will receive 75 mg daily. 
• 
Those who weigh >44-≤68 kg will receive 100 mg daily. 
• 
Those who weigh >68-≤83 kg will receive 150 mg daily. 
• 
Those who weigh >83 kg will receive 200 mg daily.  
All doses will be administered once daily in the evening. 
At the end of the 8-week treatment phase, subjects will titrate off therapy and receive ecopipam HCl 
doses or matching placebo that will be reduced by 25 mg/day until off of drug; signs of symptoms of 
withdrawal will be monitored. 


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Duration of treatment:  
Four weeks Screening Phase, Baseline Visit, 4-week Titration Period, 8-week Treatment Period and 
2-week Follow-up Period.  There will also be a phone call to subjects 30 days after study completion 
or early termination to assess any adverse events. 
Reference therapy, dosage, and mode of administration:  
Placebo-controlled, matching placebo tablets given by mouth (PO) in the evening. 
Criteria for evaluation: 
Efficacy:   
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the change in the Yale Global Tic Severity Scale – Total Tic Score 
(YGTSS-TTS, i.e., sum of the motor and phonic tic scores) from baseline (YGTSS-TTS score from 
Baseline visit) to end of therapy (YGTSS-TTS score from Week 12).  
 
Key Secondary Efficacy Endpoint: 
• 
Change in Clinical Global Impression of Tourette Syndrome Severity (CGI-TS-S) from 
Baseline to Week 12 
Other Secondary efficacy endpoints include: 
• 
Change in Clinician Global Impression Tourette Syndrome of Improvement (CGI-TS-I) from 
Week 4 to Week 12 
• 
Change in YGTSS-Global Score (GS) from Baseline to Week 12 
• 
Change in Caregiver Global Impression of Change (CaGI-C) from Week 4 to Week 12 
• 
Change in Gilles de la Tourette Syndrome–Quality of Life Scale for Children and 
Adolescents (C&A-GTS-QOL) from Baseline to Week12 
• 
Percentage of subjects with a 25% improvement on the YGTSS-TTS 
• 
Percentage of subjects with complete remission of tics on the YGTSS-TTS 
• 
Change in YGTSS-TTS from Baseline to Weeks 4, 6, and 8  
• 
Change in CGI-TS-S from Baseline to Weeks 4, 6, and 8 
• 
Change in CGI-TS-I from Baseline to Weeks 4, 6, and 8 
• 
Change in YGTSS-GS from Baseline to Weeks 4, 6, and 8 
• 
Change in CaGI-C from Baseline to Weeks 4, 6, and 8 
• 
Change in the C&A-GTS-QOL from Baseline to Weeks 4, 6, and 8 
Rank order of hierarchy of the secondary endpoints will be outlined in the statistical analysis plan.  
Safety:   
Study Visits at Weeks 4, 6, 8 and 12 after randomization may be completed in locations other than 
clinic and/or safety assessments required at these visits will be made available for remote 
administration due to restrictions as a consequence of the COVID-19 pandemic or other qualifying 
event.  Safety will be assessed by monitoring and recording all adverse events (AEs) and Serious 
Adverse Events (SAEs) (all Visits), regular monitoring of hematology, blood chemistry, and urine 
values (Screening, Baseline, Week 12 and 7 and 14 day Follow Up visits).  HbA1c will be measured 
at the baseline and completion/early termination visits.  Regular measurement of vital signs and the 
performance of a physical examination and an ECG will occur at Screening, Baseline and Weeks 4, 6, 
8 and 12 and 7 and 14 day Follow Up visits.  An additional assessment will include the Columbia-


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Suicide Severity Rating Scale (C-SSRS) (all Visits except 30 day Follow up visit).  Additional safety 
outcomes (Baseline and Weeks 4, 6, 8 and 12) will include the Abnormal Involuntary Movement 
Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), the Swanson, Nolan and Pelham (SNAP-
IV) questionnaire, the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the 
Children's Depression Rating Scale-Revised (CDRS-R), the Giles de la Tourette Syndrome – Quality 
of Life Scale for Children and Adolescents (C&A-GTS-QOL) and the Pediatric Anxiety Rating Scale 
(PARS).  Subjects will be monitored for signs of abuse, and withdrawal or dependence.  
PK: 
Blood samples will be collected to measure concentrations of ecopipam and/or its major (active) 
metabolites at Weeks 4 and 12.  If visits at Weeks 4 and 12 are not conducted at a site due to 
restrictions as a consequence of the COVID-19 pandemic or other qualifying event, collection of PK 
samples is optional.   
For the Week 4 visit, a morning appointment is suggested.  Parents/caregivers will be instructed not to 
administer the study medication to the subject on the evening prior to the Week 4 visit and to record 
the time of administration of the last dose of study medication taken.  The study drug administration 
will occur on the day of the Week 4 visit at the site under the supervision of the study investigator.  
An intravenous catheter will be placed, and the subject will have samples collected at the following 
time windows:  one sample at pre-dose (34 to 44 hours since the last dose), one sample between 0.5 
and 1.5 hour after administration of study medication, and one sample between 2 and 4 hours after 
study drug administration.  Any samples should be collected at least 30 min apart.   
For the Week 12 visit, parents/caregivers will be asked to record the time of study drug administration 
on the evening prior to the visit.  An appointment is suggested to be made for the morning of the 
Week 12 visit.  A blood sample will be collected at the end of the visit.  The time of sample collection 
will be recorded.  Blood samples will be processed as outlined in the protocol and serum/plasma will 
be frozen, shipped and analyzed for ecopipam and SCH40853. 
Statistical methods: 
Efficacy:  
The Modified Intention-to-Treat (mITT) population will include all randomized subjects who 
received at least one dose of study drug.  The mITT population will be used for the analysis of the 
efficacy endpoints. 
The primary efficacy endpoint for this study will be the change from Baseline (YGTSS-TTS from 
Baseline) to end of therapy (YGTSS-TTS from Week 12).   
The primary endpoint will be assessed with a Mixed Model for Repeated Measures (MMRM) model 
which will include fixed effects for treatment, visit (categorical week in study), interaction between 
treatment and visit, center and a covariate for baseline YGTSS-TTS.  Taking consideration of missing 
data, multiple imputation or tipping point method may be used as a sensitivity analysis  
Secondary endpoints will be evaluated in a similar manner with hierarchy to preserve alpha.  
Additional analyses may need to be conducted for data not collected at sites and/or collected via 
remote administration due to restrictions as a consequence of the COVID-19 pandemic or other 
qualifying event, details of these additional analyses will be specified in the SAP.  
The full details will be specified in the SAP. 
Safety: 
The safety population will include all randomized subjects who received at least one dose of study 
drug.  The safety population will be used for the analysis of the safety endpoints. 


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PK:  
Plasma concentration-time data will be summarized in the Clinical Study Report (CSR).  Population 
pharmacokinetic analysis will be conducted and summarized separately, using data from this study 
along with data from adults using the same tablet formulation (if available).  The methodology for 
analyses will be reported in a separate analysis plan. 


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3. 
TABLE OF CONTENTS 
1. 
PROTOCOL AMENDMENT CHANGES ..................................................................2 
SIGNATURE PAGE .....................................................................................................................19 
INVESTIGATOR’S AGREEMENT .............................................................................................20 
PROCEDURES IN CASE OF EMERGENCY .............................................................................21 
2. 
SYNOPSIS .................................................................................................................22 
3. 
TABLE OF CONTENTS ...........................................................................................29 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................33 
5. 
INTRODUCTION ......................................................................................................35 
5.1 
Background on Tourette’s Syndrome .........................................................................35 
5.1.1. 
Disrupted Dopamine Systems in Tourette’s Syndrome..............................................36 
5.2. 
Background on Ecopipam ...........................................................................................37 
5.2.1.1. 
Toxicology ..................................................................................................................37 
5.2.2. 
Clinical Data ...............................................................................................................37 
5.2.2.1. 
Safety in Humans ........................................................................................................37 
5.3. 
Risk-Benefit Assessment ............................................................................................41 
5.3.1. 
Assessment of Risk .....................................................................................................41 
5.3.2. 
Assessment of Benefit ................................................................................................42 
5.3.3. 
Methods to Minimize Risks ........................................................................................43 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................45 
6.1. 
Primary Objective .......................................................................................................45 
6.2. 
Secondary Objectives .................................................................................................45 
7. 
INVESTIGATIONAL PLAN .....................................................................................46 
7.1. 
Overall Study Design ..................................................................................................46 
7.2. 
Number of Subjects ....................................................................................................46 
7.3. 
Treatment Assignment ................................................................................................46 
7.4. 
Dose Adjustment Criteria ...........................................................................................46 
7.5. 
Criteria for Subject Study Discontinuation .................................................................47 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................51 
8.1. 
Inclusion Criteria ........................................................................................................51 
8.2. 
Exclusion Criteria .......................................................................................................51 
CCI


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8.3. 
Subject Withdrawal, Removal, and Replacement Criteria .........................................53 
9. 
TREATMENT OF SUBJECTS ..................................................................................54 
9.1. 
Description of Study Drug ..........................................................................................54 
9.2. 
Concomitant Medications ...........................................................................................54 
9.3. 
Prohibited Therapies ...................................................................................................54 
9.4. 
Treatment Compliance ................................................................................................55 
9.5. 
Randomization and Blinding ......................................................................................55 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................56 
10.1. 
Study Drug ..................................................................................................................56 
10.2. 
Study Drug Packaging and Labeling ..........................................................................56 
10.3. 
Study Drug Storage .....................................................................................................56 
10.4. 
Study Drug Preparation ..............................................................................................56 
10.5. 
Administration ............................................................................................................56 
10.6. 
Dosing Rationale ........................................................................................................57 
10.7. 
Study Drug Accountability .........................................................................................59 
10.8. 
Study Drug Handling and Disposal ............................................................................60 
11. 
ASSESSMENT OF EFFICACY ................................................................................61 
11.1. 
Primary Efficacy Assessment .....................................................................................61 
11.2. 
Secondary Efficacy Assessments ...............................................................................61 
11.3. 
Pharmacokinetics Parameters .....................................................................................62 
12. 
ASSESSMENT OF SAFETY .....................................................................................63 
12.1. 
Safety Parameters .......................................................................................................63 
12.1.1. 
Columbia Suicide Severity Rating Scale ....................................................................63 
12.1.2. 
Other Safety Outcome Scales .....................................................................................63 
12.1.3. 
Other Safety Assessments ...........................................................................................64 
12.2. 
Adverse and Serious Adverse Events .........................................................................65 
12.2.1. 
Definition of Adverse Events .....................................................................................65 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................65 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................65 
12.2.1.3. 
Other Adverse Event (OAE) .......................................................................................66 
12.3. 
Relationship to Study Drug ........................................................................................66 
12.4. 
Recording Adverse Events .........................................................................................66 


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12.5. 
Reporting Adverse Events ..........................................................................................67 
13. 
STATISTICS ..............................................................................................................68 
13.1. 
Analysis Population ....................................................................................................68 
13.2. 
Planned Analysis ........................................................................................................68 
13.2.1. 
Efficacy Analysis ........................................................................................................68 
13.2.2. 
Safety Analysis ...........................................................................................................69 
13.2.3. 
Pharmacokinetics Analysis .........................................................................................69 
13.2.4. 
Data Safety Monitoring Board ....................................................................................69 
13.2.5. 
Interim Analysis ..........................................................................................................70 
13.3. 
Sample Size Justifications ..........................................................................................70 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................71 
14.1. 
Study Monitoring ........................................................................................................71 
14.2. 
Audits and Inspections ................................................................................................71 
14.3. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................72 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................73 
16. 
ETHICS ......................................................................................................................74 
16.1. 
Ethics Review .............................................................................................................74 
16.2. 
Ethical Conduct of the Study ......................................................................................74 
16.3. 
Written Informed Consent ..........................................................................................74 
16.4. 
Subject Confidentiality ...............................................................................................74 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................76 
17.1. 
Inspection of Records .................................................................................................76 
17.2. 
Retention of Records ..................................................................................................76 
18. 
PUBLICATION POLICY ..........................................................................................77 
19. 
LIST OF REFERENCES ............................................................................................78 
20. 
REFERENCES FOR QUESTIONNAIRES AND SCALES .....................................79 
21. 
APPENDICES ............................................................................................................81 
WMA DECLARATION OF HELSINKI – ETHICAL PRINCIPLES FOR MEDICAL 
RESEARCH INVOLVING HUMAN SUBJECTS .......................................................................81 
CONTRACEPTION GUIDELINES .............................................................................................87 
PROHIBITED MEDICATIONS LIST ..........................................................................................88 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information .................................................................................21 
Table 2: 
Schedule of Assessments ............................................................................................48 
Table 3: 
Investigational Product ...............................................................................................54 
Table 4: 
Proposed Dosing Regimen .........................................................................................58 
Table 5: 
Animal:Human Exposure Ratios with the Proposed Dosage Regimen of 
Ecopipam to 7- to 16-Year-Olds .................................................................................59 
 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviations 
Terms  
ADD 
Attention Deficit Disorder 
ADHD 
attention deficit/hyperactivity disorder 
ADL 
Activities of Daily Living 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
AMP 
adenosine monophosphate 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Classification 
AUC 
area under the plasma-concentration time course profile  
AUC(0-24 hr) 
area under the plasma-concentration time course profile from  
time 0 (dosing) to 24 hours after dosing 
BUN 
blood urea nitrogen 
C&A-GTS-QOL 
Child and Adolescent Gilles De La Tourette Syndrome-Quality 
of Life Scale 
CaGI-C 
Caregiver Global Impression of Change 
CFR 
Code of Federal Regulations 
CDI 
Children’s Depression Inventory 
CDRS-R 
Children’s Depression Rating Scale-Revised 
CY-BOCS 
Children’s Yale-Brown Obsessive Compulsive Scale 
CGI 
Clinical Global Impression 
CGI-TS-I 
Clinical Global Impression Tourette’s Syndrome of 
Improvement 
CGI-TS-S 
Clinical Global Impression Tourette’s Syndrome of Severity 
Cmax 
maximum observed concentration 
CNS 
Central nervous system 
COVID-19 
SARS-CoV-2 (coronavirus) 
CRA 
Clinical research associate 
CRO 
Clinical research organization 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTC 
Common Toxicity Criteria 
CV 
coefficient of variation 
C-YBOCS 
Child Yale-Brown Obsessive Compulsive Scale  
DCI 
Diagnostic Confidence Index 
DSM-5 CC-SM 
Diagnostic and Statistical Manual of Mental Disorders – 
5th Edition Cross-Cutting Symptom Measures 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
FDA 
Food and Drug Administration 


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GCP 
Good Clinical Practices 
GS 
Global score 
HCl 
Hydrochloride 
123I-β-CIT SPECT 
(2β-carbomethoxy-3β-[4-iodophenyl]tropane) single photon 
emission computed tomography 
HbA1c 
Hemoglobin A1c 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IRB 
Institutional Review Board 
IV 
Intravenous 
Ki 
Inhibition constant 
LDH 
lactate dehydrogenase 
LFT 
Liver function test(s) 
LND 
Lesch-Nyhan Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
OCD 
Obsessive-Compulsive Disorder 
PARS 
Pediatric Anxiety Rating Scale 
PCP 
Phencyclidine 
PET 
Positron emission tomography 
PO 
Oral (per os) 
QD 
Once daily 
SAE 
serious adverse event 
SC 
Subcutaneous 
SCH 
Schering-Plough drug code indicator 
SNAP-IV 
Swanson, Nolan, and Pelham questionnaire 
tmax 
time from dosing to the maximum observed concentration 
TS 
Tourette’s Syndrome 
TTS 
Total Tic Score 
US 
United States 
YGTSS-TTS 
Yale Global Tic Severity Scale-Total Tic Score 


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5. 
INTRODUCTION 
5.1 
Background on Tourette’s Syndrome 
Tourette’s Syndrome (TS) is a neurological disorder characterized by motor or vocal tics that 
begin in childhood and persist over time (see box below with the Diagnostic and Statistical 
Manual for Mental Disorders – 5th Edition [DSM-5 diagnostic criteria).  The tics are brief in 
duration, occur spontaneously, and do not show a regular temporal pattern.  Further the tics are 
not caused by medications, other medical reasons, or confirmed neurological abnormality.  They 
can be consciously suppressed for some time and are exacerbated by stress.  Males are more 
susceptible than females with a ratio of about 4.1 to 3.  Motor tics can include such things as eye-
blinking, facial grimacing, mouth movements, head jerks, shoulder shrugs and arm/leg jerks. In 
more severe cases gyrating, bending, pivoting and dystonic movements are possible.  Vocal tics 
are fast meaningless sounds or noises, and include such things as sniffing, throat clearing, 
grunting, barks and squealing.  Complex vocal tics can include shouting out of single words, 
whole sentences or repeating words (echolalia).  In small numbers of subjects, explosive 
obscenities (coprolalia) are possible.P1,2
P  Diagnosis of TS is complicated because it often co-exists 
with other psychiatric illnesses.  Common co-morbid conditions include attention 
deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, and 
depression.P2
P  These symptoms often mask TS and make diagnosis difficult.  Tic severity can 
range from mild to severe according to its frequency and intensity.  The tics have a variable 
course, with severe bouts interspersed with complete absence of symptoms.  Onset of tics is seen 
early in childhood (average approximately 7 years) and peaks in the teenage years.  Vocal tics 
appears several years after the onset of motor tics.  For most subjects, the period of worst-ever tic 
severity is between 7 and 15 years of age, followed by a steady decline in tic severity.  As 
subjects mature, the vast majority of tics will disappear permanently, with a small percentage of 
subjects having tics that persist into adulthood and require treatment.  Complete remission of tics 
is reported in approximately 50% of subjects.  Severe tics are thought to occur only in about 10% 
of the cases.P3
P  
 
DSM-5 Diagnostic Criteria For Tourette's Syndrome 
 Note: A tic is a sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or 
vocalization. 
A. Both multiple motor and one or more vocal tics have been present at some time during the 
illness, although not necessarily concurrently.  
B. The tics may wax and wane in frequency but have persisted for more than 1 year since 
first tic onset. 
C. The onset is before age 18 years. 
D. The disturbance is not attributable to the physiological effects of a substance (e.g. Cocaine) 
or another medical condition (e.g. Huntington’s disease, postviral encephalitis). 


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Natural History of Tics 
 
 
Approaches to the treatment of tics include: education, behavioral therapy, pharmacological 
therapy and treatment of comorbid conditions (ADD, OCD).  Approximately, 20% of subjects do 
not need treatment.  Counseling and behavioral therapy may be sufficient with mild symptoms.  
Medications should be considered when tics interfere with peer relationships, social interactions, 
job or school performance or interfere with activities of daily living.  Medications should be 
started at low doses, titrated up slowly to lowest effective dose and tapered slowly during non-
stressful periods.  Medication therapy incudes: dopamine receptor blocking agents, dopamine 
depleting agents, benzodiazepines, low dose dopamine agonists, botulinum toxin and 
neurosurgical treatment.  Non-selective dopamine receptor blocking agents have been the 
mainstay of treatment and are the most effective.  They suppress tics in 70-80% of subjects.  
Many subjects eventually discontinue medication therapy due to adverse events, including extra-
pyramidal disorders, somnolence, blood glucose changes, weight gain and effects on lipids.  A 
selective D1 dopamine receptor blocking agent may mitigate against some of these adverse 
events and has to potential to offer a safer alternative option.  
5.1.1. 
Disrupted Dopamine Systems in Tourette’s Syndrome 
The underlying mechanism responsible for TS is unknown.  Although the disease tends to run in 
families, there have been no definitive genetic mutations identified.P4
P  Research to date has 
indicated that dopamine circuits in the central nervous system (CNS) are intimately involved 
based on the following observations.P5,6,7
P  
• Dopamine-rich areas of the brain (e.g., striatum) are believed to control motor tics. 
• Clinical neuroimaging studies of TS subjects implicate dopamine-rich brain areas. 


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• Dopamine antagonists can ameliorate tics.  
• Catecholamine depletors (e.g., tetrabenazine) can ameliorate tics. 
5.2. 
Background on Ecopipam 
Please refer to the Investigator’s Brochure for more detailed information about the known 
benefits and risks of ecopipam. 
5.2.2. 
Clinical Data 
5.2.2.1. 
Safety in Humans 
Clinical Summary: Legacy Schering-Plough Studies in Indications other than TS 
The early clinical program for ecopipam conducted by Schering-Plough investigated the safety 
and effectiveness of ecopipam for the treatment of obesity, cocaine addiction and schizophrenia 
in adults.  These comprised 30 Phase 1 studies; seven Phase 2 pilot studies, 5 in subjects with 
schizophrenia and 2 (including 1 extension study) in subjects with cocaine addiction; and 
1 completed Phase 2 and 3 discontinued Phase 3 studies in subjects with a primary diagnosis of 
moderate to severe obesity.  
CCI


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The Phase 1 studies examined ecopipam's pharmacokinetics, pharmacodynamics, bioavailability, 
distribution, food-effects on absorption, interactions with other drugs, bioequivalence of different 
formulations, and various physiological effects in cocaine users, smokers, or healthy subjects.  
The results of these studies demonstrate that ecopipam was well-tolerated with no clinically 
significant changes in physical examinations, vital signs, electrocardiograms (ECGs), laboratory 
tests, electroencephalograms (EEGs), neurological examinations, or liver function tests (LFTs).  
Most of the reported adverse events were mild to moderate in intensity.  The most commonly 
reported adverse event in Phase I clinical studies was somnolence.  Other commonly reported 
adverse events in Phase I clinical studies were headache, fatigue, nausea and insomnia. 
In a Phase 2 study (C197-184), 279 subjects with cocaine dependence in three dose groups (10-, 
25-, and 100 mg/day) were exposed to ecopipam for eight weeks in a placebo-controlled study.  
No differences in the reduction of cocaine use were demonstrated in favor of ecopipam 
compared with placebo.  The most common adverse events reported among all subjects in the 
cocaine addiction studies were fatigue, headache, nausea, insomnia, and somnolence.  Fatigue 
and somnolence appeared to be reported more often in subjects treated with ecopipam than 
placebo.  Somnolence appeared to occur in a dose-related fashion, occurring in 28% (26/94), 
31% (29/94), 43% (39/91), and 20% (19/93) of subjects treated with ecopipam HCl, 10, 25, and 
100 mg/day, and placebo, respectively.   
Five open-label safety, tolerability and Phase 2 studies of ecopipam in 56 subjects with 
schizophrenia were conducted.  Subjects diagnosed with acute schizophrenia, schizophreniform 
disorder, or bipolar schizoaffective disorders were treated with ecopipam HCl up to a daily dose 
of 600 mg.  The maximum duration of treatment was six weeks.  Ecopipam, when administered 
to subjects with schizophrenia, did not demonstrate efficacy in these studies.  The most 
commonly reported adverse events were somnolence (21%, 12/56), headache, nausea, vomiting 
and dizziness (each reported in 14%, 8/56 subjects), insomnia (9%, 5/56), dyspepsia (7%, 4/56), 
and anxiety (7%, 4/56).  
In a Phase 2, double-blind, placebo-controlled study (C/I98-271), 185 subjects with a primary 
diagnosis of moderate to severe obesity were treated with ecopipam HCl (10, 30, or 100 mg PO, 
once per day) for 12 weeks.  Subjects receiving ecopipam HCl showed a dose-dependent weight 
loss.  The most commonly reported adverse events by subjects receiving ecopipam HCl were 
headache, 19% (36/185), viral infection, 19% (36/185), somnolence, 18% (34/185), insomnia, 
9% (17/185), and nausea, 9% (16/185).   
In three Phase 3, double-blind, placebo-controlled studies (P00359, P00396, and P00741), obese 
subjects including type 2 diabetic subjects were treated with ecopipam HCl (50 or 100 mg PO, 
QD) for 52 weeks.  Subjects receiving ecopipam HCl showed a dose-dependent weight loss.  
These Phase 3 studies were discontinued because of unexpected psychiatric adverse events 
(ecopipam 31% vs. placebo 15%), including depression, anxiety, and suicidal ideation, thereby 
excluding its projected use in weight management.  The most frequently reported adverse events 
in all Phase 3 obesity studies receiving ecopipam HCl were upper respiratory tract infection, 
30% (439 of 1482 subjects reporting), insomnia 17% (248/1482), headache, 16% (244/1482), 
depression, 16% (236/1482), somnolence, 15% (216/1482), fatigue, 15% (215/1482), anxiety, 
14% (211/1482), pharyngitis, 9% (137/1482), back pain, 8% (114/1482), nausea, 7% (107/1482).  
The frequencies of insomnia, depression, somnolence and anxiety were about twice as frequent 
in subjects receiving ecopipam HCl compared to placebo.  The frequencies of upper respiratory 


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tract infection, headache, fatigue, pharyngitis, back pain and nausea were similar in frequencies 
in subjects receiving ecopipam and placebo.   
Clinical Summary: Legacy Psyadon Studies in Indications other than TS 
Following acquisition of ecopipam by Psyadon from Schering-Plough, two Phase 1 studies, one 
study in Lesch-Nyhan Disease (LND) subjects aged  ≥6 years old (PSY101) and one study of the 
pharmacokinetics of ecopipam controlled release capsules in male adult volunteers (PSY401), 
were completed.   
One Phase 2a study in adult subjects with Pathological Gambling (PG) (PSY201) was also 
completed.  In addition, a Phase 3, multicenter, randomized, double-blind, 3-period crossover 
study with an open-label extension in subjects with LND (≥ 6 years old) (PSY102) was 
discontinued before completion for financial (non-safety related) reasons. 
In the Phase 1 LND study (PSY101), in which 4 of 5 subjects were children, the most commonly 
reported adverse events were sedation (3 subjects), dystonia (2 subjects) and nausea (2 subjects). 
In a Phase 2a, single-blind (the subjects were blinded to treatment assignment), nonrandomized 
study, 28 subjects with PG (PSY201) received placebo (1-2 tablets/day orally depending on their 
urge to gamble) for 1 week and then ecopipam (1-2 50 mg tablets/day orally depending on their 
urge to gamble) for 6 weeks.  The most commonly reported adverse events (incidence≥5%) were 
drowsiness (11%), fatigue (11%), anxiety (11%), vomiting (11%), headache (7%), fever (7%), 
depression (7%) and rhinorrhea (7%).  
A Phase 3 study (PSY102) of ecopipam for the treatment of self-injurious behaviors in LND 
subjects was conducted.  A total of nine pediatric subjects were enrolled before the study was 
terminated for non-safety related reasons.  Ecopipam was administered at either 50 mg/day 
(<20 kg body weight) or 100 mg/day (>20 kg body weight).  In the PSY102 LND study, one 
subject aged 10 years old experienced dystonia, swallowing difficulty and depressed mood 
which involved persistent or significant disability or incapacity.  The same subject experienced 
renal calculus, dystonia and bronchospasm which involved persistent or significant disability or 
incapacity and was determined that these symptoms were not related to the study drug.  Another 
subject aged 6 years old experienced dysphagia, somnolence and depressed mood which 
involved persistent or significant disability or incapacity and were assessed possibly related to 
the study drug.  Since dystonia and dysphagia have not been seen previously in other study 
populations and because LND subjects have a genetic mutation known to impact dopaminergic 
systems, it is believed that these adverse events are uniquely seen in this population and are 
unlikely to occur in subjects without this disorder. 
Clinical Summary: Psyadon Clinical Studies in TS Subjects 
Two Phase 2 studies in subjects with TS have been conducted. 
Study PSY301 
In a Phase 2a multicenter, open-label, nonrandomized study, 18 adult subjects with TS (PSY301) 
were given ecopipam HCl 50 mg for 2 weeks followed by 100 mg for 6 weeks.  The primary 
outcome measure was Yale Global Tic Severity Scale (YGTSS).  After ecopipam treatment, 
YGTSS total scores, motor tics scores, phonic tics scores and overall impairment were all 
significantly decreased from baseline to endpoint, which indicated that the severity of tics was 


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decreased.  The most commonly reported adverse events (incidence≥20%) were sedation (33%), 
insomnia (33%), fatigue (33%), somnolence (28%), headache (22%), muscle twitching (22%) 
and anxiety (22%).  
Study PSY302 
In a Phase 2b multicenter, double blind, randomized, crossover study (PSY302), 40 children/ 
adolescents (ages 7-17 years) were given ecopipam up to 50 mg/day (if <75 lbs) or 100 mg/day 
(if >75 lbs) for four weeks.  The primary endpoint was the YGTSS Total (MP) Scores which 
were the sum of the motor and phonic subscales of YGTSS. In the ITT population, the mean 
(±SD) YGTSS Total (MP) Scores at baseline were 32.8 (±7.1) prior to ecopipam treatment and 
33.7 (±6.7) prior to placebo treatment.  On Day 16 of the treatment period, YGTSS Total (MP) 
Scores decreased 5.1 (±8.5) points on ecopipam and 2.1(±4.7) points on placebo.  On Day 30, 
YGTSS Total (MP) Scores decreased 5.5 (±8.7) points on Ecopipam and 3.4 (±5.8) points on 
placebo. Similar results were observed in the Evaluable population.  
In the ITT population, LS means (±SE) of the difference between ecopipam and placebo 
treatment were -2.8885±1.5282 (95%CI: -5.9822, 0.2053, p=0.0664) on Day 16 and -2.1366 
±1.6551 (95%CI: -5.4871, 1.2139, p=0.2045) on Day 30.  The treatment difference was more 
obvious in the evaluable population for both dates (on Day 16, p=0.0155, and on Day 30, 
p=0.0435). 
With respect to secondary endpoints, the changes of subscale scores were similar to YGTSS 
Total (MP) Scores results. In the ITT population, the mean (±SD) motor, phonic, impairment and 
global scores (the sum of motor, phonic and impairment scores) at baseline were 18.4 (±3.3), 
14.4 (±4.9), 28.0 (±10.7) and 60.8 (±16.5) prior to ecopipam, and 18.3 (±3.4), 15.4 (±4.5), 27.5 
(±9.3) and 61.2 (±14.0) prior to placebo, respectively.  After 30-day treatment, the decreases in 
scores compared to baseline were 3.3 (±4.2), 2.3 (±4.9), 7.0 (±11.6) and 12.6 (±18.7) on 
ecopipam and 1.6 (±3.3), 1.8 (±3.6), 3.0 (±9.1) and 6.4 (±13.4) on placebo, respectively.  Similar 
results were observed in evaluable population. 
In the ITT population, after 30-days of treatment, CGI Severity Scores decreased 0.8 (±0.7) 
points on ecopipam and 0.2 (±0.9) points on placebo.  Also, after ecopipam treatment, the 
percentages of subjects with much improved, minimally improved, no change, minimally worse 
CGI Improvement ratings were 40.00%, 15.00%, 20.00% and 12.5%, while the percentages on 
placebo were 20.00%, 27.50%, 32.50% and 12.50%, respectively.  Similar results were observed 
in evaluable population.  These data suggest that the subjects’ disease severity decreased and that 
they had greater improvement while on ecopipam. 
In the ITT population, the mean (±SD) DuPaul ADHD rating scale at baseline was 20.2 (±11.6) 
points prior to ecopipam and 22.1 (±11.3) points prior to placebo.  On Day 30, ADHD scores 
decreased 1.9 (±5.2) points on ecopipam and 2.7 (±6.6) points on placebo. ADHD scales were 
almost unchanged after ecopipam treatment.  Similar results were observed in evaluable 
population. 
In the ITT population, the mean (±SD) YBOCS total scores at baseline were 5.7 (±6.3) prior to 
ecopipam and 6.6 (±6.9) prior to placebo.  On Day 30 of the treatment period, YBOCS total 
scores decreased 0.8 (±3.3) points on ecopipam and 0.9(±4.1) points on placebo.  The results of 
obsession and compulsion subscales were similar to the total scores. 


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The safety population was the same as the ITT population. 
A total of 149 TEAEs were reported in 35 of the 40 treated subjects (87.50%).  There was one 
serious TEAE during placebo treatment and one TEAE resulting in dose withdrawn permanently 
during ecopipam treatment.  More patients on placebo had severe adverse events (7.5%) 
compared to ecopipam (5%).  No TEAE resulted in death.  There were 20 subjects (50%) 
reporting TEAEs related to study drug during ecopipam treatment and 10 subjects (25%) during 
placebo treatment.  Forty percent (40%) of TEAEs were mild and 37.50% were moderate.  
Subject 02-12 decreased the dosage due to fatigue at one day after starting ecopipam. Subject 06-
11 was discontinued from the study due to rash starting at Day 0 of the second treatment phase 
(ecopipam). 
The most common TEAEs during ecopipam treatment were headache (6 of 40), upper abdominal 
pain (4 of 40), nausea (4 of 40), vomiting (4 of 40), insomnia (4 of 40) and somnolence (4 of 40).  
The most common TEAEs during placebo treatment were nasopharyngitis (5 of 40), headache (5 
of 40), upper abdominal pain (4 of 40) and diarrhea (4 of 40).  The most common related TEAEs 
during ecopipam treatment were nausea (4 of 40) and somnolence (4 of 40).  The most common 
related TEAEs during placebo treatment were headache (3 of 40), somnolence (2 of 40) and 
initial insomnia (2 of 40). 
There was no evidence that administration of ecopipam affected weight, CDI scores, or C-SSRS 
in the subjects.  There were no clinically significant lab abnormalities, changes in vital signs, 
ECG, or physical exam findings after ecopipam administration. 
5.3. 
Risk-Benefit Assessment 
A consideration of the potential of risks that TS subjects may be exposed to, approaches to 
reducing any such risks, and the possible benefits that they may derive from their participation in 
EBS-101-CL-001 is outlined below.  
5.3.1. 
Assessment of Risk 
As 2651 human subjects have been exposed to single and multiple doses of ecopipam and safety 
data including collection of adverse events, physical examinations, laboratory tests, ECGs etc. 
have been systematically collected, there exists a fair body of information to base the 
understanding of potential risks and approaches to minimizing them in current and future studies.  
Of the 2651 human subjects that have been exposed to ecopipam, 540 adults have participated in 
studies to investigate the safety, tolerability, pharmacodynamics and pharmacokinetics of 
ecopipam after single and multiple dose administration.  Of the 2651 human subjects that have 
been exposed to ecopipam, a total of 2058 adult subjects have received treatment with ecopipam 
in therapeutic studies, including 1667 with obesity, 279 with cocaine addiction, 56 with 
schizophrenia, schizoaffective disorder and schizophreniform disorder, 28 with pathological 
gambling, 1 adult with LND, 18 adults with TS, 40 children/adolescents with TS and 9 adults 
with stuttering.  These have shown that ecopipam is generally well tolerated with the adverse 
events affecting primarily the CNS (e.g., sedation, insomnia, psychiatric changes such as 
depression, anxiety and suicidal ideation) and the gastrointestinal system (e.g., nausea and 
vomiting). 


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In subjects with TS, ecopipam has been evaluated in two studies, one study in adult subjects with 
TS and one study in children/adolescents with TS.  In the pediatric TS study, overall, adverse 
events were more common in ecopipam compared to placebo.  There were no serious adverse 
events (SAEs) and only one subject discontinued treatment due to an adverse event in the 
ecopipam group.  Most adverse events were mild to moderate in severity.  Adverse events in the 
Psychiatric Disorders, Central Nervous System Disorders and Gastrointestinal Disorders 
categories were more common with ecopipam than placebo.  Notably, more subjects experienced 
adverse events of somnolence, insomnia, sedation, restlessness, irritability, nausea and vomiting 
with ecopipam than with placebo.  There were no AEs of extra-pyramidal symptoms in the 
pediatric study.  A higher percentage of subjects on ecopipam gained 5 pounds or more during 
the study than with placebo (17.5% compared to 15%).  Orthostatic blood pressure assessments 
were not done (or not reported).  A table of weight changes was provided for the open-label 
extension study (PSY302A) and almost all of the children gained weight after 3, 6, 9 or 
12 months of treatment.  Suicidal ideation was seen both during the blinded study as well as the 
open-label extension study in pediatric subjects ecopipam.  There did not appear to be clinically 
significant ECG findings.  However, open-label extension adverse event data have not yet been 
analyzed.  
In the adult study in TS, the most commonly reported adverse events (incidence ≥20%) were 
sedation (33%), insomnia (33%), fatigue (33%), somnolence (28%), headache (22%), muscle 
twitching (22%) and anxiety (22%).  Two subjects developed adverse event of akathisia and one 
developed an adverse event of tremor, both of which are extrapyramidal reactions.  Three of 
18 subjects (16.7%) also discontinued study drug due to an adverse event. 
For the older obesity and cocaine dependence program, there were subjects who experienced 
adverse events of weight gain, suicidal ideation, diabetes, extrapyramidal reactions, somnolence, 
insomnia, hypotension and sexual side effects.  There was no raw data on orthostatic blood 
pressure.  In a table of all adverse events during the whole program, the adverse event of 
dyskinesia is listed but is not in any of the data tables.  When reviewing the large Phase 2 and 
Phase 3 studies in obesity and the other indications, the rate of tardive dyskinesia appears to be 
extremely low (or absent) and the rate of other extrapyramidal reactions (akathisia, tremor, etc.) 
appears at rates that are largely less than what is seen with D1/D2 antagonists.  Data for shifts in 
fasting glucose or lipids were not in the Investigator’s Brochure prepared by a previous sponsor 
and comments were made that there were no significant laboratory changes.  There did not 
appear to be a high rate of increased blood glucose or lipids in the adverse event tables for the 
other studies.  Additionally, data on orthostatic blood pressure changes were not documented but 
no adverse events of orthostatic hypotension were observed. 
5.3.2. 
Assessment of Benefit 
A review of the efficacy evaluations for ecopipam in the two studies conducted in subjects with 
TS reveals improvement on the YGTSS scores and other measures of illness severity from 
baseline to end point.  
In a Phase 2a, open-label, non-randomized study (PSY301), the activity and safety of ecopipam 
in 18 adult subjects with TS was evaluated. Subjects were to receive ecopipam HCl 50 mg for 
2 weeks followed by 100 mg for 6 weeks.  The primary outcome measure was the YGTSS Total 
(MP) score.  After ecopipam treatment, the YGTSS Total score, motor tics score, phonic tics 


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score and overall impairment decreased from baseline to endpoint, suggesting that the severity of 
tics was decreased (Table 16, Investigator’s Brochure).  
In a Phase 2b double-blind, randomized crossover study in children/adolescents (ages 7-17 
years) with TS (PSY302), 40 subjects were enrolled and 38 (95.0%) completed the study.  The 
primary endpoint was the YGTSS Total (MP) score.   
Ecopipam treatment resulted in a numerical decrease in the YGTSS Total score relative to the 
placebo treatment, but the decrease was not statistically significant (Figure 9, Investigator’s 
Brochure).  The least squares means (±SE) of the difference between ecopipam and placebo 
treatment were -2.8885 (±1.5282); 95% CI: -5.9822, 0.2053, p=0.0664) on Day 16 and -2.1366 
(±1.6551; 95% CI: -5.4871, 1.2139, p=0.2045) on Day 30.  
Based on the available safety data, there are some safety advantages for ecopipam compared to 
D2 antagonists, but the full measure of differentiation will not be known until after a larger and 
longer Phase 3 program.  The rate of tardive dyskinesia and other extrapyramidal reactions 
commonly associated with D2 antagonists appears much lower with ecopipam.  Other possible 
advantages include a decreased risk of lipid changes, hyperglycemia and orthostatic hypotension. 
An individual subject may not receive any therapeutic benefit from participating in an 
investigational study however, by contributing to medical research, others will be helped.  All 
subjects participating in the study will receive physical examinations, various laboratory tests, 
ECGs and a systematic evaluation of their condition. Ecopipam may help improve symptoms for 
participants.  
5.3.3. 
Methods to Minimize Risks 
The following steps are incorporated in the protocol to minimize risks to subjects:  
• Subjects will be screened for appropriateness to participate in the study. 
• All subjects will be evaluated for safety every two weeks while receiving study 
medication, with 4 evaluations conducted at the site and 2 via telephone assessments. 
• All subjects will be evaluated using the following scales to assess possible worsening 
of other psychiatric symptoms or other side effects: 
− Abnormal Involuntary Movements Scale 
− Barnes Akathisia Rating Scale 
− Caregiver Global Impression of Change 
− Columbia Suicide Severity Rating Scale 
− Children’s Depression Rating Scale 
− Children’s Yale-Brown Obsessive Compulsive Scale 
− Gilles de la Tourette Syndrome Quality of Life Scale 
− Pediatric Anxiety Scale 
− Swanson, Nolan and Pelham Questionnaire 


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In summary, ecopipam is a new chemical entity with a novel mechanism of action that has some 
evidence that it may be of therapeutic benefit to subjects with TS.  There is also evidence that it 
is likely to have lower side effect burden (for movement disorders, extra-pyramidal symptoms, 
tardive dyskinesia, etc., metabolic syndrome and elevated prolactin) than the currently used 
dopamine antagonists.  The protocol has processes to minimize potential risks from study 
medication that participants may be exposed to such that risks from the study balance the 
potential benefits. 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of ecopipam tablets in pediatric 
subjects (aged >6 to <18 years) with Tourette’s Syndrome (TS). 
6.2. 
Secondary Objectives 
The secondary objectives of this study are to evaluate the safety of ecopipam tablets in pediatric 
subjects (aged >6 to <18 years) with TS and characterize the pharmacokinetics (PK) of 
ecopipam. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2b 
study in pediatric subjects (aged >6 to <18 years) with TS.  Following a Screening period up to 
28 days and Baseline visit, eligible subjects will be randomized 1:1 to receive either a target 
steady-state dose of 2 mg/kg/day ecopipam HCl or matching placebo for a 4-week Titration 
period followed by an 8-week Treatment period.  Following titration, subjects who weigh ≥18 kg 
to <23 kg will receive a 37.5-mg active dose (or placebo), subjects who weigh >23 kg to <34 kg 
will receive a 50-mg active dose (or placebo), subjects who weigh >34 kg to <44 kg will receive 
a 75-mg active dose (or placebo), subjects who weigh >44 kg to <68 kg will receive a 100-mg 
active dose (or placebo), subjects who weigh >68 kg to <83 kg will receive a 150-mg active dose 
(or placebo), and subjects who weigh >83 kg will receive a 200-mg active dose (or placebo). 
After the Screening period, subjects will return to the clinic at Baseline and at 4, 6, 8, and 
12 weeks after Randomization.  Study visits at Weeks 4, 6, 8 and 12 after randomization may be 
completed in locations other than clinic and/or safety and efficacy assessments required at these 
visits will be made available for remote administration due to restrictions as a consequence of the 
COVID-19 pandemic or other qualifying event.  Subjects will have telephone visits on Weeks 2 
and 10 to assess adverse events and other safety parameters.  Efficacy assessments will be 
conducted at Weeks 4, 6, 8, and 12, and safety assessments will be conducted at all visits as well.  
A Follow Up visit will be conducted in the clinic 7 and 14 days after the last dose of study 
medication.  The follow up visits on Day 7 and 14 after the last dose of study medication may be 
completed in locations other than clinic and required assessments at these visits will be made 
available for remote administration due to restrictions as a consequence of the COVID-19 
pandemic or other qualifying event.  Subjects will also be contacted 30 days after the last dose of 
study medication to determine any adverse events.  At study completion or early termination, 
subjects will be tapered off study drug as outlined in the protocol.  
7.2. 
Number of Subjects 
One hundred and fifty subjects will participate in the study. 
7.3. 
Treatment Assignment 
Subjects will be randomized 1:1 to either ecopipam or matching placebo.  Randomization 
assignment will be stratified by weight. 
7.4. 
Dose Adjustment Criteria 
Doses will be titrated up to and down from the target dose based on the subject’s weight at 
Baseline according to the following weight bands to better achieve the targeted 2 mg/kg/day 
target dose: ≥18 to ≤23 kg, >23 to ≤34 kg, >34 to ≤44 kg, >44 to ≤68 kg, >68 to ≤83 kg, >83 kg.  
Those who cannot tolerate the target dose will be withdrawn from study.  Weight band 
assignments will not change during the duration of the study.  See Section 10.5 for direction on 
administration of study drug. 


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7.5. 
Criteria for Subject Study Discontinuation 
A subject may elect to discontinue from the study at any time for safety or personal reasons.  All 
subjects who discontinue from the study should complete the early study discontinuation 
procedures. 
Any subject with a new positive response on questions 4 and/or 5 of the Columbia Suicide 
Severity Rating Scale (C-SSRS) will be immediately discontinued and evaluated for risk.  
Dosing may be restarted at the discretion of the Investigator following consultation with the 
Sponsor or its designee. 
Subjects who discontinue early from the study will be evaluated for one of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, and 
administrative/other.  In addition to the primary reason, the subject may have indicated one or 
more of these reasons as secondary reasons for discontinuation.  Study disposition information 
will be collected on the CRF. 
Subjects who discontinue treatment for any reason, other than an SAE (even if the SAE is not 
treatment related) or an AE (unless the AE can be determined to be unrelated to treatment), may 
be replaced only after consultation with Sponsor or its designee. 
 


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Table 2: 
Schedule of Assessments 
Assessment 
Screeninga 
Baseline 
Titration 
Treatment 
Completion/ 
Early 
Termination 
7 Day  
Follow-up 
14 Day 
Follow-up 
30 day  
Follow-up* 
Study Week 
Up to -4 
0 
2* 
4g 
6g 
8g 
10* 
12g 
13/14g 
14/15g 
16/17 
Study Days 
Up to -28 
0 
14+3 
28+3 
42+3 
56+3 
70+3 
84+3 
7 Days  
Post Last 
Dose +3 
14 Days 
Post Last 
Dose +3 
30 Days  
Post Last 
Dose +3 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric/medicat
ion History  
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Exam/Vital Signsb 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
ECG 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Laboratory tests 
(Hematology and 
Chemistry)c 
X 
X 
 
 
 
 
 
X 
X 
X c 
 
Urine Drug Screen 
X 
X 
 
 
 
 
 
X 
 
 
 
Urine Pregnancy Test 
X 
X 
 
 
 
 
 
X 
 
X 
 
DSM-5 Criteria for TS 
X 
 
 
 
 
 
 
 
 
 
 
Yale Global Tic Severity 
Scale 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
Clinical Global Impression - 
Tourette’s Syndrome of 
Severity 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Clinical Global Impression - 
Tourette’s Syndrome of 
Improvement 
 
 
 
X 
X 
X 
 
X 
 
 
 


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Assessment 
Screeninga 
Baseline 
Titration 
Treatment 
Completion/ 
Early 
Termination 
7 Day  
Follow-up 
14 Day 
Follow-up 
30 day  
Follow-up* 
Study Week 
Up to -4 
0 
2* 
4g 
6g 
8g 
10* 
12g 
13/14g 
14/15g 
16/17 
Study Days 
Up to -28 
0 
14+3 
28+3 
42+3 
56+3 
70+3 
84+3 
7 Days  
Post Last 
Dose +3 
14 Days 
Post Last 
Dose +3 
30 Days  
Post Last 
Dose +3 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Caregiver Global 
Impression of Change 
 
 
 
X 
X 
X 
 
X 
 
 
 
Columbia Suicide Severity 
Rating Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abnormal Involuntary 
Movementd 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Barnes Akathisia Rating 
Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Swanson, Nolan, and 
Pelham Questionnaire 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Children’s Yale-Brown 
Obsessive Compulsive Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Children’s Depression 
Rating Scale - Revised 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Gilles de la Tourette 
Syndrome Quality of Life 
Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Pediatric Anxiety Scale 
 
X 
 
X 
X 
X 
 
X 
 
 
 
PK Blood Drawse,h 
 
 
 
X 
 
 
 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
Concomitant Medications 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Dispense Study Drug 
 
X 
 
X 
X 
X 
 
Xf 
 
 
 


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Assessment 
Screeninga 
Baseline 
Titration 
Treatment 
Completion/ 
Early 
Termination 
7 Day  
Follow-up 
14 Day 
Follow-up 
30 day  
Follow-up* 
Study Week 
Up to -4 
0 
2* 
4g 
6g 
8g 
10* 
12g 
13/14g 
14/15g 
16/17 
Study Days 
Up to -28 
0 
14+3 
28+3 
42+3 
56+3 
70+3 
84+3 
7 Days  
Post Last 
Dose +3 
14 Days 
Post Last 
Dose +3 
30 Days  
Post Last 
Dose +3 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Collect Unused Study 
Drug/Assess drug 
compliance 
 
 
 
X 
X 
X 
 
X 
X 
 
 
Abbreviations: AE = adverse event; BP = blood pressure; ECG = electrocardiogram; HR = heart rate; PK = pharmacokinetic(s) 
a 
Informed consent must be performed prior to any screening procedures.  All screening procedures are to occur after washout of any applicable medications.  
Rescreening is allowed after approval by the Medical Advisor.    
b 
Vital signs will include, pulse, BP, orthostatic BP (done 5 minutes after being supine and then 3 minutes after standing), height and weight. 
c 
Subjects should be in a fasting state (8 hours) for laboratory tests. HbA1c will be measured at the baseline and completion/early termination visits. 
d 
Every attempt should be made to perform this assessment at the same time at each visit. 
e 
At Week 4 Study dose should not be taken until after pre-dose blood draw at the site. PK draws should be pre-dose, between 0.5 and 1.5 hours after study 
drug administration, and between 2 and 4 hours after study drug administration. Both Week 4 and Week 12, visits should be scheduled for the morning. At 
Week 12, blood sample will be collected in the afternoon at the end of the visit.  
f 
Study drug will be dispensed for dose down titration. 
* Weeks 2 and 10 will be telephone visits. If there are any abnormal findings, the subject will be brought to the site for full assessment. A telephone call will be 
made to the subject 30 days after the last dose to assess any adverse events that may have occurred. 
g 
Assessments for these visits may be completed in locations other than study clinic and/or safety and efficacy assessments required at these visits will be made 
available for remote administration due to restrictions as a consequence of the COVID-19 pandemic or other qualifying event.  
h 
If visits at Weeks 4 and 12 are completed in locations other than study clinic due to restrictions as a consequence of the COVID-19 pandemic or other 
qualifying event, then collection of labs for PK assessments are optional 
 
 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Inclusion Criteria 
Individuals must meet all of the following criteria to be included in the study: 
1) Subject’s parent or legal guardian must sign a written informed consent.  
2) Subject must sign a written informed assent according to the requirements of the 
site’s IRB/EC.   
3) Subjects must be ≥6 to <18 years of age at time of screening. 
4) Subjects must weigh ≥18 kg (39.6 lbs). 
5) Subjects must have TS based on Diagnostic and Statistical Manual for Mental 
Disorders – 5th Edition (DSM-5 diagnostic criteria) for TS.  
6) Subjects must exhibit both motor and vocal tics that cause impairment with 
normal routines. 
7) Subjects must have a minimum score of 20 on the YGTSS-TTS at Screening and 
at Baseline visits with tic symptoms in the Investigator’s judgment causing: 
a. Subjective discomfort (e.g., pain or injury) 
b. Sustained social problems (e.g., social isolation or bullying) 
c. Social and emotional problems 
d. Functional interference (e.g., impairment of academic achievements) 
8) Subjects may not be taking any medications used to treat motor or vocal tics for at 
least 14 days prior to Baseline. 
9) Adolescent females of childbearing potential who are sexually active must be 
using highly effective contraception (i.e., oral contraceptives, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized 
male partner) and agree to continue use of highly effective contraception for the 
duration of their participation in the study. They must also agree to use highly 
effective contraception for 30 days after their last dose of study drug.  
10) Sexually active male subjects must use a highly effective method of contraception 
during the study and agree to continue the use of highly effective contraception 
for at least 30 days after the last dose of study drug. 
11) For subjects enrolled outside of the United States and Canada, the subject has 
received an adequate trial of non-pharmacological therapy without adequate 
response prior to study enrollment as documented by the Investigator. 
8.2. 
Exclusion Criteria 
Individuals meeting any of the following criteria at Screening or Baseline are ineligible to 
participate in the study: 
1) Subjects with any unstable primary mood disorder (DSM-5 criteria) at Screening. 


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2) Subjects who have unstable medical illness or clinically significant abnormalities 
on laboratory tests, or ECG at Screening as determined by the Principal 
Investigator.  
3) Subjects with a significant risk of committing suicide based on history, routine 
psychiatric status examination, investigator’s judgment, or who had an answer of 
“yes” on any question other than 1–3 (currently or within the past 30 days) on the 
baseline/screening version of the C-SSRS. 
4) Subjects with a clinical presentation at Screening and/or history consistent with 
another neurologic condition that may have had accompanying abnormal 
movements (e.g., Huntington’s disease, Parkinson’s disease, Wilson’s disease, 
stroke, Restless Legs Syndrome). 
5) Female subjects who are currently pregnant or lactating or planning to become 
pregnant during the course of the study.  
6) Subjects who have moderate to severe renal insufficiency at Screening. 
7) Subjects who have hepatic impairment at Screening. 
8) Subjects with current or recent (past 3 months) history of DSM-5 substance use 
disorder (with the exception of nicotine).  
9) Subjects with positive urine drug screen for cocaine, amphetamine, 
methamphetamine, benzodiazepines, barbiturates, phencyclidine (PCP) or opiates 
at Screening except those receiving stable, prescribed treatment for ADHD.  
10) Subjects with > 25% absolute change in YGTSS-TTS score between the 
Screening Visit and Baseline visit assessments. 
11) Subjects with a lifetime history of bipolar disorder type I or II, dementia, 
schizophrenia, or any other psychotic disorder.  
12) Subjects with a major depressive episode in the past 2 years. 
13) Subjects with a history of attempted suicide. 
14) Subjects with a history of seizures (excluding febrile seizures that occurred 
<2 years prior to Screening). 
15) Subjects with history of neuroleptic malignant syndrome. 
16) Subjects with a myocardial infarction within 6 months.  
17) Subjects who have had previous treatment with ecopipam. 
18) Subjects who have had previous treatment with:  
a. investigational medication within 1 month prior to Screening  
b. depot neuroleptics within 3 months prior to Screening  
c. oral neuroleptics within 4 weeks prior to Screening 
19) Subjects receiving anti-depressant, anti-anxiety or anti-ADHD medications unless 
the dosage has been stable for a minimum of 4 weeks prior to Screening and not 
prescribed to relieve the neurological symptoms related to TS. 
20) Subjects who have a need for medications which would have unfavorable 
interactions with ecopipam, e.g., dopamine antagonists or agonists [including 
bupropion], tetrabenazine, monoamine oxidase inhibitors, or St. John’s Wort.  
21) Initiation or changes in behavioral therapies for TS during the course of the study 
(i.e., Habit Reversal Training or Comprehensive Behavioral Intervention for Tics) 
as well as deep brain stimulation. 
22) Subjects who have initiated new behavior therapies fewer than 10 weeks prior to 
Baseline visit. 


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23) Subjects unable to swallow tablets. 
24) Subjects with a known hypersensitivity to ecopipam or any of its excipients. 
25) Any subject who in the opinion of the investigator is not a suitable candidate for 
the study. 
8.3. 
Subject Withdrawal, Removal, and Replacement Criteria 
Any subject with a CDRS-R assessment indicative of the onset of a new depressive episode at 
any visit can be discontinued from study participation at the discretion of the Investigator.  Any 
subject with a new positive response on questions 4 and/or 5 of the C-SSRS will be immediately 
discontinued and evaluated for risk.  Dosing may be restarted at the discretion of the Investigator 
following consultation with the Sponsor or its designee. 
The Investigator or subject may choose to stop study treatment at any time for safety or personal 
reasons. 
Where possible, a subject who discontinues treatment will undergo protocol-specified end-of 
study procedures at the time of discontinuation.  Date and reason(s) of premature discontinuation 
will be described in the CRF.  In addition, the date of last dose of study treatment will be 
recorded on the Study Treatment Dosing CRF.   
Subjects who discontinue treatment for any reason, other than an SAE (even if the SAE is not 
treatment related) or an AE (unless the AE can be determined to be unrelated to treatment), may 
be replaced only after consultation with Sponsor or its representative. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
Table 3: 
Investigational Product 
 
Investigational Product 
Product Name 
Ecopipam HCl 
Placebo 
Dosage Form 
Tablets 
Matching Tablets 
Unit Dose of Ecopipam HCl 
12.5, 50, 75 and 100 mg  
Matching unit dose tablets 
Route of Administration 
Oral 
Oral 
Physical Description 
Round, biconvex, light blue 
film-coated tablet, plain on 
both side 
Round, biconvex, light blue 
film-coated tablet, plain on 
both sides 
Manufacturer 
Corealis Pharma Inc 
Corealis Pharma Inc 
9.2. 
Concomitant Medications 
For subjects who receive study treatment, any medication (including over-the-counter 
medications) administered to the subject during the course of the study (starting at the date of 
informed consent) will be recorded on the Prior and Concomitant Medication CRF.  
Nonpharmacologic therapies/procedures will also be captured on the CRF.  The Investigator will 
record any AE on the Adverse Events CRF for which the concomitant medication was 
administered. 
9.3. 
Prohibited Therapies 
Since ecopipam and its metabolite (SCH40853) may inhibit CYP2D6, OATP1B1, PGP and 
UGT1A9, for any drug that is a substrate of these enzymes, the label for the drug should be 
consulted to decide if a dose adjustment is needed.  Drugs that are strong inducers of these 
enzymes are prohibited.  An illustrative list of such drugs is provided in the Prohibited 
Medications List in the Appendices.  
Prohibited therapies per the exclusion criteria (Section 8.2) include: 
• Previous treatment with ecopipam 
• Any investigational medication within 1 month prior to Screening 
• Depot neuroleptics within 3 months prior to Screening 
• Oral neuroleptics within 4 weeks prior to Screening 


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• Current use of anti-depressant, anti-anxiety or anti-ADHD medications unless the 
dosage has been stable for a minimum of 4 weeks prior to Screening and are not 
prescribed to relieve the neurological symptoms related to TS 
• Medications which would have unfavorable interactions with ecopipam, e.g., 
dopamine antagonists or agonists (including bupropion), tetrabenazine, monoamine 
oxidase inhibitors, or St. John’s Wort 
• Initiation or changes in behavioral therapies for TS during the course of the study 
(i.e., Habit Reversal Training or Comprehensive Behavioral Intervention for Tics) as 
well as deep brain stimulation 
• New behavior therapies to treat TS that were initiated fewer than 10 weeks prior to 
the Baseline visit 
9.4. 
Treatment Compliance 
During the study period, subject compliance will be monitored by review of the tablet counts at 
the study site visits.  Any violation of compliance will require evaluation by the Investigator and 
Sponsor or its representative to determine if the subject may continue the study. 
9.5. 
Randomization and Blinding 
Randomization will be stratified by weight band. Throughout the study, subjects and all 
personnel involved with the conduct and interpretation of the study, including the investigators, 
site personnel, and sponsor staff will be blinded to the treatment codes.  Randomization data will 
be kept strictly confidential, filed securely by an appropriate group with the Sponsor or CRO and 
accessible only to authorized persons (e.g., Safety) until the time of unblinding.  
A master list of all treatments and the subject numbers associated with them will be maintained 
electronically by the unblinded clinical supply vendor and the unblinded personnel at the CRO.  
The process to request a randomization code will be outlined in a separate document.  The site 
will be trained in this process and should only be used in an emergency.  These codes should 
only be broken only if knowledge of the subject’s randomization code will affect his/her medical 
treatment.  If necessary, the Investigator may consult with the sponsor before breaking the blind.  
The Investigator is to record the date and time of requesting the code and the reason for breaking 
the code.   


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Ecopipam tablets and matching placebo tablets. 
10.2. 
Study Drug Packaging and Labeling 
Study drug will be supplied in labeled containers by the Sponsor.  The product release 
certificates for ecopipam HCl will be included in the clinical study report for this protocol.  Any 
special storage conditions will be noted on the label and should be followed by the study site.  
The labels will be produced by PCI Pharma Services.  Minimally, the labels will contain the 
following information.  This will be adapted for any local laws and regulations:  
1. Name, address and telephone number of the Sponsor  
2. Pharmaceutical dosage form, route of administration, quantity of dosage units, identifier, 
and dose strength  
3. Lot number  
4. Protocol Number 
5. Study identifier 
6. Study subject identification number  
7. Directions of use  
8. “Caution:  New Drug - Limited by Federal (US) law to investigational use” (or equivalent 
for rest of world) 
9. Storage Conditions  
10. Expiration Date 
10.3. 
Study Drug Storage 
Study drug must be stored as instructed on the study drug label.  All relevant site-specific 
guidelines and country-specific labeling requirements must be followed.  Study drug must be 
kept in a secure location and carefully stored at the study site within its original container and 
protected from light.  A daily temperature log for monitoring of proper storage conditions must 
be maintained by the site. 
10.4. 
Study Drug Preparation 
Study drug will be prepared in 15-count bottles for ecopipam and matching placebo. 
10.5. 
Administration 
During the 4-week titration period, the following ecopipam HCl doses or matching placebo will 
be administered PO for each of the weight bands:  


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• Those who weigh ≥18-<23 kg will titrate from 12.5 mg daily to 37.5 mg daily: 12.5 mg 
during Week 1, 25 mg during Week 2, and 37.5 mg during Weeks 3 and 4. 
• Those who weigh >23-<34 kg will titrate from 12.5 mg daily to 50 mg daily: 12.5 mg 
during Week 1, 25 mg during Week 2, 37.5 mg during Week 3 and 50 mg during 
Week 4. 
• Those who weigh >34-<44 kg will titrate from 12.5 mg daily to 75 mg daily: 12.5 mg 
during week 1, 25 mg during week 2, 50 mg during Week 3 and 75 mg during Week 4. 
• Those who weigh >44-<68 kg will titrate from 25 mg daily to 100 mg daily: 25 mg 
during Week 1, 50 mg during Week 2, 75 mg during Week 3 and 100 mg during Week 4. 
• Those who weigh >68-<83 kg will titrate from 25 mg daily to 150 mg daily: 25 mg 
during Week 1, 50 mg during Week 2, 100 mg during Week 3 and 150 mg during 
Week 4. 
• Those who weigh >83 kg will titrate from 25 mg daily to 200 mg daily: 25 mg during 
Week 1, 50 mg during Week 2, 100 mg during Week 3, and 200 mg during Week 4. 
Subjects who do not tolerate the dose titration up to the full designated dose for their weight 
stratum will be discontinued from the study.  These subjects will also be tapered off their current 
dose of study drug according to their weight stratum. 
During the 8-week treatment phase, the following ecopipam HCl doses or matching placebo will 
be administered for each of the weight bands:  
• Those who weigh ≥18-≤23 kg will receive 37.5 mg daily. 
• Those who weigh >23-≤34 kg will receive 50 mg daily. 
• Those who weigh >34-≤44 kg will receive 75 mg daily. 
• Those who weigh >44-≤68 kg will receive 100 mg daily. 
• Those who weigh >68-≤83 kg will receive 150 mg daily. 
• Those who weigh >83 kg will receive 200 mg daily.  
All doses will be administered PO once daily in the evening.  Subjects who have changes in 
weight during the study will not have their doses adjusted for the duration of the study.  
At the end of the 8-week treatment phase, subjects will titrate off therapy and receive ecopipam 
HCl doses or matching placebo that will be reduced by 25 mg/day until off of study drug.  Signs 
of symptoms of withdrawal will be monitored. 
10.6. 
Dosing Rationale 
An ecopipam HCl dose of 2 mg/kg/day with titration is targeted in pediatric subjects aged >6 to 
<18 years using the dosage regimen proposed in Table 4.


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Table 4: 
Proposed Dosing Regimen 
Weight 
(kg) 
Dose (mg)  
Week #1 
Dose (mg)  
Week #2 
Dose (mg)  
Week #3  
Dose (mg)  
Week #4 onward 
>18 to ≤23 
12.5 
25 (2 × 12.5) 
37.5 (3 × 12.5) 
37.5 (3 × 12.5) 
>23 to ≤34 
12.5 
25 (2 × 12.5) 
37.5 (3 × 12.5) 
50 
>34 to ≤44 
12.5 
25 (2 × 12.5) 
50 
75 
>44 to ≤68 
25 (2 × 12.5) 
50 
75 
100 
>68 to ≤83 
25 (2 × 12.5) 
50 
100 
150 (2 × 75) 
>83 
25 (2 × 12.5) 
50 
100 
200 (2 × 100) 
This dosing regimen was chosen based on modeling and simulation with the results and 
important information summarized below: 
• A double-blind, placebo-controlled, crossover study of 40 subjects with TS aged 7 to 
17 years receiving ecopipam HCl at 50 mg (if <75 pounds) or 100 mg (if >75 pounds), 
after a titration, showed that it is likely that ecopipam has modest efficacy based on a 
post-hoc analysis (Study PSY302); 
• 2 mg/kg targets a mg/kg dose that is above the median mg/kg dose in 75% of subjects in 
Study PSY302, with the remaining 25% of subjects having a mg/kg dose that is 
substantially below the 95Pth
P percentile from Study PSY302; 
• The predicted plasma concentration-time curves for the median, 5Pth
P percentile and 95Pth
P 
percentile are within the exposures studied in PSY302 and similar to other proposed 
dosing regimens; 
• The animal:human ratios for the active moieties (unconjugated parent plus active 
metabolite, SCH40853) are adequate based on the no-observed-adverse-effects-level 
(NOAEL) in the 3-month GLP toxicology study for mice (30 mg/kg), the 3-month GLP 
toxicology study in rhesus monkeys at 12 mg/kg, and the 1-year GLP toxicology study in 
cynomolgus monkeys at 12 mg/kg and do not differ from those in Study PSY302 
(Table 5).  For rhesus and cynomolgus monkeys, the main toxicities observed at 
12 mg/kg were decreased activity, decreased appetite, and decreased defecation.  For 
cynomolgus monkeys, these AEs were reported during the first 1 to 3 weeks (hence, the 
need for titration in the proposed clinical study Protocol EBS-101-CL-001). 
• In Study PSY302, the treatment emergent adverse events (TEAEs) were gastrointestinal 
disorders (e.g., nausea, upper abdominal pain), general disorders and administrative site 
conditions (e.g., decreased appetite, fatigue), and nervous systems disorders (e.g., 
somnolence, headache, sedation).  The current study will incorporate a two-week titration 
which has the potential to improve tolerability.   
• While studying multiple dose levels is important in a Phase 2b study, a dose titration 
approach (instead of fixed 3-dose parallel design study) was chosen because the PSY302 
study suggested that doses lower than ∼1.4 mg/kg the 25Pth
P percentile would be unlikely to 
have substantial efficacy.  The exposure between ∼1.4 mg/kg and ∼2 mg/kg would have 
significant overlap in exposure (i.e., they would not be distinctly different doses), doses 
higher than ∼2 mg/kg may not be well tolerated, and doses higher than ∼2 mg/kg would 
result in animal:human exposures significantly lower than 1.   


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Table 5: 
Animal:Human Exposure Ratios with the Proposed Dosage Regimen of 
Ecopipam to 7- to 16-Year-Olds 
Week 
PK 
Mice: 
Human 
Ratiob,c 
Rhesus Monkey: 
Human Ratioc 
Cynomolgus Monkey: 
Human Ratioc 
 
 
30 mg/kg 
3 mg/kg  
12 mg/kg 
3 mg/kg 
12 mg/kg 
Combined AUCa (ng*hr/mL) 
1 
146 
17.2x 
2.1x 
5.9x 
2.1x 
10.6x 
2 
289 
8.7x 
1.1x 
3.0x 
1.1x 
5.3x 
Full Dose 
535 
4.7x 
0.6x 
1.6x 
0.6x 
2.9x 
Combined Cmaxa (ng/mL) 
1 
17.1 
16.9x 
1.4x 
3.4x 
1.5x 
8.7x 
2 
34.3 
8.4x 
0.7x 
1.7x 
0.8x 
4.3x 
Full Dose 
62.6 
4.6xPc 
0.4x 
0.92x 
0.4x 
2.4xPc 
a Animal: human ratios were calculated based on combined unconjugated parent ecopipam plus active metabolite 
SCH40853 AUC and Cmax. 
b The ratios for rats at 6 mg/kg are not included due to the fact that the assay sensitivity was not adequate 
(LLOQ=0.5 µg/mL), the AUC was determined with <3 data points, and there were too few concentrations above 
the LLOQ to determine the Cmax. 
c Ratios were calculated using the predicted exposure in PSY302.  These animal:human ratios did not differ in most 
cases for the full dose where the animal:human Cmax ratios differed by 0.1× where noted.   
10.7. 
Study Drug Accountability 
The Investigator (or pharmacist, as appropriate) must maintain records of the delivery of the 
study drug to the study site, the inventory at the site, use for each subject, and return of the study 
drug to a delegate of the Sponsor.  Total study site accountability will be conducted at the end of 
the study and the Investigator must explain all discrepancies.  
A Drug Dispensing Log must be kept current and should contain the following information:  
• Identification (subject number and initials or as allowed per local requirements) of 
subject to whom the study drug was dispensed 
• The dates and lot numbers for the study drug dispensed  
• Initial inventory on receipt of drug at the site  
• Final inventory on completion of the study  
All records and inventory must be available for inspection by the Clinical Research Associate 
(CRA).  


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Due to the COVID-19 pandemic, in some cases direct to patient shipments may be necessary.  In 
this case, study medication may be transported to the subject by a third party vendor who has 
systems in place to protect blinding, patient privacy, and data integrity.   
On close-out of the site, all used and unused investigational product must be shipped to the 
Emalex-designated location.  The Drug Dispensing Log must be available for monitoring, 
auditing, or inspection. 
10.8. 
Study Drug Handling and Disposal 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries from 
the sponsor are received by a responsible person (e.g., pharmacist), and that: 
• 
such deliveries are recorded; 
• 
study drug is handled and stored safely and properly; 
• 
study drug is only dispensed to study subjects in accordance with the protocol; 
• 
any unused study drug is returned to the sponsor or standard procedures for the alternative 
disposition of unused study drug are followed. 
 


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11. 
ASSESSMENT OF EFFICACY 
Assessments may be completed in locations other than study clinic and/or via remote 
administration due to restrictions as a consequence of the COVID-19 pandemic or other 
qualifying event. 
11.1. 
Primary Efficacy Assessment 
YGTSS will be assessed at Screening, Baseline and at Weeks 4, 6, 8 and 12.  
Change in the Yale Global Tic Severity Scale – Total Tic Score (TTS, i.e., sum of the motor and 
phonic tic scores) from baseline (YGTSS-TTS score from Baseline visit) to end of therapy 
(YGTSS-TTS score at Week 12).  
The YGTSS is a clinician-completed rating scale used to quantify overall tic severity as well as 
specific subdomains of tic number, frequency, duration, intensity, and complexity.  Each of 
these subdomains is scored, on a 5-point scale, separately for motor and vocal tics and then 
summed across both motor and vocal tics to yield a tic severity score ranging from 0 to 50.  
The YGTSS also provides for an overall impairment rating (0 = ‘‘none’’ to 50 = ‘‘severe’’).  
The YGTSS has demonstrated acceptable internal consistency, good interrater reliability, and 
acceptable convergent and divergent validity. 
11.2. 
Secondary Efficacy Assessments 
Key Secondary Efficacy Endpoint: 
• Change in Clinical Global Impression of Tourette Syndrome Severity (CGI-TS-S) from 
Baseline to Week 12 
Other Secondary efficacy endpoints include: 
• Change in Clinician Global Impression Tourette Syndrome of Improvement (CGI-TS-I) 
from Week 4 to Week 12 
• Change in YGTSS-Global Score (GS) from Baseline to Week 12 
• Change in Caregiver Global Impression of Change (CaGI-C) from Week 4 to Week 12 
• Change in Gilles de la Tourette Syndrome–Quality of Life Scale for Children and 
Adolescents (C&A-GTS-QOL) from Baseline to Week12 
• Percentage of subjects with a 25% improvement on the YGTSS-TTS 
• Percentage of subjects with complete remission of tics on the YGTSS-TTS 
• Change in YGTSS-TTS from Baseline to Weeks 4, 6, and 8  
• Change in CGI-TS-S from Baseline to Weeks 4, 6, and 8 
• Change in CGI-TS-I from Baseline to Weeks 4, 6, and 8 
• Change in YGTSS-GS from Baseline to Weeks 4, 6, and 8 
• Change in CaGI-C from Baseline to Weeks 4, 6, and 8 


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• Change in the C&A-GTS-QOL from Baseline to Weeks 4, 6, and 8 
Rank order of hierarchy of the secondary endpoints will be outlined in the statistical analysis 
plan. 
The CGI consists of two reliable and valid 7-item Likert scales used to assess severity and 
change in clinical symptoms.  The improvement scale will be used at every visit after the 
Screening and Baseline Visits.  The scale ranges from 1 = “very much improved” to 7 = very 
much worse.”  The CGI severity scale will be used at each study site visit and ranges from 
1 = “not ill at all” to 7 = “among the most extremely ill.” 
Gilles de la Tourette Syndrome–Quality of Life Scale for Children and Adolescents (C&A-GTS-
QOL) is a patient-reported health related quality of life measure developed for children and 
adolescents. 
11.3. 
Pharmacokinetics Parameters 
Blood samples will be collected to measure concentrations of ecopipam and/or its major (active) 
metabolites at Weeks 4 and 12.   
For the Week 4 visit, a morning appointment is suggested.  Parents/caregivers will be instructed 
not to administer the study medication to the subject on the evening prior to the Week 4 visit and 
to record the time of administration of the last dose of study medication taken.  The study drug 
administration will occur at the site on the day of the Week 4 visit under the supervision of the 
study investigator.  An intravenous catheter will be placed, and the subject will have samples 
collected at the following time windows:  one sample at pre-dose (34 to 44 hours since the last 
dose), one sample between 0.5 and 1.5 hour after administration of study medication, and one 
sample between 2 and 4 hours after study drug administration.  Any samples should be collected 
at least 30 min apart.   
For the Week 12 visit, parents/caregivers will be asked to record the time of study drug 
administration on the evening prior to the visit.  An appointment is suggested to be made for the 
morning of the Week 12 visit.  A blood sample will be collected at the end of the visit.  The time 
of sample collection will be recorded. Blood samples will be processed as outlined in the 
protocol and serum/plasma will be frozen, shipped and analyzed for ecopipam and SCH40853. 
If visits at Weeks 4 and 12 are completed in locations other than study clinic due to restrictions 
as a consequence of the COVID-19 pandemic or other qualifying event, then collection of labs 
for PK assessments are optional. 
 


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12. 
ASSESSMENT OF SAFETY 
Assessments may be completed in locations other than study clinic and/or via remote 
administration due to restrictions as a consequence of the COVID-19 pandemic or other 
qualifying event. 
12.1. 
Safety Parameters 
Safety will be assessed by monitoring and recording all adverse events (AEs) and SAEs (all 
visits), regular monitoring of hematology, blood chemistry and urine values (Screening, 
Baseline, Weeks 12, 7 and 14 day Follow-up visits).  HbA1c will be measured at the baseline 
and completion/early termination visits.  Regular measurement of vital signs, physical 
examination and an ECG (Screening, Baseline, Weeks 4, 6, 8, 12, 7 and 14 day Follow Up visit) 
will be performed.   
12.1.1. 
Columbia Suicide Severity Rating Scale 
An additional assessment will include the Columbia-Suicide Severity Rating Scale (C-SSRS) (all 
Visits except the 30-day Follow-up visit).  
The C-SSRS is a low burden (approximately 5 minutes for completion) instrument to assess both 
suicidal behavior and ideation.  The scale is appropriate for subjects from age 6 through to an 
elderly population.  
12.1.2. 
Other Safety Outcome Scales 
Additional safety outcomes (Baseline and Weeks 4, 6, 8 and 12) will include the following: 
Abnormal Involuntary Movement Scale (AIMS) records the occurrences of tardive dyskinesia 
(TD) in subjects receiving neuroleptic medications.  The test is used to detect TD and to follow 
the severity over time. 
Barnes Akathisia Rating Scale (BARS) scale to assess the severity of drug-induced akathisia.  
Objective and subjective items in the scale measure the level of subject’s restlessness. 
Swanson, Nolan and Pelham (SNAP-IV) questionnaire measure designed assess ADHD and 
oppositional defiant disorder (ODD) symptoms in children and adolescents. 
Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) is a reliable and valid scale to 
both determine severity of OCD and to monitor improvement during treatment.  The scale is a 
clinician-rated, 10-item scale that includes questions about the amount of spent on 
obsessions/compulsions, level of impairment or distress, and how much resistance and control 
subjects have over these thoughts. 
Children's Depression Rating Scale-Revised (CDRS-R) is a clinically validated rating scale 
designed to assess psychiatric signs and symptoms of depressions. 
Gilles de la Tourette Syndrome–Quality of Life Scale for Children and Adolescents (C&A-GTS-
QOL) is a subject-reported health related quality of life measure developed for children and 
adolescents. 


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Pediatric Anxiety Rating Scale (PARS) is a clinician-rated instrument for assessing the severity 
of anxiety symptoms associated with common anxiety disorders and generalized anxiety in 
children and adolescents. 
12.1.3. 
Other Safety Assessments 
Vital signs will be collected at each clinic visit (Screening, Baseline, Weeks 4, 6, 8, 12, 7 and 
14 day Follow Up visits).  It includes blood pressure, orthostatic blood pressure (after being 
supine for 5 minutes and 3 minutes after standing) pulse, height and weight. 
Clinical Laboratory Assessments: 
During the following clinic visit (Screening, Baseline, Week 12, 7-day and 14 day Follow Up 
visits), the following clinical laboratory tests will be performed.  HbA1c will be measured at the 
baseline and completion/early termination visits. 
 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Red blood cell count, hemoglobin, 
hematocrit, platelets, and white blood cell 
count with differential (neutrophils, bands 
lymphocytes, monocytes, eosinophils, 
basophils) 
Chemistry 
Electrolytes 
Sodium, potassium, chloride, bicarbonate 
Liver function tests 
Alkaline phosphatase, aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, 
direct bilirubin 
Renal function parameters 
Blood urea/blood urea nitrogen (BUN), 
creatinine 
Other 
Glucose, calcium, albumin, cholesterol, 
triglycerides, phosphorus, lactate 
dehydrogenase (LDH), total protein, 
globulin 
Pregnancy Test 
Urine test (for women of childbearing 
potential only) 
Special Parameters 
Hemoglobin A1c (HbA1c) 
 
Contraception Guidelines: 
As specified in the Inclusion Criteria (Section 8.1), adolescent females of childbearing potential 
who are sexually active and male subjects who are sexually active must use a highly effective 
form of contraception throughout the study and for 30 days after the last dose of study drug.  See 
the Contraception Guidelines for additional information. 


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Subjects must be monitored for signs of study drug abuse, and withdrawal or dependence and if 
detected must be recorded as AEs.  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered 
a study drug and 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 study drug, whether or not 
related to the study drug. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, 
physical exam) should be defined as an AE only if the abnormality meets one of the following 
criteria: 
• 
Induces clinical signs or symptoms 
• 
Requires active intervention 
• 
Requires interruption or discontinuation of study medication 
• 
The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
12.2.1.1. Adverse Event (AE) 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition including worsening of TS following or during exposure to a 
pharmaceutical product, whether or not considered casually related to the product.  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
baseline or washout periods, even if no study treatment has been administered. 
All AEs that occur after any subject has been screened, enrolled, before treatment, during 
treatment, or within 30 days following the cessation of treatment, whether or not they are related 
to the study, must be recorded on forms provided by Sponsor or its representatives. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during any study phase (i.e., baseline, treatment, 
washout, or follow-up), and at any dose of the investigational product, comparator or placebo, 
that fulfils one or more of the following: 
• Results in death 
• It is immediately life-threatening. 
• It requires in-subject hospitalization or prolongation of existing hospitalization. 
• It results in persistent or significant disability or incapacity. 
• Results in a congenital abnormality or birth defect 


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• It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
All SAEs that occur after any subject/subject has been enrolled, before treatment, during 
treatment, or within 30 days following the cessation of treatment, whether or not they are related 
to the study, must be recorded on forms provided by the Sponsor or its representatives. 
12.2.1.3. Other Adverse Event (OAE) 
OAEs will be identified by the Drug Safety Physician and if applicable also by the Clinical Study 
Team Physician during the evaluation of safety data for the Clinical Study Report.  Significant 
adverse events of particular clinical importance, other than SAEs and those AEs leading to 
discontinuation of the subject/subject from the study, will be classified as OAEs.  For each OAE, 
a narrative may be written and included in the Clinical Study Report.  Adverse events of special 
interest (AESI) include weight gain and extra-pyramidal reactions. 
12.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related or Probably Related).  The 
Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If no valid reason 
exists for suggesting a relationship, then the AE should be classified as “unrelated.”  If there is 
any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship 
between the investigational product and the occurrence of the AE, then the AE should be 
considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered related to the Investigational Product for 
the purposes of expedited regulatory reporting. 
12.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site.  Clinically significant changes in laboratory values, blood pressure, and 
pulse can be reported as AEs per the investigator’s judgement.  However, abnormal values that 
constitute an SAE or lead to discontinuation of administration of study drug must be reported 
and recorded as an AE.  Information about AEs will be collected from the signing of consent 
form until the end of the study.  SAE information will be collected from signing of consent form 
until 30 days following the last dose of study drug.  The AE term should be reported in standard 
medical terminology when possible.  For each AE, the investigator will evaluate and report the 
onset (date and time), resolution (date and time), intensity, causality, action taken, serious 
outcome (if applicable), and whether or not it caused the subject to discontinue the study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 


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• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2.  An AE of severe intensity 
may not be considered serious. 
Should a pregnancy of a subject or partner occur, it must be reported and recorded on Sponsor’s 
or Sponsor approved pregnancy form.  Pregnancy in itself is not regarded as an AE unless there 
is a suspicion that an investigational product may have interfered with the effectiveness of a 
contraceptive medication.  Reports of pregnancy must be submitted to Syneos Health Safety & 
Pharmacovigilance within one business day:  
Email Address: SafetyPV@syneoshealth.com  
Fax no. Americas: +1 866 856 1649 
Fax no. Europe and ROW +44 1628 461184 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages should 
also be reported and handled as SAEs.  Elective abortions without complications should not be 
handled as AEs. 
12.5. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from the signing of consent form until 30 days 
following the end of treatment exposure.  Any SAEs considered possibly or probably related to 
the investigational product and discovered by the Investigator at any time after the study should 
be reported.  All SAEs must be reported to Syneos Health Safety & Pharmacovigilance within 
1 business day of the first awareness of the event:   
Email Address: SafetyPV@syneoshealth.com  
Fax no. Americas: +1 866 856 1649 
Fax no. Europe and ROW +44 1628 461184 
The Investigator must complete, sign and date the SAE pages, verify the accuracy of the 
information recorded on the SAE pages with the corresponding source documents, and send a 
copy to the Sponsor or its representatives.   
Additional follow-up information, if required or available, should all be sent to the Sponsor or its 
representatives within one business day of receipt and this should be completed on a follow-up 
SAE form and placed with the original SAE information and kept with the appropriate section of 
the CRF and/or study file. 
The Sponsor and its representatives are responsible for notifying the relevant regulatory 
authorities of certain events.  It is the Principal Investigator’s responsibility to notify the IRB or 
IEC of all SAEs that occur at his or her site.  Investigators will also be notified of all unexpected, 
serious, drug-related events (7/15 Day Safety Reports) that occur during the clinical study.  Each 
site is responsible for notifying its IRB or IEC of these additional SAEs. 
 


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13. 
STATISTICS 
All data analyses will be performed by the Sponsor or its representatives after the study is 
completed and the database is finalized and released.  The statistical analyses described in this 
section will be performed using SAS 9.4.  All collected data will be listed.  Additional analyses 
may need to be conducted for data not collected at sites and/or via remote administration due to 
restrictions as a consequence of the COVID-19 pandemic or other qualifying event, details of 
these additional analyses will be specified in the SAP.  
13.1. 
Analysis Population  
The Modified Intention-to-Treat (mITT) population will include all randomized subjects who 
received at least one dose of study drug and have at least one post Baseline scoring of the 
YGTSS.  The mITT population will be used for the analysis of primary and secondary efficacy 
endpoints.   
The Per-Protocol (PP) population will include subjects from mITT population who have no 
major protocol deviations.  Before data are released for statistical analysis, a blinded review of 
all data will be performed by the Sponsor’s clinical team to identify protocol deviations that may 
potentially affect the results.  At this time, it will be determined if subjects and/or data should be 
excluded from the PP Population.  The list of subjects or observations to be excluded from the 
PP Population, along with the reason for exclusion, will be finalized prior to database 
unblinding.  Protocol deviations that occur due to COVID-19 related issues will be categorized 
separately as applicable.    
The Safety population will include all subjects who received at least one dose of study drug.  The 
safety population will be used for the analysis of the safety endpoints. 
The Pharmacokinetics (PK) population will include all subjects from safety population who have 
a valid concentration measurement.  
13.2. 
Planned Analysis 
13.2.1. 
Efficacy Analysis 
The primary efficacy endpoint for this study will be the change from Baseline (score of YGTSS-
TTS at Baseline) to end of therapy (score of YGTSS-TTS at Week 12).  The analysis of primary 
efficacy endpoint will be performed in mITT and PP populations according to the randomized 
treatment. 
The primary endpoint will be assessed with a Mixed Model for Repeated Measures (MMRM) 
model using (SAS MIXED procedure with REPEATED statement) with no imputation.  The 
model will include fixed effects for treatment, visit interaction between treatment and visit, 
center, and covariate for baseline YGTSS-TTS score.  If the sample size has been increased as a 
result of the interim analysis, the CHW (Cui-Hung-Wang) method will be used to control the 
type 1 error in the MMRM model.  Taking consideration of missing data, multiple imputation or 
tipping point method may be used as a sensitivity analysis.  
YGTSS-Global Score (YGTSS-GS), Clinical Global Impression of Tourette Syndrome Severity 
(CGI-TS-S), Clinical Global Impression of Tourette Syndrome Improvement (CGI-TS-I), 


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Caregiver Clinical Global Impression of Change (CaGI-C) and C&A-GTS-QOL will be 
analyzed using MMRM if appropriate.  The treatment difference at Week 4, 8 and 12 can be 
estimated based on MMRM. 
The percentage of subjects with a 25% improvement on the YGTSS-TS can be analyzed using 
Fisher Exact test.  
All secondary endpoints will be analyzed in the mITT population according to randomized 
treatment.  
All efficacy endpoints may also be summarized by treatment group.  The fixed-sequence 
statistical strategy will be used to test all efficacy endpoints in a predefined rank order hierarchy 
which will be outlined in the SAP. 
The full details and any sensitivity analyses will be specified in the SAP. 
13.2.2. 
Safety Analysis 
All safety data will be summarized in Safety population according to the actual treatment. 
Treatment-emergent adverse events (TEAEs) are defined as adverse events that are newly 
occurring or worsening after the first dose of study medication.  The incidence of TEAEs will be 
summarized by treatment group, by severity and by relationship to study medication.  Serious 
TEAEs and TEAEs leading to the study termination will be summarized by treatment group.  
Laboratory data, vital sign, physical examination and ECG will be summarized by treatment and 
visit. 
The Columbia-Suicide Severity Rating Scale (C-SSRS), Abnormal Involuntary Movement Scale 
(AIMS), the Barnes Akathisia Rating Scale, the Swanson, Nolan and Pelham (SNAP-IV) 
questionnaire, the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the 
Children's Depression Rating Scale-Revised (CDRS-R) and the Pediatric Anxiety Rating Scale 
(PARS) will also be summarized descriptively.  
13.2.3. 
Pharmacokinetics Analysis 
The pharmacokinetics concentrations of ecopipam and its major metabolites at Weeks 4 and 12 
will be summarized descriptively in the pharmacokinetics population.  
13.2.4. 
Data Safety Monitoring Board   
An independent data safety and monitoring board (DSMB) consisting of a physician experienced 
in the conduct of clinical studies (Chairman with TS experience), one clinician and one 
statistician experienced in TS will review the data at the interim analysis.  The data will be 
cleaned by the data management group, and the analysis and reporting of the interim data to the 
DSMB will be the responsibility of an independent statistical group (who will not be directly 
involved in the conduct of the study).  The DSMB will meet after the data presentation and issue 
recommendations relating to safety and study conduct; after the interim analysis, these 
recommendations may also include stopping the study for futility or increasing the sample size.  
The rationale for these recommendations will be documented in a set of minutes as to the safety 
and viability (i.e., conditional power) of the study to reach its goals at study completion.  The 


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minutes of the DSMB will be submitted to the sponsor after the study has been unblinded and 
will be appended to the final study report. 
13.2.5. 
Interim Analysis  
Interim analyses will be completed in coordination with the Data Safety Monitoring Board 
(DSMB) meetings to primarily assess safety and preliminary efficacy.  An interim analysis will 
be conducted after approximately 50% of subjects have enrolled and completed treatment or 
early termination procedures are completed.  These interim analyses will be performed by an 
independent statistician and governed by an external DSMB.  The DSMB will assess the safety 
data as well as the probability of a successful study based on observed data (conditional power).  
The DSMB could recommend stopping the study for futility.  The decision to stop the study will 
include evaluating the probability of successful study (conditional power), as well as safety data 
and other prespecified criteria to be described in the DSMB charter.  The DSMB can also 
recommend the continuation of the study as planned or with a sample size adjustment based on 
the conditional power.  If the sample size is adjusted, the CHW (Cui-Hung-Wang) method will 
be used to control the type 1 error in the final analysis. 
Full details of the DSMB procedures including primary responsibilities of the DSMB, its 
relationship with other study components, its membership, and the purpose and timings of its 
meetings will be documented in a DSMB charter.  These details will also include procedures to 
ensure confidentiality and proper communication, the guidelines to be implemented by the 
DSMB and an outline of the content of the closed reports (unblinded) and open reports (blinded) 
that will be provided to the DSMB.   
13.3. 
Sample Size Justifications  
A sample size of 75 subjects per group will provide >80% power to detect difference between 
groups of 3 points on change from baseline the Yale Global Tic Severity Scale-Total Tic Score 
(YGTSS-TTS), with standard deviation = 6.1 and alpha = 0.05, assuming 10% drop out. 


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14. 
 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The sponsor should ensure that it is specified in the protocol or other written agreement that the 
investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC review, and 
regulatory inspection(s) by providing direct access to source data/documents. 
14.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, the Sponsor or its representatives 
will visit the investigational study site to: 
• Determine the adequacy of the facilities. 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Emalex or its representatives.  This will be 
documented in a Clinical Study Agreement between Emalex and the investigator. 
During the study, a monitor from the Sponsor or its representatives will have regular contacts 
with the investigational site, for the following: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed. 
• Perform source data verification.  This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, and other 
records relevant to the study.  This will require direct access to all original records for 
each subject (e.g. clinic charts). 
• Record and report any protocol deviations not previously sent to Emalex. 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to the Sponsor or its representatives and those SAEs that met 
criteria for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Authorized representatives of the Sponsor or its representatives, a regulatory authority, an 
Independent Ethics Committee or an Institutional Review Board may visit the site to perform 
audits or inspections, including source data verification.  The purpose of an Emalex audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice guidelines of 
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The investigator should contact the Sponsor or its representatives immediately if contacted by a 
regulatory agency about an inspection. 
14.3. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) 
IRB/IEC approval for the investigation must be obtained prior to initial dosing of any subjects.  
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
subject consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
The Investigator shall make accurate and adequate written progress reports to the IRB/IEC at 
appropriate intervals, not exceeding one year.  The Investigator shall make an accurate and 
adequate final report to the IRB/IEC within 90 days after the close-out visit within one year after 
last subject out (LPO) or termination of the study. 
 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
the Sponsor or its designee may conduct a quality assurance audit.  Please see Section 14.2 for 
more details regarding the audit process. 
The Sponsor or its designee will implement and maintain quality assurance and quality control 
systems with written SOPs to ensure that studies are conducted, and data are generated, 
documented (record), and reported in compliance with the Protocol, GCP, and applicable 
regulatory requirement(s). 
 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Forms, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate.  The 
investigator must submit written approval to the Sponsor or its representatives before he or she 
can enroll any subject/subject into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the Protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all advertising 
and materials used to recruit and retain subjects for the study.  The protocol must be re-approved 
by the IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  The Sponsor or its designee will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (please see Appendix <insert #>) and are consistent with ICH/Good 
Clinical Practice, applicable regulatory requirements and the Sponsor’s policy on Bioethics. 
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study.  
Subjects must also be notified that they are free to discontinue from the study at any time.  The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
For subjects <18 years of age at Baseline, the parents’ or legal guardian’s signed and dated 
informed consent and the subject’s signed and dated assent form must be obtained before 
conducting any study procedures.  Subject assents will be administered according to the 
requirements of the site’s IRB/IEC. Subjects ≥18 years of age must execute a written informed 
consent.  
The Principal Investigator(s) must maintain the original, signed informed consent form and 
assent form.  A copy of the signed informed consent form and assent form must be given to the 
subject and his/her parents or legal guardian. 
16.4. 
Subject Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and disclosure 
to third parties other than those noted below is strictly prohibited.  Upon the subject’s 


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permission, medical information may be given to his or her personal physician or other 
appropriate medical personnel responsible for his or her medical welfare.  
The Sponsor will use the information obtained during the conduct of this study for the 
development of ecopipam.  The study Investigator is obliged to provide the Sponsor with 
complete test results and all data developed in this study, as described in this protocol. 
Monitors, auditors, and other authorized agents of the Sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and competent authority in each participating country, as 
well as that of any other applicable agency(ies), will be granted direct access to the 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. 
 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sponsor or its designee will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor to 
inspect the drug storage area, study drug stocks, drug accountability records, subject charts and 
study source documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of time after 
the last marketing application approval, or if not approved period of time following the 
discontinuance of the test article for investigation based on country and local regulations.  If it 
becomes necessary for Emalex or the Regulatory Authority to review any documentation relating 
to the study, the Investigator must permit access to such records. 
 


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18. 
PUBLICATION POLICY 
The Principle Investigator is obliged to provide the sponsor with complete data derived from the 
program.  During the program, only Emalex Biosciences may make information available to 
other participating physicians or to regulatory agencies, except as required by law or regulation.  
Except as otherwise allowable in the Clinical Site Agreement, any public disclosure (including 
publicly accessible websites) related to the protocol or program results, is the sole responsibility 
of Emalex Biosciences. 
Emalex Biosciences may publish any data and information from the program (including data and 
information generated by the physicians) without the consent of the treating physician.  
Manuscript authorship for any peer-reviewed publication will appropriately reflect contributions 
to the production and review of the document.  All publications and presentations must be 
prepared in accordance with this section and the Clinical Site Agreement.  In the event of any 
discrepancy between the protocol and the Clinical Site Agreement, the Clinical Site Agreement 
will prevail.  All scientific publications generated by Emalex Biosciences and its agents will be 
consistent with the principals outlined in Good Publication Practices. 
Data from all sites participating in the program will be pooled and analyzed by Emalex 
Biosciences or its designees.  The first publication of the results shall be made in conjunction 
with the results from other sites as a multicenter publication.  If a multicenter publication is not 
forthcoming within 24 months of completion of the program at all sites, the treating physician 
may publish or present the results generated at his or her site. 
The treating physician will provide Emalex Biosciences with a copy of any proposed publication 
or presentation for review and comment at least 60 days prior to such presentation or submission 
for publication.  Emalex Biosciences shall inform the investigator in writing of any changes or 
deletions in such presentation or publication required to protect Emalex Biosciences’ 
confidential and proprietary technical information and to address inaccurate data or inappropriate 
interpretations in the context of any pooled multicenter results.  At the expiration of such 60-day 
period, the physician may proceed with the presentation or submission for publication unless 
Emalex Biosciences has notified the institution or the physician in writing that such proposed 
publication or presentation discloses Emalex Biosciences’ confidential and proprietary technical 
information.  Further, upon the request of Emalex Biosciences, the physician will delay the 
publication or presentation for an additional 90 days to permit Emalex Biosciences to take 
necessary actions to protect its intellectual property interests. 
 


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19. 
LIST OF REFERENCES 
 
1. 
Leckman JF, Bloch MH, Scahill L, and King RA.  Tourette syndrome: The self under 
siege. J Child Neurol 2006;21:642-649. 
2. 
Gaze C, Kepley HO, and Walkup JT. Co-occurring psychiatric disorders in children and 
adolescents with Tourette’s syndrome. J Child Neurol 2006;21:657-664. 
3. 
Leckman JF. Phenomenology of tics and natural history of tic disorders. Brain Devel 
2003;25(S1):S24-S28. 
4. 
Keen-Kim D and Freimer NB. Genetics and epidemiology of Tourette syndrome. J Child 
Neurol 2006;21:665-671. 
5. 
Srour M, Lesperance P, Richer F, and Chouinard S. Pediatric psychopharmacology: 
psychopharmacology of tic disorders. J Can Aca Child Adolesc Psychiatry 2008;17:150-
159. 
6. 
Harris K and Singer HS. Tic disorders: Neural circuits, neurochemistry, and 
neuroimmunology. J Child Neurol 2006;21:678-689. 
7. 
Mink JW. Basal ganglia dysfunction in Tourette’s syndrome: A new hypothesis. Pediatr 
Neurol 2001;25:190-198. 
 


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20. 
REFERENCES FOR QUESTIONNAIRES AND SCALES 
 
1. Robertson, M.M., Banerjee, S., Kurlan, R., Cohen, D.J., Leckman, J.F., McMahon, W., 
Pauls, D.L., Sandor, P., van de Wetering, B.J.M. The Tourette Syndrome Diagnostic 
Confidence Index: Development and Clinical Associations.  Neurology Dec 1999, 53 (9) 
2108-2112. 
2.   Leckman JF, Riddle MA, Hardin MT, Ort SI, Swartz KL, Stevenson J, et al. The Yale 
Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am 
Acad Child Adolesc Psychiatry 1989;28(4):566-73 
3.   Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, 
Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77  
4.   First MB, Williams JBW, Karg RS, Spitzer RL: Structured Clinical Interview for DSM-
5 Disorders, Clinical Trials Version (SCID-5-CT). Arlington, VA, American Psychiatric 
Association, 2015 
5.   Leckman JF, Towbin KE, Ort SI, Cohen DJ. Clinical assessment of tic disorders severity. 
In: Cohen DJ, Bruun RD, Leckman JF, editors. Tourette’s Syndrome and Tic Disorders: 
Clinical Understanding and Treatment. New York: John Wiley & Sons; 1988 
6.   Guy, William (1976). "Clinical Global Impressions". ECDEU Assessment Manual for 
Psychopharmacology—Revised. Rockville, MD: U.S. Department of Health, Education, 
and Welfare; Public Health Service, Alcohol; Drug Abuse, and Mental Health 
Administration; National Institute of Mental Health; Psychopharmacology Research 
Branch; Division of Extramural Research Programs 
7.   Abnormal involuntary movement scale [AIMS] (1976). National Institute of Mental 
Health Psychopharmacology Research Branch. Guy, W. (1976). ECDEU assessment 
manual for psychopharmacology. Rev. Rockville, MD: U.S. National Institute of Health, 
Psychopharmacology Research Branch. Pg. 534-537 
8.   Barnes T.R. A rating scale for drug-induced akathisia.  British Journal of Psychiatry. 
1989;154:672-676. 
9.   Swanson JM, Kraemer HC, Hinshaw SP, Arnold LE, Conners CK, Abikoff HB, 
Clevenger W, Davies M, Elliott GR, Greenhill LL, Hechtman L, Hoza B, Jensen PS, 
March JS, Newcorn JH, Owens EB, Pelham WE, Schiller E, Severe JB, Simpson S, 
Vitiello B, Wells K, Wigal T, Wu M. Clinical relevance of the primary findings of the 
MTA: success rates based on severity of ADHD and ODD symptoms at the end of 
treatment. J Am Acad Child Adolesc Psychiatry. 2001;40(2):168-79 
10. Scahill L, Riddle MA, McSwiggin-Hardin M, Ort SI, King RA, Goodman WK, Cicchetti 
D, Leckman JF. Children's Yale-Brown Obsessive Compulsive Scale: reliability and 
validity. J Am Acad Child Adolesc Psychiatry. 1997 Jun;36(6):844-52  
11. Poznanski EO, Freeman LN, Mokros HB. Children's Depression Rating Scale Revised 
(September 1984). Psychopharmacol Bull 1985; 21:979-989. 


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12. Su M, McFarlane F, Cavanna A, et al. The English Version of the Gilles de la Tourette 
Syndrome–Quality of Life Scale for Children and Adolescents (C&A-GTS-QOL). J 
Child Neurol 2017;32(1):76-83. 
13. Research Units on Pediatric Psychopharmacology Anxiety Study Group. The Pediatric 
Anxiety Rating Scale (PARS): development and psychometric properties. J Am Acad 
Child Adolesc Psychiatry 2002;41;1061-9. 
 


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21. 
APPENDICES 
WMA DECLARATION OF HELSINKI – ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
be applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles. 
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my subject will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the subject’s best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights 
of subjects, including those who are involved in medical research. The physician’s knowledge 
and conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6.         The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility 
and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects must 


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always rest with the physician or other health care professionals and never with the research 
subjects, even though they have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement should 
reduce or eliminate any of the protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12.       Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on subjects 
or healthy volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14.       Physicians who combine medical research with medical care should involve their 
subjects in research only to the extent that this is justified by its potential preventive, diagnostic 
or therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the subjects who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits 
16.       In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by the 
condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18.       Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed. 


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When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20.       Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or 
interventions that result from the research. 
Scientific Requirements and Research Protocols 
21.       Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and adequate laboratory and, as appropriate, animal experimentation. The 
welfare of animals used for research must be respected. 
22.       The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This committee 
must be transparent in its functioning, must be independent of the researcher, the sponsor and 
any other undue influence and must be duly qualified. It must take into consideration the laws 
and regulations of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by the 


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committee. After the end of the study, the researchers must submit a final report to the committee 
containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24.       Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25.       Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
26.       In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits 
and potential risks of the study and the discomfort it may entail, post-study provisions and any 
other relevant aspects of the study. The potential subject must be informed of the right to refuse 
to participate in the study or to withdraw consent to participate at any time without reprisal. 
Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27.       When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the physician 
or may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for them 
unless it is intended to promote the health of the group represented by the potential subject, the 
research cannot instead be performed with persons capable of providing informed consent, and 
the research entails only minimal risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that 


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assent in addition to the consent of the legally authorised representative. The potential subject’s 
dissent should be respected. 
30.       Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious subjects, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. Consent 
to remain in the research must be obtained as soon as possible from the subject or a legally 
authorised representative. 
31.       The physician must fully inform the subject which aspects of their care are related to the 
research. The refusal of a subject to participate in a study or the subject’s decision to withdraw 
from the study must never adversely affect the subject-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 
consent for its collection, storage and/or reuse. There may be exceptional situations where 
consent would be impossible or impracticable to obtain for such research. In such situations the 
research may be done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention 
and the subjects who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a result of 
not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention identified 
as beneficial in the trial. This information must also be disclosed to participants during the 
informed consent process. 


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Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable for 
the completeness and accuracy of their reports. All parties should adhere to accepted guidelines 
for ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual subject, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the subject or a legally authorised representative, may use an unproven 
intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available 


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CONTRACEPTION GUIDELINES 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical studies include the use of highly effective forms of birth control.  
These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized male partner 
− Vasectomised partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the woman of childbearing potential study 
participant and that the vasectomised partner has received medical assessment of 
the surgical success. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of exposure associated with the study treatment). 
− In the context of this guidance, sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the subject. 
 
 
Adapted from: Clinical Trials Facilitation Group (CTFG).  Recommendations Related to Contraception and 
Pregnancy Testing in Clinical Trials. September 15, 2014. 
Available at: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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PROHIBITED MEDICATIONS LIST 
Examples below are not exclusive. 
• Any new stimulant for the treatment of ADHD that the subject was not taking at 
randomization is also prohibited. 
• Other medications used to treat TS are prohibited. 
• Dopamine depleting medications are prohibited. 
• D2 receptor antagonists prohibited.  
 
Prohibited Antipsychotic Medications 
Aripiprazole 
Loxapine 
Cisapride 
Methylphenidate 
Clonidine 
Paliperidone 
Dextroamphetamine 
Pimozide 
Dronedarone 
Risperidone 
Droperidol 
Thioridazine 
Fluoxetine 
Topiramate 
Guanfacine 
Ziprasidone 
Haloperidol 
 
 
Other Prohibited Medications 
for the Treatment of Tics 
Mechanism 
Any dopamine agonist (e.g., ropinirole, pramipexole) 
Baclofen 
GABA-B receptor agonist 
Clonazepam 
GABA-A receptor positive allosteric modulation 
Duetetrabenazine 
VMAT2 inhibitor / monoamine depleter 
Guanfacine 
Alpha-2A adrenergic receptor agonist 
Reserpine 
VMAT1/2 inhibitor / inhibits uptake of dopamine 
Tetrabenazine 
VMAT2 inhibitor / monoamine depleter 
Valbenazine 
VMAT2 inhibitor / monoamine depleter 


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Other Prohibited 
Medications  
Mechanism 
Chloroethylnorapomorphine 
D2 receptor antagonist 
Chlorpromazine 
D2 receptor antagonist/ antipsychotic  
Cinnarizine 
Antihistamine/ calcium channel blocker/ Interaction with D2 receptors 
Desmethoxyfallypride 
D2/D3 receptor antagonist used as PET radiotracer 
Domperidone 
D2/D3 receptor antagonist/ antiemetic 
Eticlopride 
D2 receptor antagonist 
Fallypride 
D2/D3 receptor antagonist used as PET radiotracer 
Hydroxyzine 
H1 receptor antagonist  
Itopride 
D2 receptor antagonist/used as treatment for GI disorders 
Metclopropramide 
D2 receptor antagonist/ antiemetic 
 
Strong Inducers of Drug Metabolism 
Apalutamide 
Strong inducer of drug metabolism 
Avasimibe 
Strong inducer of drug metabolism 
Carbamazepine 
Strong inducer of drug metabolism 
Enzalutamide 
Strong inducer of drug metabolism 
Ivosidenib 
Strong inducer of drug metabolism 
Lumacaftor 
Strong inducer of drug metabolism 
Mitotane 
Strong inducer of drug metabolism 
Phenobarbital 
Strong inducer of drug metabolism 
Phenytoin 
Strong inducer of drug metabolism 
Rifampin 
Strong inducer of drug metabolism 
Rifapentine 
Strong inducer of drug metabolism 
St John's Wort extract 
Strong inducer of drug metabolism 


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The dose of Sensitive CYP2D6 substrates that may need to be reduced 
(according to their respective labels) 
Atomoxetine 
Sensitive CYP2D6 substrate 
Codeine 
Sensitive CYP2D6 substrate 
Desipramine 
Sensitive CYP2D6 substrate 
Dextromethorphan 
Sensitive CYP2D6 substrate 
Deutetrabenazine 
Sensitive CYP2D6 substrate 
Doxepin 
Sensitive CYP2D6 substrate 
Eliglustat 
Sensitive CYP2D6 substrate 
Encainide 
Sensitive CYP2D6 substrate 
Enclomiphene 
Sensitive CYP2D6 substrate 
Ibogaine 
Sensitive CYP2D6 substrate 
Metoprolol 
Sensitive CYP2D6 substrate 
Methoxyphenamine 
Sensitive CYP2D6 substrate 
Nebivolol 
Sensitive CYP2D6 substrate 
Nicergoline 
Sensitive CYP2D6 substrate 
Paroxetine 
Sensitive CYP2D6 substrate 
Perhexiline 
Sensitive CYP2D6 substrate 
Perphenazine 
Sensitive CYP2D6 substrate 
Prajmaline 
Sensitive CYP2D6 substrate 
Propafenone 
Sensitive CYP2D6 substrate 
Repinotan (IV) 
Sensitive CYP2D6 substrate 
Risperidone 
Sensitive CYP2D6 substrate 
Tamoxifen 
Sensitive CYP2D6 substrate 
Tolperisone 
Sensitive CYP2D6 substrate 
Tolterodine 
Sensitive CYP2D6 substrate 
Tramadol  
Sensitive CYP2D6 substrate 
Traxoprodil 
Sensitive CYP2D6 substrate 
Trimipramine 
Sensitive CYP2D6 substrate 
Tropisetron 
Sensitive CYP2D6 substrate 
Venlafaxine 
Sensitive CYP2D6 substrate 
Vernakalant  
Sensitive CYP2D6 substrate 
 


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OATP1B1 substrates:  dose of these OATP1B1 substrates should be 
adjusted based on their label 
Bosentan 
OATP1B1 substrate 
Cerivastatin (acid) 
OATP1B1 substrate 
Clazosentan 
OATP1B1 substrate 
Danoprevir 
OATP1B1 substrate 
Eluxadoline 
OATP1B1 substrate 
Fimasartan 
OATP1B1 substrate 
Fluvastatin 
OATP1B1 substrate 
Glecaprevir 
OATP1B1 substrate 
Letermovir 
OATP1B1 substrate 
Pitavastatin (acid) 
OATP1B1 substrate 
Rosuvastatin (acid) 
OATP1B1 substrate 
Velpatasvir 
OATP1B1 substrate 
Voxilaprevir 
OATP1B1 substrate 
 
PGP substrates: dose of these PGP substrates should  be 
adjusted based on their respective labels 
Acalabrutinib 
PGP substrates 
Adafosbuvir (AL-335) 
PGP substrates 
Albendazole 
PGP substrates 
Aliskiren 
PGP substrates 
Alisporivir 
PGP substrates 
Ambrisentan 
PGP substrates 
Amd070 
PGP substrates 
Amenamevir 
PGP substrates 
Apixaban 
PGP substrates 
Asunaprevir 
PGP substrates 
Atecegatran metoxil 
PGP substrates 
Atorvastatin (acid) 
PGP substrates 
Avatrombopag 
PGP substrates 
Azithromycin 
PGP substrates 
Betrixaban 
PGP substrates 


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PGP substrates: dose of these PGP substrates should  be 
adjusted based on their respective labels 
Bictegravir 
PGP substrates 
Buprenorphine 
PGP substrates 
Celiprolol 
PGP substrates 
Cerivastatin (acid) 
PGP substrates 
Colchicine 
PGP substrates 
Copanlisib 
PGP substrates 
Cp-481,715 
PGP substrates 
Cyclosporine 
PGP substrates 
Dabigatran 
PGP substrates 
Danoprevir 
PGP substrates 
Deflazacort 
PGP substrates 
Dicloxacillin 
PGP substrates 
Digoxin 
PGP substrates 
Docetaxel 
PGP substrates 
Domperidone 
PGP substrates 
Doravirine 
PGP substrates 
Doxorubicin 
PGP substrates 
Edoxaban 
PGP substrates 
Elbasvir 
PGP substrates 
Emtricitabine 
PGP substrates 
Erlotinib 
PGP substrates 
Erythromycin 
PGP substrates 
Etoposide 
PGP substrates 
Everolimus 
PGP substrates 
Fentanyl 
PGP substrates 
Fexofenadine 
PGP substrates 
Glecaprevir 
PGP substrates 
Idarubicin 
PGP substrates 
Indinavir 
PGP substrates 
Irinotecan 
PGP substrates 
Itraconazole 
PGP substrates 


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PGP substrates: dose of these PGP substrates should  be 
adjusted based on their respective labels 
Ivosidenib 
PGP substrates 
Lapatinib 
PGP substrates 
Larotrectinib 
PGP substrates 
Ledipasvir 
PGP substrates 
Letermovir 
PGP substrates 
Linezolid 
PGP substrates 
Loperamide 
PGP substrates 
Losartan 
PGP substrates 
Maraviroc 
PGP substrates 
Maraviroc 
PGP substrates 
Mirabegron 
PGP substrates 
Mitoxantrone 
PGP substrates 
Morphine 
PGP substrates 
Nadolol 
PGP substrates 
Naldemedine 
PGP substrates 
Naloxegol 
PGP substrates 
Nevirapine 
PGP substrates 
Nintedanib 
PGP substrates 
Octreotide 
PGP substrates 
Olodaterol 
PGP substrates 
Paclitaxel 
PGP substrates 
Paritaprevir 
PGP substrates 
Paroxetine 
PGP substrates 
Pazopanib 
PGP substrates 
Phenytoin 
PGP substrates 
Pibrentasvir 
PGP substrates 
Pravastatin (acid) 
PGP substrates 
Proguanil 
PGP substrates 
Quetiapine 
PGP substrates 
Quinidine 
PGP substrates 
Ranitidine 
PGP substrates 


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PGP substrates: dose of these PGP substrates should  be 
adjusted based on their respective labels 
Ranolazine 
PGP substrates 
Rivaroxaban 
PGP substrates 
Rosuvastatin (acid) 
PGP substrates 
Saquinavir 
PGP substrates 
Selexipag 
PGP substrates 
Simeprevir 
PGP substrates 
Simvastatin (lactone) 
PGP substrates 
Sirolimus 
PGP substrates 
Sofosbuvir 
PGP substrates 
Sotrastaurin 
PGP substrates 
Tacrolimus 
PGP substrates 
Talinolol 
PGP substrates 
Tedisamil 
PGP substrates 
Teneligliptin 
PGP substrates 
Tenofovir 
PGP substrates 
Ticagrelor 
PGP substrates 
Velpatasvir 
PGP substrates 
Venetoclax 
PGP substrates 
Venlafaxine 
PGP substrates 
Verapamil 
PGP substrates 
Vinblastine 
PGP substrates 
Vincristine 
PGP substrates 
Voclosporin 
PGP substrates 
Ximelagatran 
PGP substrates 


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UGT1A1 substrates: dose of these UGT1A1 substrates should  be 
adjusted based on their respective labels 
Clopidogrel 
UGT1A9 substrate 
Furosemide 
UGT1A9 substrate 
Mycophenolic acid 
UGT1A9 substrate 
Probenecid 
UGT1A9 substrate 
Propofol 
UGT1A9 substrate 
 

SAP_001.pdf: 
 
 
 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1  of 4 8  
 
St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
 
 
 
S p o n s or N a m e: E m al e x Bi o s ci e n c e s, I n c.  
 
 
Pr ot o c ol N u m b er: E B S -1 0 1 -C L -0 0 1  
 
 
Pr ot o c ol Titl e:  
A M ulti c e nt er, Pl a c e b o -C o ntr oll e d, D o u bl e -Bli n d, R a n d o mi z e d, P ar all el -Gr o u p, P h a s e 2 b St u d y t o 
E v al u at e t h e Effi c a c y a n d S af et y of E c o pi p a m T a bl et s i n C hil dr e n a n d A d ol e s c e nt S u bj e ct s wit h 
T o ur ett e’ s S y n dr o m e  
 
 
Pr ot o c ol V er si o n a n d D at e: ( D D -M m m -Y Y Y Y):  
1. 0, 2 4 -D e c -2 0 1 8  
2. 0, A m e n d m e nt 1, 0 7 -F e b -2 0 1 9  
3. 0, A m e n d m e nt 2, 2 8 -F e b -2 0 1 9  
4. 0, A m e n d m e nt 3, 2 8- M a y -2 0 1 9  
5 . 0, A m e n d m e nt 4 , 25- O ct -2 0 1 9  
6 . 0, A m e n d m e nt 5 , 1 3 -A pr -2 0 2 0  
 
 
 
 
 
S y n e o s H e alt h Pr oj e ct C o d e: 7 0 0 1 7 3 6  
 
 
A ut h or: 
 
 
 
 
 
 
 
 
 
N oti c e of C o nfi d e nti al a n d Pr o pri et ar y I nf or m ati o n:  
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al b el o n gi n g t o E m al e x Bi o s ci e n c e s, I n c. 
A c c e pt a n c e of t hi s d o c u m e nt c o n stit ut e s a gr e e m e nt b y t h e r e ci pi e nt t h at n o i nf or m ati o n c o nt ai n e d h er ei n 
will b e p u bli s h e d or di s cl o s e d wit h o ut pri or writt e n a ut h ori z ati o n fr o m a n offi ci al of E m al e x Bi o s ci e n c e s, 
I n c.  H o w e v er, t hi s d o c u m e nt m a y b e di s cl o s e d t o a p pr o pri at e I n stit uti o n al R e vi e w B o ar d a n d Et hi c s 
C o m mitt e e s or d ul y a ut h ori z e d r e pr e s e nt ati v e s of a n ati o n al r e g ul at or y a ut h orit y u n d er t h e c o n diti o n t h at 
t h e y ar e r e q u e st e d t o k e e p it c o nfi d e nti al. I n t h e e v e nt of a n a ct u al or s u s p e ct e d br e a c h of t hi s o bli g ati o n, 
S y n e o s H e alt h s h o ul d b e n otifi e d pr o m ptl y.  
P P D
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2  of 4 8  
R e vi si o n Hi st or y  
V er si o n #  
D at e  
( D D-M m m -Y Y Y Y)  
D o c u m e nt O w n er  
R e vi si o n S u m m ar y  
1. 0  
2 6 -M a y -2 0 2 0  
 
Fi n al V er si o n 1. 0  
1. 1  
3- M a y -2 0 2 1  
 
U p d at e s b a s e d o n F D A 0 1 S e pt e m b er 2 0 2 0 c o m m e nt s 
a n d s p o n s or r e q u e st s . M aj or c h a n g e s i n cl u d e: cl e arl y 
d efi n e d t h e e sti m a n d of pri m ar y i nt er e st, pr o vi di n g d et ail s 
a b o ut s e n siti vit y a n al y s e s a n d a d di n g pr o gr a m mi n g 
c o d e s  t o t h e a p p e n di x. 
1. 2  
2 8 -M a y -2 0 2 1  
 
U p d at e s b a s e d o n s p o n s or c o m m e nt s  a n d a d diti o n al 
r e q u e st s. M aj or c h a n g e s i n cl u d e: a d di n g s u b gr o u p s  f or 
effi c a c y s u m m ari e s , pr o vi di n g ti p pi n g p oi nt a n al y si s a n d 
pr o gr a m mi n g c o d e, a d di n g d et ail s a b o ut A E s of s p e ci al 
i nt er e st a n d a d di n g A E b y s u b gr o u p a n d ti m e i nt er v al 
s u m m ari e s . 
2. 0  
J u n -2 0 2 1  
 
Cl e a n u p a n d fi n al v er si o n.  
3. 0 
S e p- 2 0 2 1  
 
U p d at e s b a s e d o n F D A r e s p o n s e. U p d at e s i n cl u d e e dit s 
t o t h e pri m ar y e sti m a n d a n d i nt er c urr e nt e v e nt s. 
 
P P D
P P D
P P D
P P D
P P D
C CI


P P D
P P D
P P D
P P D
P P D
P
P
D
P P D
P P D
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 4  of 4 8  
T a bl e of C o nt e nt s  
R e vi si o n Hi st or y  .......................................................................................................................... 2 
A p pr o v al s  .................................................................................................................................. 3 
 
Gl o s s ar y of A b br e vi at i o n s ................................................................................................... 7 
 
P ur p o s e  .............................................................................................................................. 9 
 
St u d y O bj e cti v e s  .............................................................................................................. 1 0  
 
E n d p oi nt s  ......................................................................................................................... 1 3  
 
A n al y si s S et s  .................................................................................................................... 1 5  
 
G e n er al A s p e ct s f or St ati sti c al A n al y si s  ........................................................................... 1 6  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 5  of 4 8  
 
D e m o gr a p hi c, Ot h er B a s eli n e C h ar a ct eri sti c s a n d M e di c ati o n  ......................................... 1 8  
 
Effi c a c y  ............................................................................................................................ 2 0  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D:
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 6  of 4 8  
 
A n al y si s of P h ar m a c o ki n eti c s  ........................................................................................... 2 8  
 S af et y  ............................................................................................................................... 2 9  
 I nt eri m A n al y s e s ............................................................................................................... 3 6  
 C h a n g e s fr o m A n al y si s Pl a n n e d i n Pr ot o c ol ..................................................................... 3 9  
 R ef er e n c e Li st  .................................................................................................................. 4 0  
 A p p e n di c e s  ...................................................................................................................... 4 2  
 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D:
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 7  of 4 8  
 
Gl o s s ar y of A b br e vi ati o n s  
A b br e vi ati o n  
D e s cri pti o n  
A D R  
A d v er s e D r u g R e a cti o n  
A E  
A d v er s e E v e nt  
A E SI  
A d v er s e E v e nt of S p e ci al I nt er e st  
AI M S   
 
A b n or m al I n v ol u nt ar y M o v e m e nt S c al e  
A T C  
A n at o mi c T h er a p e uti c Cl a s sifi c ati o n  
B A R S  
B ar n e s A k at hi si a R ati n g S c al e  
C & A -G T S -Q O L  
C hil d a n d A d ol e s c e nt Gill e s D e L a T o ur ett e S y n dr o m e -Q u alit y of Lif e 
S c al e  
C a GI - C 
C ar e gi v er Gl o b al I m pr e s si o n of C h a n g e  
C D R S - R 
C hil dr e n’ s D e pr e s si o n R ati n g S c al e -R e vi s e d  
C GI  
Cli ni c al Gl o b al I m pr e s si o n  
C GI -T S -I 
Cli ni c al Gl o b al I m pr e s si o n T o ur ett e’ s S y n dr o m e of I m p r o v e m e nt 
C GI -T S - S 
Cli ni c al Gl o b al I m pr e s si o n T o ur ett e’ s S y n dr o m e of S e v erit y  
C H W  
C ui -H u n g -W a n g  
C S R  
Cli ni c al St u d y R e p ort  
C T C  
C o m m o n T o xi cit y Crit eri a  
C T C A E  
C o m m o n T o xi cit y Crit eri a f or A d v er s e E v e nt s  
C Y -B O C S  
C hil d Y al e -Br o w n O b s e s si v e C o m p ul si v e S c al e  
D S M B  
D at a S af et y M o nit ori n g B o ar d  
E C G  
El e ctr o c ar di o gr a m  
e C R F  
El e ctr o ni c C a s e R e p ort F or m  
G C P  
G o o d Cli ni c al Pr a cti c e s  
G S  
Gl o b al s c or e  
H Cl  
H y dr o c hl ori d e  
H b A 1 c  
H e m o gl o bi n A 1 c  
I C H 
I nt er n ati o n al C o nf er e n c e o n H ar m o ni z ati o n  
M A R  
Mi s si n g at R a n d o m  
M N A R  
Mi s si n g N ot at R a n d o m  
M e d D R A  
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
mI T T  
M o difi e d I nt e nt t o Tr e at  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 8  of 4 8  
A b br e vi ati o n  
D e s cri pti o n  
N CI  
N ati o n al C a n c er I n stit ut e  
P A R S  
P e di atri c A n xi et y R ati n g S c al e  
P K  
P h ar m a c o ki n eti c s  
P O  
Or al ( p er o s)  
P P  
P er -Pr ot o c ol  
S A E  
s eri o u s a d v er s e e v e nt  
S A P  
St ati sti c al A n al y si s Pl a n  
S D  
st a n d ar d d e vi ati o n  
S N A P -I V 
S w a n s o n, N ol a n, a n d P el h a m q u e sti o n n air e  
S S  
S af et y S et  
T E A E  
Tr e at m e nt e m er g e nt a d v er s e e v e nt  
T S  
T o ur ett e’ s S y n dr o m e  
T T S  
T ot al Ti c S c or e  
Y G T S S -T T S  
Y al e Gl o b al Ti c S e v erit y S c al e -T ot al Ti c S c or e  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 9  of 4 8  
 
P ur p o s e  
T h e p ur p o s e of t hi s st ati sti c al a n al y si s pl a n ( S A P) i s t o e n s ur e t h at t h e d at a li sti n g s, s u m m ar y t a bl e s, a n d 
fi g ur e s  w hi c h  will  b e  pr o d u c e d,  a n d  t h e  st ati sti c al  m et h o d ol o gi e s  t h at  will  b e  u s e d,  ar e  c o m pl et e  a n d 
a p pr o pri at e t o all o w v ali d c o n cl u si o n s r e g ar di n g t h e st u d y o bj e cti v e s.  
 
R e s p o n si biliti e s  
S y n e o s H e alt h will p erf or m t h e st ati sti c al a n al y s e s a n d ar e r e s p o n si bl e f or t h e pr o d u cti o n a n d q u alit y c o ntr ol 
of all t a bl e s, fi g ur e s, a n d li sti n g s . 
 
Ti mi n g s of A n al y s e s  
T h e pri m ar y a n al y si s of s af et y a n d effi c a c y a n d/ or p h ar m a c o ki n eti c s i s pl a n n e d aft er all s u bj e ct s c o m pl et e 
t h e fi n al st u d y vi sit or t er mi n at e e arl y fr o m t h e st u d y. 
I nt eri m a n al y s e s will b e c o m pl et e d i n c o or di n ati o n wit h t h e D at a S af et y M o nit ori n g B o ar d ( D S M B) 
m e eti n g s t o pri m aril y a s s e s s s af et y a n d pr eli mi n ar y effi c a c y. A n i nt eri m a n al y si s will b e c o n d u ct e d aft er 
a p pr o xi m at el y 5 0 % of s u bj e ct s h a v e e nr oll e d a n d c o m pl et e d tr e at m e nt or e arl y t er mi n ati o n pr o c e d ur e s 
ar e c o m pl et e d. S e e S e cti o n 1 1 f or c o m pl et e d et ail s.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1 0  of 4 8  
 
St u d y O bj e cti v e s  
 
Pri m ar y O bj e cti v e  
T h e pri m ar y o bj e cti v e of t hi s st u d y i s t o e v al u at e t h e effi c a c y of e c o pi p a m t a bl et s i n p e di atri c s u bj e ct s 
( a g e d > 6 t o < 1 8 y e ar s) wit h T o ur ett e’ s S y n dr o m e ( T S).  
 
S e c o n d ar y O bj e cti v e( s)  
T h e s e c o n d ar y o bj e cti v e s of t hi s st u d y ar e t o e v al u at e t h e s af et y of e c o pi p a m t a bl et s i n p e di atri c s u bj e ct s 
( a g e d > 6 t o < 1 8 y e ar s) wit h T S a n d c h ar a ct eri z e t h e p h ar m a c o ki n eti c s ( P K) of e c o pi p a m.  
 
Bri ef D e s cri pti o n  
T hi s i s a m ulti c e nt er, pl a c e b o -c o ntr oll e d, d o u bl e -bli n d, r a n d o mi z e d, p ar all el -gr o u p, P h a s e 2 b st u d y i n 
p e di atri c s u bj e ct s ( a g e d > 6 t o < 1 8 y e ar s) wit h T S.  F oll o wi n g a S cr e e ni n g p eri o d u p t o 2 8 d a y s a n d 
B a s eli n e vi sit, eli gi bl e s u bj e ct s will b e r a n d o mi z e d 1: 1 t o r e c ei v e eit h er a t ar g et st e a d y -st at e d o s e of 2 
m g/ k g/ d a y e c o pi p a m H Cl or m at c hi n g pl a c e b o f or a 4 -w e e k Titr ati o n p eri o d f oll o w e d b y a n 8 -w e e k 
Tr e at m e nt p eri o d.  F oll o wi n g titr ati o n, s u bj e ct s w h o w ei g h ≥1 8 k g t o < 2 3 k g will r e c ei v e a 3 7. 5 -m g a cti v e 
d o s e ( or pl a c e b o), s u bj e ct s w h o w ei g h > 2 3 k g t o < 3 4 k g will r e c ei v e a 5 0 -m g a cti v e d o s e ( or pl a c e b o), 
s u bj e ct s w h o w ei g h > 3 4 k g t o < 4 4 k g will r e c ei v e a 7 5 -m g a cti v e d o s e ( or pl a c e b o), s u bj e ct s w h o w ei g h 
> 4 4 k g t o < 6 8 k g will r e c ei v e a 1 0 0 -m g a cti v e d o s e ( or pl a c e b o), s u bj e ct s w h o w ei g h > 6 8 k g t o < 8 3  k g will 
r e c ei v e a 1 5 0-m g a cti v e d o s e ( or pl a c e b o), a n d s u bj e ct s w h o w ei g h > 8 3 k g will r e c ei v e a 2 0 0 -m g a cti v e 
d o s e ( or pl a c e b o).  
Aft er t h e S cr e e ni n g p eri o d, s u bj e ct s will r et ur n t o t h e cli ni c at B a s eli n e a n d at 4, 6, 8, a n d 1 2  w e e k s aft er 
R a n d o mi z ati o n. S u bj e ct s will h a v e t el e p h o n e vi sit s o n W e e k s 2 a n d 1 0 t o a s s e s s a d v er s e e v e nt s a n d 
ot h er s af et y p ar a m et er s. Effi c a c y a s s e s s m e nt s will b e c o n d u ct e d at W e e k s 4, 6, 8, a n d 1 2 a n d s af et y 
a s s e s s m e nt s will b e c o n d u ct e d at all vi sit s a s w ell.  A F oll o w U p vi sit wi ll b e c o n d u ct e d i n t h e cli ni c 7 a n d 
1 4 d a y s aft er t h e l a st d o s e of st u d y m e di c ati o n. S u bj e ct s will al s o b e c o nt a ct e d 3 0 d a y s aft er t h e l a st 
d o s e of st u d y m e di c ati o n t o d et er mi n e a n y a d v er s e e v e nt s. At st u d y c o m pl eti o n or e arl y t er mi n ati o n, 
s u bj e ct s will b e  t a p er e d off st u d y dr u g a s o utli n e d i n t h e pr ot o c ol. 
 
S u bj e ct S el e cti o n  
 
I n cl u si o n Crit eri a 
S u bj e ct s eli gi bl e f or i n cl u si o n i n t hi s st u d y m u st f ulfill all of t h e crit eri a li st e d i n s e cti o n 8. 1 of t h e pr ot o c ol.  
 
E x cl u si o n Crit eri a  
S u bj e ct s will n ot b e eli gi bl e  if t h e y m e et a n y of t h e crit eri a li st e d i n s e cti o n 8. 2 of t h e pr ot o c ol. 
 
D et er mi n ati o n of S a m pl e Si z e  
A s a m pl e si z e of 7 5 s u bj e ct s p er gr o u p will pr o vi d e > 8 0 % p o w er t o d et e ct diff er e n c e b et w e e n gr o u p s of 3 
p oi nt s o n c h a n g e fr o m b a s eli n e t h e Y al e Gl o b al Ti c  S e v erit y S c al e -T ot al Ti c S c or e ( Y G T S S -T T S), wit h 
st a n d ar d d e vi ati o n = 6. 1 a n d al p h a = 0. 0 5, a s s u mi n g 1 0 % dr o p o ut.  
 
Tr e at m e nt A s si g n m e nt & Bli n di n g  
S u bj e ct s will b e r a n d o mi z e d 1: 1 t o eit h er e c o pi p a m or m at c hi n g pl a c e b o. R a n d o mi z ati o n will b e str atifi e d 
b y w ei g ht b a n d ( ≥1 8 t o ≤2 3 k g, > 2 3 t o ≤3 4 k g, > 3 4 t o ≤4 4 k g, > 4 4 t o ≤6 8 k g, > 6 8 t o ≤8 3 k g, > 8 3 k g). 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1 1  of 4 8  
T hr o u g h o ut t h e st u d y, s u bj e ct s a n d all p er s o n n el i n v ol v e d wit h t h e c o n d u ct a n d i nt er pr et ati o n of t h e 
st u d y, i n cl u di n g t h e s u bj e ct, p ar e nt s/ g u ar di a n s, i n v e sti g at or s, sit e p er s o n n el, a n d s p o n s or st aff will b e 
bli n d e d t o t h e tr e at m e nt c o d e s.  R a n d o mi z ati o n d at a will b e k e pt stri ctl y c o nfi d e nti al, fil e d s e c ur el y b y a n 
a p pr o pri at e gr o u p wit h t h e S p o n s or or S y n e o s a n d a c c e s si bl e o nl y t o a ut h ori z e d p er s o n s ( e. g., S af et y) 
u ntil t h e ti m e of u n bli n di n g.  
A m a st er li st of all tr e at m e nt s a n d t h e s u bj e ct n u m b er s a s s o ci at e d wit h t h e m will b e m ai nt ai n e d 
el e ctr o ni c all y b y t h e u n bli n d e d cli ni c al s u p pl y v e n d or a n d t h e u n bli n d e d p er s o n n el at S y n e o s. T h e 
pr o c e s s t o r e q u e st u n bli n di n g a n d t h e r a n d o mi z ati o n c o d e will b e o utli n e d i n a s e p ar at e d o c u m e nt. T h e 
sit e will b e tr ai n e d i n t hi s pr o c e s s a n d it s h o ul d b e u s e d o nl y i n a n e m er g e n c y. T h e s e c o d e s s h o ul d o nl y 
b e br o k e n if k n o wl e d g e of t h e s u bj e ct’ s r a n d o mi z ati o n c o d e will aff e ct hi s/ h er m e di c al tr e at m e nt.  If 
p o s si bl e, b ef or e br e a ki n g t h e bli n d, t h e I n v e sti g at or s h o ul d c o n s ult wit h t h e S p o n s or t o a s c ert ai n t h e 
n e c e s sit y of br e a ki n g t h e c o d e.  T h e I n v e sti g at or i s t o r e c or d t h e d at e a n d ti m e of r e q u e sti n g t h e c o d e 
a n d t h e r e a s o n f or br e a ki n g t h e c o d e.  
 
A d mi ni str ati o n of St u d y M e di c ati o n  
D uri n g t h e 4 -w e e k titr ati o n p eri o d, t h e f oll o wi n g e c o pi p a m H Cl d o s e s or m at c hi n g pl a c e b o will b e 
a d mi ni st er e d o r al ( p er o s) (P O ) f or e a c h of t h e w ei g ht b a n d s:  
•  
T h o s e w h o w ei g h ≥1 8 - <2 3 k g will titr at e fr o m 1 2. 5 m g d ail y t o 3 7. 5 m g d ail y: 1 2. 5 m g d uri n g 
W e e k 1, 2 5 m g d uri n g W e e k 2, a n d 3 7. 5 m g d uri n g W e e k s 3 a n d 4.  
•  
T h o s e w h o w ei g h > 2 3 - <3 4 k g will titr at e fr o m 1 2. 5 m g d ail y t o 5 0 m g d ail y: 1 2. 5 m g d uri n g W e e k 
1, 2 5 m g d uri n g W e e k 2, 3 7. 5 m g d uri n g W e e k 3 a n d 5 0 m g d uri n g W e e k  4.  
•  
T h o s e w h o w ei g h > 3 4 - <4 4 k g will titr at e fr o m 1 2. 5 m g d ail y t o 7 5 m g d ail y: 1 2. 5 m g d uri n g w e e k 
1, 2 5 m g d uri n g w e e k 2, 5 0 m g d uri n g W e e k 3 a n d 7 5 m g d uri n g W e e k 4.  
•  
T h o s e w h o w ei g h > 4 4 - <6 8 k g will titr at e fr o m 2 5 m g d ail y t o 1 0 0 m g d ail y: 2 5 m g d uri n g W e e k 1, 
5 0 m g d uri n g W e e k 2, 7 5 m g d uri n g W e e k 3 a n d 1 0 0 m g d uri n g W e e k 4.  
•  
T h o s e w h o w ei g h > 6 8 - <8 3 k g will titr at e fr o m 2 5 m g d ail y t o 1 5 0 m g d ail y: 2 5 m g d uri n g W e e k 1, 
5 0 m g d uri n g W e e k 2, 1 0 0 m g d uri n g W e e k 3 a n d 1 5 0 m g d uri n g W e e k  4.  
•  
T h o s e w h o w ei g h > 8 3 k g will titr at e fr o m 2 5 m g d ail y t o 2 0 0 m g d ail y: 2 5 m g d uri n g W e e k 1, 5 0 
m g d uri n g W e e k 2, 1 0 0 m g d uri n g W e e k 3, a n d 2 0 0 m g d uri n g W e e k 4.  
S u bj e ct s w h o d o n ot t ol er at e t h e d o s e titr ati o n u p t o t h e f ull d e si g n at e d d o s e f or t h eir  w ei g ht str at u m will 
b e di s c o nti n u e d fr o m t h e st u d y. T h e s e s u bj e ct s will al s o b e t a p er e d off t h eir c urr e nt d o s e of st u d y dr u g 
a c c or di n g t o t h eir w ei g ht str at u m.  
D uri n g t h e 8 -w e e k tr e at m e nt p h a s e, t h e f oll o wi n g e c o pi p a m H Cl d o s e s or m at c hi n g pl a c e b o will b e  
a d mi ni st er e d f or e a c h of t h e w ei g ht b a n d s:  
•  
T h o s e w h o w ei g h ≥1 8 -≤2 3 k g will r e c ei v e 3 7. 5 m g d ail y.  
•  
T h o s e w h o w ei g h > 2 3 -≤3 4 k g will r e c ei v e 5 0 m g d ail y.  
•  
T h o s e w h o w ei g h > 3 4 -≤4 4 k g will r e c ei v e 7 5 m g d ail y.  
•  
T h o s e w h o w ei g h > 4 4 -≤6 8 k g will r e c ei v e 1 0 0 m g d ai l y. 
•  
T h o s e w h o w ei g h > 6 8 -≤8 3 k g will r e c ei v e 1 5 0 m g d ail y.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1 2  of 4 8  
•  
T h o s e w h o w ei g h > 8 3 k g will r e c ei v e 2 0 0 m g d ail y.  
All d o s e s will b e a d mi ni st er e d P O o n c e d ail y i n t h e e v e ni n g. S u bj e ct s w h o h a v e c h a n g e s i n w ei g ht d uri n g 
t h e st u d y will n ot h a v e t h eir d o s e s a dj u st e d f or t h e d ur ati o n of t h e st u d y.  
At t h e e n d of t h e 8 -w e e k tr e at m e nt p h a s e, s u bj e ct s will titr at e off t h er a p y a n d r e c ei v e e c o pi p a m H Cl 
d o s e s or m at c hi n g pl a c e b o t h at will b e r e d u c e d b y 2 5 m g/ d a y u ntil off of st u d y dr u g. Si g n s of s y m pt o m s 
of wit h dr a w al will  b e m o nit or e d.  
 
St u d y Pr o c e d ur e s a n d Fl o w c h art  
Aft er t h e s cr e e ni n g p eri o d, s u bj e ct s will r et ur n t o t h e cli ni c at B a s eli n e a n d 4, 6, 8 a n d 1 2 w e e k s aft er 
R a n d o mi z ati o n. S u bj e ct s will h a v e t el e p h o n e vi sit s o n W e e k s 2 a n d 1 0 t o a s s e s s a d v er s e e v e nt s a n d 
ot h er s af et y p ar a m et er s. Effi c a c y a s s e s s m e nt s will b e c o n d u ct e d at w e e k s 4, 6, 8 a n d 1 2. S af et y 
a s s e s s m e nt s will b e c o n d u ct e d at t h e s e vi sit s a s w ell. A F oll o w U p vi sit will b e c o n d u ct e d i n t h e cli ni c 7 
a n d 1 4 d a y s aft er t h e l a st d o s e of st u d y m e di c ati o n. S u bj e ct s will al s o b e c o nt a ct e d 3 0 d a y s aft er t h e l a st 
d o s e of st u d y m e di c ati o n t o d et er mi n e a n y a d v er s e e v e nt s. At st u d y c o m pl eti o n or e arl y t er mi n ati o n, 
s u bj e ct s will b e t a p er e d off st u d y dr u g a s o utli n e d i n t h e pr ot o c ol.  S e e A p p e n di x s e cti o n 1 4. 1  f or t h e 
St u d y of A s s e s s m e nt s Fl o w c h art.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1 3  of 4 8  
 
E n d p oi nt s  
 
Pri m ar y Effi c a c y E n d p oi nt  
T h e pri m ar y effi c a c y e n d p oi nt i s t h e c h a n g e i n t h e Y al e Gl o b al Ti c S e v erit y S c al e – T ot al Ti c S c or e 
( Y G T S S-T T S, i. e., s u m of t h e m ot or a n d p h o ni c ti c s c or e s) fr o m b a s eli n e ( Y G T S S -T T S s c or e fr o m 
B a s eli n e vi sit) t o e n d of t h er a p y ( Y G T S S -T T S s c or e fr o m W e e k 1 2).  
 
Pri m ar y Effi c a c y E sti m a n d  
T h e m e a n c h a n g e  fr o m b a s eli n e i n t h e Y al e Gl o b al Ti c S e v erit y S c al e – T ot al Ti c S c or e t o e n d of t h er a p y  
ar e c o m p ar e d b et w e e n e c o pi p a m a n d pl a c e b o f or p ati e nt s a g e d 6 t o l e s s t h a n 1 8 y e ar s eli gi bl e f or t h e 
tri al. 
  
T h e pri m ar y e sti m a n d i s d efi n e d a s t h e f oll o wi n g:  
Tr e at m e nt: 4 -w e e k titr ati o n p eri o d f oll o w e d b y 8 -w e e k tr e at m e nt p h a s e wit h e c o pi p a m H CI d o s e s or 
m at c hi n g pl a c e b o . 
T ar g et P o p ul ati o n:  all c hil dr e n a n d a d ol e s c e nt p ati e nt s wit h T o ur ett e’ s s y n dr o m e w h o w er e r a n d o mi z e d, 
r e c ei v e d at l e a st o n e d o s e of st u d y dr u g, a n d h a d at l e a st o n e p o st B a s eli n e s c ori n g of t h e Y G T S S ( mI T T 
p o p ul ati o n).  
V ari a bl e: t h e c h a n g e i n t h e Y al e Gl o b al Ti c S e v erit y S c al e ( Y G T S S) fr o m b a s eli n e t o W e e k 1 2.  
I nt er c urr e nt e v e nt s: F or t h e int er c urr e nt e v e nt s , r e c ei vi n g pr o hi bit e d c o n c o mit a nt m e di c ati o n, c h a n ge i n 
d o si n g of all o w e d c o n c o mit a nt m e di c ati o n, a n d n o d o si n g a dj u st m e nt wit h B MI c h a n g e, th e tr e at m e nt 
p oli c y str at e g y will b e u s e d f or t h e pri m ar y a n al y si s, m e a ni n g  t h e o b s er v e d d at a at W e e k 1 2 will b e u s e d 
f or t h e c h a n g e fr o m b a s eli n e i n Y G T S S. F or t h e i nt er c urr e nt e v e nt of st u d y tr e at m e nt di s c o nti n u ati o n  d u e 
t o l a c k of effi c a c y a n d tr e at m e nt r el at e d a d v er s e e v e nt s, f or s u bj e ct s wit h n o Y G T S S at W e e k 1 2, t h e 
h y p ot h eti c al str at e g y  will b e u s e d , m e a ni n g  t h e n o n-c oll e ct e d d at a of Y G T S S at W e e k 1 2 will b e m ulti pl e 
i m p ut e d u si n g si mil ar s u bj e ct s (r el e v a nt d e m o gr a p hi c/ b a s eli n e c h ar a ct eri sti c s) fr o m t h e pl a c e b o ar m.  
T h e i nt er c urr e nt e v e nt ‘ d e at h pri or t o W e e k 1 2’ will b e h a n dl e d u si n g t h e ‘ w hil e ali v e a n d o n -tr e at m e nt 
str at e g y' u si n g t h e l a st o b s er v e d Y G T S S a s s e s s m e nt f or t h e a n al y si s of W e e k 1 2.  
P o p ul ati o n -l e v el s u m m ar y: tr e at m e nt diff er e n c e b et w e e n e c o pi p a m a n d pl a c e b o tr e at m e nt gr o u p s u si n g 
M M R M m o d el i n mI T T p o p ul ati o n aft er h a vi n g a p pli e d t h e h y p ot h eti c al str at e g y a n d t h e w hil e -o n -
tr e at m e nt str at e g y, r e s p e cti v el y, t o t h e n o n-c oll e ct e d / n o n -o b s er v e d W e e k 1 2 Y G T S S a s s e s s m e nt s  
s p e cifi e d a b o v e . 
T h e p ri m ar y effi c a c y a n al y si s a p pr o a c h i s i n li n e wit h t h e pri m ar y e sti m a n d. P ot e nti al c o nf o u n d er s will b e 
i d e ntifi e d a n d  s e n siti vit y a n d/ or s u p pl e m e nt ar y a n al y si s m a y b e u s e d t o d e al wit h mi s si n g d at a a n d 
a s s e s s t h e r o b u st n e s s of c o n cl u si o n s.  
 
S e c o n d ar y Effi c a c y E n d p oi nt s  
K e y S e c o n d ar y Effi c a c y E n d p oi nt:  
•  
C h a n g e i n Cli ni c al Gl o b al I m pr e s si o n of T o ur ett e S y n dr o m e S e v erit y ( C GI -T S -S) fr o m B a s eli n e 
t o W e e k 1 2 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1 4  of 4 8  
Ot h er S e c o n d ar y effi c a c y e n d p oi nt s i n cl u d e:  
•  
C h a n g e i n Cli ni ci a n Gl o b al I m pr e s si o n T o ur ett e S y n dr o m e of I m pr o v e m e nt ( C GI -T S -I) fr o m 
W e e k 4 t o W e e k 1 2  
•  
C h a n g e i n Y G T S S -Gl o b al S c or e ( G S) fr o m B a s eli n e t o W e e k 1 2  
•  
C h a n g e i n C ar e gi v er Gl o b al I m pr e s si o n of C h a n g e ( C a GI -C)  fr o m W e e k 4 t o W e e k 1 2  
•  
C h a n g e i n Gill e s d e l a T o ur ett e S y n dr o m e – Q u alit y of Lif e S c al e f or C hil dr e n a n d A d ol e s c e nt s 
( C & A-G T S -Q O L) fr o m B a s eli n e t o W e e k  1 2  
•  
P er c e nt a g e of s u bj e ct s wit h a 2 5 % , 5 0 %, a n d 7 5 % i m pr o v e m e nt o n t h e Y G T S S-T T S  
•  
P er c e nt a g e of s u bj e ct s wit h c o m pl et e r e mi s si o n of ti c s o n t h e Y G T S S -T T S  ( 1 0 0 % i m pr o v e m e nt) 
•  
C h a n g e i n Y G T S S -T T S fr o m B a s eli n e t o W e e k s 4, 6, a n d 8  
•  
C h a n g e i n C GI -T S -S fr o m B a s eli n e t o W e e k s 4, 6, a n d 8  
•  
C h a n g e i n C GI -T S -I fr o m B a s eli n e t o W e e k s 4, 6, a n d 8 
•  
C h a n g e i n Y G T S S -G S fr o m B a s eli n e t o W e e k s 4, 6, a n d 8  
•  
C h a n g e i n C a GI -C fr o m B a s eli n e t o W e e k s 4, 6, a n d 8 
•  
C h a n g e i n t h e C & A- G T S -Q O L fr o m B a s eli n e t o W e e k s 4, 6, a n d 8.  
 
E x pl or at or y E n d p oi nt s  
T o e v al u at e  t h e P K/ p h ar m a c o d y n a mi c r el ati o n s hi p b et w e e n pl a s m a l e v el s of e c o pi p a m a n d tr e at m e nt 
eff e ct if p o s si bl e. 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1 5  of 4 8  
 
A n al y si s S et s  
 
S cr e e n e d S et  
T h e S cr e e n e d S et will i n cl u d e all s u bj e ct s s cr e e n e d. U nl e s s s p e cifi e d ot h er wi s e, t hi s s et will b e u s e d f or 
s u bj e ct li sti n g s a n d f or s u m m ari e s of s u bj e ct di s p o siti o n.   
 
S af et y S et  
T h e S af et y S et  ( S S) will i n cl u d e all s u bj e ct s w h o r e c ei v e d at l e a st o n e d o s e of st u d y dr u g.  T h e S S  will b e 
u s e d f or t h e a n al y si s of t h e s af et y e n d p oi nt s.  
 
M o difi e d I nt e nt -t o-Tr e at  S et  
T h e M o difi e d I nt e nti o n -t o-Tr e at ( mI T T) s et  will i n cl u d e all r a n d o mi z e d s u bj e ct s w h o r e c ei v e d at l e a st o n e 
d o s e of st u d y dr u g a n d h a v e at l e a st o n e p o st B a s eli n e s c ori n g of t h e Y G T S S.  T h e mI T T s et  will b e u s e d 
f or  t h e  a n al y si s  of  pri m ar y  a n d  s e c o n d ar y  effi c a c y  e n d p oi nt s.   S u bj e ct s  will  b e  a n al y z e d  a c c or di n g  t o 
r a n d o mi z e d tr e at m e nt. 
 
P er Pr ot o c ol S et  
T h e P er -Pr ot o c ol ( P P) s et  will i n cl u d e s u bj e ct s fr o m mI T T s et  w h o h a v e n o m aj or pr ot o c ol d e vi ati o n s. 
B ef or e d at a ar e r el e a s e d f or st ati sti c al a n al y si s, a bli n d e d r e vi e w of all d at a will b e p erf or m e d b y t h e 
S p o n s or’ s cli ni c al t e a m t o i d e ntif y pr ot o c ol d e vi ati o n s t h at m a y p ot e nti all y aff e ct t h e r e s ult s.  At t hi s ti m e,  it 
will b e d et er mi n e d if s u bj e ct s a n d/ or d at a s h o ul d b e e x cl u d e d fr o m t h e P P s et .  T h e li st of s u bj e ct s or 
o b s er v ati o n s t o b e e x cl u d e d fr o m t h e P P s et , al o n g wit h t h e r e a s o n f or e x cl u si o n, will b e fi n ali z e d pri or t o 
d at a b a s e u n bli n di n g.  
 
P h ar m a c o ki n eti c S e t   
T h e  P h ar m a c o ki n eti c s  ( P K) s et  will  i n cl u d e  all  s u bj e ct s  fr o m  s af et y s et  w h o  h a v e  a  v ali d  c o n c e ntr ati o n 
m e a s ur e m e nt.  
 
Pr ot o c ol D e vi ati o n s  
Pr ot o c ol d e vi ati o n s will b e c oll e ct e d a n d c at e g ori z e d a s  s h o w n i n t h e pr ot o c ol d e vi ati o n a n d n o n -
c o m pli a n c e m a n a g e m e nt pl a n.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1 6  of 4 8  
 
G e n er al A s p e ct s f or St ati sti c al A n al y si s  
 
G e n er al M et h o d s  
All a n al y s e s a n d o ut p ut s will b e pr o d u c e d u si n g S A S ®  v er si o n 9. 4 or l at er. U nl e s s ot h er wi s e s p e cifi e d, 
effi c a c y a n d s af et y s u m m ari e s will b e pr e s e nt e d f or e a c h tr e at m e nt. All ot h er s u m m ari e s will b e pr e s e nt e d 
f or e a c h tr e at m e nt a n d o v er all. C o nti n u o u s v ari a bl e s will b e s u m m ari z e d u si n g t h e n u m b er of 
o b s er v a ti o n s ( n), m e a n, st a n d ar d d e vi ati o n ( S D), m e di a n, mi ni m u m, a n d m a xi m u m. C at e g ori c al v ari a bl e s 
will b e s u m m ari z e d u si n g n u m b er of o b s er v ati o n s ( n), fr e q u e n c y, a n d p er c e nt a g e s of s u bj e ct s . 
All r el e v a nt s u bj e ct d at a will b e i n cl u d e d i n li sti n g s. All r a n d o mi z e d s u bj e ct s e nt er e d i nt o t h e d at a b a s e will 
b e i n cl u d e d i n s u bj e ct d at a li sti n g s . All b y vi sit s u m m ari e s will u s e t h e n o mi n al vi sit. U n s c h e d ul e d vi sit s 
will n ot b e s u m m ari z e d b ut will b e i n cl u d e d i n t h e li sti n g s.  
 
K e y D efi niti o n s  
Tr e at m e nt e m er g e nt a d v er s e e v e nt s ( T E A E s) ar e d efi n e d a s a n y a d v er s e e v e nt s t h at st art or i n cr e a s e i n 
i nt e n sit y o n or aft er t h e fir st d o s e of D o u bl e-bli n d tr e at m e nt o n D a y 1.  
Ti mi n g s p e cifi c a d v er s e e v e nt s ar e d efi n e d a s a n y a d v er s e e v e nt s t h at o c c ur or i n cr e a s e i n i nt e n sit y 
d uri n g  a n y s p e cifi c all y d efi n e d st u d y mil e st o n e s: tr e at m e nt p h a s e ( T P A E), t a p er d o w n ( T D A E) a n d off 
st u d y dr u g ( O D A E).  
D ur ati o n of e x p o s ur e i s d efi n e d a s ( D at e of L a st D o s e – D at e of Fir st D o s e) + 1. If d at e of l a st d o s e i s 
u n k n o w n t h e n t h e d at e of l a st cli ni c al  vi sit will b e u s e d t o i m p ut e t h e d at e of l a st d o s e.  
B a s eli n e i s d efi n e d a s t h e l a st m e a s ur e m e nt t a k e n b ef or e t h e fir st d o s e of d o u bl e -bli n d tr e at m e nt o n D a y 
1.  
 
Mi s si n g D at a  
P arti al d at e s of m e di c ati o n s will b e i m p ut e d s ol el y f or t h e p ur p o s e of d efi ni n g pri or/ c o n c o mit a nt st at u s f or 
m e di c ati o n s.  D at e s will b e d efi n e d u si n g t h e hi er ar c h y of d eri v ati o n s b el o w.  
•  
F or mi s si n g st art d a y w h er e m o nt h a n d y e ar ar e pr e s e nt, t h e st art d a y will b e s et t o t h e 1 st of t h e 
m o nt h, u nl e s s t h e m o nt h a n d y e ar ar e t h e s a m e a s t h e fir st d o s e m o nt h a n d y e ar a n d t h e 1 st of 
t h e m o nt h i s b ef or e t h e fir st d o s e d at e, i n w hi c h c a s e, t h e st art d at e will b e s et t o t h e fir st d o s e d at e.  
•  
F or  mi s si n g  st art  d a y  a n d  m o nt h  w h er e  y e ar  i s  pr e s e nt,  t h e  st art  d a y  a n d  m o nt h  will  b e  s et  t o 
J a n u ar y 1 s t, u nl e s s t h e y e ar i s t h e s a m e a s t h e fir st d o s e y e ar a n d J a n u ar y 1 st i s b ef or e t h e fir st 
d o s e d at e, i n w hi c h c a s e, t h e st art d at e will b e s et t o t h e fir st d o s e d at e.  
•  
F or mi s si n g e n d d a y w h er e m o nt h a n d y e ar ar e pr e s e nt, t h e e n d d a y will b e s et t o t h e l a s t d a y of 
t h e m o nt h, u nl e s s t h e m o nt h a n d  y e ar ar e t h e s a m e a s t h e tri al  t er mi n ati o n m o nt h a n d  y e ar,  i n 
w hi c h c a s e, t h e e n d d at e will b e s et t o t h e tri al t er mi n ati o n d at e.  
•  
F or  mi s si n g  e n d  d a y  a n d  m o nt h,  w h er e  y e ar  i s  pr e s e nt,  t h e  e n d  d at e  will  b e  s et  t o  t h e  tri al 
t er mi n ati o n d at e if t h e y e ar s ar e t h e s a m e.  If t h e tri al t er mi n ati o n y e ar i s gr e at er t h a n t h e e n d y e ar, 
t h e e n d d a y a n d m o nt h will b e s et t o D e c e m b er 3 1 st. 
P arti al o n s et d at e s f or a d v er s e e v e nt s will b e i m p ut e d i n t h e s a m e m a n n er d e s cri b e d a b o v e f or p arti al st art 
d at e s f or t h e p ur p o s e of d efi ni n g tr e at m e nt e m er g e nt st at u s.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1 7  of 4 8  
 
Vi sit Wi n d o w s  
Vi sit wi n d o w will n ot b e u s e d i n t h e s u m m ari z ati o n or a n al y si s of d at a.  
 
P o oli n g of C e nt er s 
A n al y s e s will n ot i n cl u d e st u d y sit e a s a f a ct or i n t h e m o d el.  R e gi o n ( N ort h A m eri c a a n d E ur o p e) will b e 
i n cl u d e d, s o sit e s will n ot b e p o ol e d b a s e d o n t h e n u m b er of s u bj e ct s, b ut b y r e gi o n.   
 
S u b gr o u p s  
 S u b gr o u p s t o b e a n al y z e d f or Y G T S S, C GI -S a n d C GI -I, C a GI - C a n d C & A -G T S -Q O L a s b el o w:  
•  
B a s el i n e A g e Gr o u p ( 6-1 1 y e ar s, 1 2 -1 7  y e ar s)  
•  
R e gi o n: N ort h A m eri c a a n d E ur o p e  
•  
G e n d er: M al e a n d F e m al e  
•  
Pri or T S Tr e at m e nt: Y e s or N o  
•  
Y G T S S T T S B a s eli n e S c or e Gr o u p: > = m e a n, < m e a n  
•  
Y G T S S T T S B a s eli n e S c or e Gr o u p: > 2 S D fr o m m e a n , wit hi n 2 S D of m e a n 
•  
B o d y W ei g ht G r o u p: > 1 0 0 K g.  
 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1 8  of 4 8  
 
D e m o gr a p hi c, Ot h er B a s eli n e C h ar a ct eri sti c s a n d M e di c ati o n  
 
S u bj e ct Di s p o siti o n a n d Wit h dr a w al s  
S u bj e ct di s p o siti o n will b e pr e s e nt e d f or all s u bj e ct s, w hi c h i n cl u d e t h e f oll o wi n g:  
•  
N u m b er of s u bj e ct s e nr oll e d  
•  
N u m b er of s cr e e n e d a n d r e a s o n f or s cr e e n f ail ur e  
•  
N u m b er ( %) of s u bj e ct s r a n d o mi z e d  
A m o n g t h e r a n d o mi z e d s u bj e ct s, t h e f oll o wi n g will b e s u m m ari z e d  
•  
N u m b er ( %) of s u bj e ct s i n t h e S af et y S et   
 
•  
N u m b er ( %) of s u bj e ct s i n t h e M o difi e d I nt e nt -t o-Tr e at S et  
•  
N u m b er ( %) of s u bj e ct s i n t h e P er -Pr ot o c ol S et  
•  
N u m b er ( %) of s u bj e ct s w h o c o m pl et e d t h e st u d y 
•  
N u m b er ( %) of s u bj e ct s w h o di s c o nti n u e d st u d y pr e m at ur el y a n d t h eir r e a s o n  
A s e p ar at e b y -s u bj e ct li sti n g of s u bj e ct di s p o siti o n a n d wit h dr a w al will al s o b e pr o vi d e d. S u bj e ct s w h o 
s cr e e n f ail e d will b e li st e d al o n g wit h t h e d at e a n d r e a s o n f or t h e s cr e e n f ail ur e.  
R a n d o mi z e d s u bj e ct s n ot i n cl u d e d i n a n a n al y si s s et a n d t h eir r e a s o n f or e x cl u si o n will b e s u m m ari z e d 
a n d li st e d.  
 
D e m o gr a p hi c a n d Ot h er B a s eli n e C h ar a ct eri sti c s  
D e m o gr a p hi c s a n d ot h er b a s eli n e c h ar a ct eri sti c s will b e s u m m ari z e d f or t h e M o difi e d I nt e nt -t o-Tr e at S et 
b y r a n d o mi z e d tr e at m e nt a n d o v er all. S u m m ar y st ati sti c s a n d b y -s u bj e ct li sti n g s will b e pr o vi d e d.  
D e m o gr a p hi c s a n d b a s eli n e c h ar a ct eri sti c s will i n cl u d e a g e, s e x, et h ni cit y, r a c e, w ei g ht , h ei g ht, b o d y 
m a s s i n d e x ( B MI).  
A g e at St u d y d a y 1 = ( St u d y d a y 1 vi sit d at e - d at e of birt h + 1) / 3 6 5. 2 5 a n d tr u n c at e d t o c o m pl et e y e ar s.  
H ei g ht (i n c m) = h ei g ht (i n i n c h e s) * 2. 5 4  
W ei g ht (i n k g) = w ei g ht (i n l b s) * 0. 4 5 3 6  
B MI ( k g/ m 2 ) = W ei g ht( k g)/[ H ei g ht( m)2 ] 
 
M e di c al Hi st or y a n d C o n c o mit a nt Di s e a s e s  
A s u m m ar y t a bl e of t h e n u m b er a n d p er c e nt a g e of s u bj e ct s b y m e di c al hi st or y, s y st e m or g a n cl a s s ( S O C) 
a n d pr ef err e d t er m will b e pr o d u c e d fr o m t h e S af et y S et. M e di c al hi st or y will b e s ort e d al p h a b eti c all y b y 
S O C a n d i n d e s c e n di n g or d er of s u bj e ct s p er pr ef err e d t er m wit hi n e a c h S O C.  
M e di c al hi st or y will b e c o d e d u si n g t h e M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s ( M e d D R A) v er si o n 
2 2. 0 or hi g h er.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 1 9  of 4 8  
A s e p ar at e b y -s u bj e ct li sti n g of m e di c al hi st or y will al s o b e pr o vi d e d.  
 
M e di c ati o n  
All pri or a n d c o n c o mit a nt m e di c ati o n s will b e s u m m ari z e d b a s e d o n cl a s sifi c ati o n u si n g t h e A n at o mi c al 
T h er a p e uti c C h e mi c al ( A T C) cl a s sifi c ati o n a n d pr ef err e d dr u g n a m e fr o m t h e W orl d H e alt h Or g a ni z ati o n 
Dr u g Di cti o n ar y, v er si o n M ar 2 0 1 9, or l at er.  
A s e p ar at e b y -s u bj e ct li sti n g of m e di c ati o n s will al s o b e pr o vi d e d.  
 
Pri or M e di c ati o n  
Pri or m e di c ati o n s ar e d efi n e d a s m e di c ati o n s e nt er e d i n t h e e C R F t h at eit h er st art, or e n d b ef or e t h e fir st 
d o s e of st u d y m e di c ati o n. Pri or m e di c ati o n s will b e s u m m ari z e d b y A T C l e v el 2 a n d pr ef err e d dr u g n a m e 
f or t h e S af et y S et . 
Pri or m e di c ati o n s w hi c h c o nti n u e aft er fir st d o s e of st u d y m e di c ati o n will al s o b e cl a s sifi e d a s a 
c o n c o mit a nt m e di c ati o n.  
 
C o n c o mit a nt M e di c ati o n  
C o n c o mit a nt m e di c ati o n s ar e d efi n e d a s m e di c ati o n o n t h e e C R F t h at ar e t a k e n o n or aft er or ar e 
o n g oi n g at t h e st art d at e of d o si n g. C o n c o mit a nt m e di c ati o n s will b e s u m m ari z e d b y A T C l e v el 2 a n d 
pr ef err e d dr u g n a m e f or t h e S af et y S et . 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2 0  of 4 8  
 
Effi c a c y  
T h e mI T T s et  will b e u s e d f or t h e a n al y si s of t h e effi c a c y e n d p oi nt s . 
 
Pri m ar y Effi c a c y E n d p oi nt a n d A n al y si s  
 
Pri m ar y Effi c a c y A n al y si s  
T h e Y al e Gl o b al Ti c S e v erit y S c al e ( Y G T S S) i s a cli ni ci a n -c o m pl et e d r ati n g  s c al e u s e d t o q u a ntif y o v er all 
ti c s e v erit y a s w ell a s s p e cifi c s u b d o m ai n s of ti c n u m b er,  fr e q u e n c y, d ur ati o n, i nt e n sit y, a n d c o m pl e xit y. 
E a c h of t h e s e s u b d o m ai n s i s s c or e d, o n a 5 -p oi nt  s c al e, s e p ar at el y f or m ot or a n d v o c al ti c s a n d t h e n 
s u m m e d a cr o s s b ot h m ot or a n d v o c al ti c s t o  yi el d a t ot al ti c s c or e ( T T S) r a n gi n g fr o m 0 t o 5 0. T h e 
Y G T S S al s o pr o vi d e s f or a n o v er all  i m p air m e nt r ati n g ( 0 = ‘‘ n o n e’’ t o 5 0 = ‘‘ s e v er e’’). T h e Y G T S S h a s 
d e m o n str at e d a c c e pt a bl e  i nt er n al c o n si st e n c y, g o o d i nt err at er r eli a bilit y, a n d a c c e pt a bl e c o n v er g e nt a n d 
di v er g e nt v ali dit y.  
Y G T S S will b e a s s e s s e d at S cr e e ni n g, B a s eli n e a n d at W e e k s 4, 6, 8 a n d 1 2.   
T h e pri m ar y effi c a c y e n d p oi nt f or t hi s tri al will b e t h e c h a n g e fr o m B a s eli n e ( s c or e of Y G T S S -T T S {i. e., 
s u m of t h e m ot or a n d p h o ni c ti c s c or e s} at B a s eli n e) t o e n d of t h er a p y ( s c or e  of Y G T S S -T T S at W e e k 
1 2).  T h e a n al y si s of pri m ar y effi c a c y e n d p oi nt will u s e t h e  MI T T s et.   R e s ult s f or t h e P P s et will al s o b e 
pr o vi d e d.  
St ati sti c al a n al y si s : 
T h e pri m ar y e n d p oi nt will b e a n al y z e d  wit h a Mi x e d M o d el f or R e p e at e d M e a s ur e s ( M M R M) m o d el u s i n g 
t h e S A S MI X E D pr o c e d ur e wit h R E P E A T E D st at e m e nt. T h e m o d el will i n cl u d e fi x e d eff e ct s f or tr e at m e nt, 
vi sit, i nt er a cti o n b et w e e n tr e at m e nt a n d vi sit, r e gi o n, a g e gr o u p ( 0 = c hil dr e n 6 -1 1, 1 = a d ol e s c e nt s 1 2 -1 7 ) 
a n d c o v ari at e f or b a s eli n e Y G T S S -T T S.  
If t h er e i s n o s a m pl e si z e i n cr e a s e at t h e i nt eri m a n al y si s, t h e n a si n gl e M M R M b a s e d o n all t h e d at a will 
b e p erf or m e d. H o w e v er, if t h e s a m pl e si z e i s i n cr e a s e d fr o m t h e pl a n n e d ( 1 5 0)  t h e n t w o M M R M m o d el s 
will b e p erf or m e d a n d c o m bi n e d u si n g t h e  C H W ( C ui -H u n g -W a n g) m et h o d , w hi c h c o ntr ol s t h e t y p e 1 
err or , on e  M M R M m o d el  o n t h e d at a fr o m St a g e 1 (t h e i nt eri m a n al y si s d at a) a n d t h e s e c o n d o n d at a 
fr o m St a g e 2 ( p o st-i nt eri m d at a). I nf or m ati o n o n tr e at m e nt eff e ct fr o m t h e t w o st a g e s will b e c o m bi n e d i n 
t h e w eig ht e d t e st -st ati sti c : 
𝑇𝑇𝐶𝐶𝐶𝐶𝐶𝐶= �𝑛𝑛1
𝑁𝑁𝑇𝑇1 + �𝑛𝑛2
𝑁𝑁𝑇𝑇2  
T C H W  will b e c o m p ar e d t o a st a n d ar d G a u s si a n di stri b uti o n t o d et er mi n e t h e l e v el of st ati sti c al 
si g nifi c a n c e. H er e n 1  i s t h e a ct u al  n u m b er of s u bj e ct s i n St a g e 1 ( pl a n n e d  t o b e 7 5 s u bj e ct s ), n2  i s t h e 
pl a n n e d  n u m b er of St a g e 2 s u bj e ct s b ef or e a n y s a m pl e si z e i n cr e a s e ( i. e., 1 5 0 mi n u s t h e a ct u al n u m b er 
i n St a g e 1), N i s t h e s u m of n1  a n d n 2  (i. e., 1 5 0), a n d T 1  a n d T 2  ar e t h e t -st ati sti c s f or tr e at m e nt diff er e n c e 
fr o m M M R M m o d el s o n d at a fr o m, r e s p e cti v el y, St a g e 1 a n d St a g e 2 d at a. At a gi v e n st a g e, t h e m e a n 
diff er e n c e ∆𝑒𝑒−𝑝𝑝 (tr e at m e nt eff e ct of e c o pi p a m v er s u s pl a c e b o) c a n b e e sti m at e d b y t h e diff er e n c e  𝛿𝛿̂ 
= 𝐿𝐿𝐿𝐿𝐿𝐿𝑒𝑒−𝐿𝐿𝐿𝐿𝐿𝐿𝑝𝑝 i n l e a st s q u ar e s (L S ) m e a n s of c h a n g e fr o m b a s eli n e at W e e k 1 2  b et w e e n t h e e c o pi p a m 
a n d pl a c e b o  tr e at m e nt gr o u p s, r e s p e cti v el y. T h e L S M E A N S st at e m e nt wit h C O V o pti o n will r e p ort t h e 
e sti m at e d c o v ari a n c e of L S m e a n s, w hi c h c a n b e u s e d t o d eri v e t h e v ari a n c e 𝑣𝑣𝑣𝑣𝑣𝑣
� �𝛿𝛿̂� of t h e diff er e n c e 𝛿𝛿̂. 
T h e t-st ati sti c T 1  or T 2  c a n t h e n b e c al c ul at e d a s:  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2 1  of 4 8  
𝑇𝑇=
𝐶𝐶�
�𝐶𝐶𝐶𝐶𝑛𝑛
�
(𝑁𝑁�)
 
If t h e pl a n n e d s a m pl e si z e i s a dj u st e d a n d t h e C H W m et h o d u s e d t o a n al y z e t h e pri m ar y e n d p oi nt, t h e 
M M R M m o d el a n d s e n siti vit y a n al y s e s of t h e c o m pl et e d at a s et a s if t h e s a m pl e si z e h a d b e e n pl a n n e d 
fr o m t h e b e gi n ni n g will b e p erf or m e d t o pr o vi d e c o m pl e m e nt ar y i nt er pr et ati o n t o t h e C H W a n al y si s.  
 
S e n siti vit y A n al y si s  
T h e pri m ar y effi c a c y a n al y si s o n c h a n g e i n t h e Y G T S S -T T S  at w e e k 1 2 i s t o u s e M M R M m o d el u si n g all 
o b s er v e d d at a. T hi s m o d el i s a p pr o pri at e w h e n d at a i s mi s si n g at r a n d o m ( M A R). T o a s s e s s t h e 
r o b u st n e s s of t h e pri m ar y effi c a c y a n al y si s, t h e f oll o wi n g a d diti o n al s e n siti vit y a n al y s e s f or mi s si n g d at a 
will  b e  i n cl u d ed f or t h e mI T T s et : 
1.  Mi s si n g at R a n d o m ( M A R ) pr e di cti v e m e a n m at c hi n g m ulti pl e i m p ut ati o n m et h o d  
2.   Mi s si n g N ot at R a n d o m ( M N A R)  j u m p t o r ef er e n c e m ulti pl e i m p ut ati o n m et h o d 
3.  Ti p pi n g p oi nt u n d er M N A R a s s u m pti o n  
D et ail s of s e n siti vit y a n al y si s f or mi s si n g d at a a n d t h e st ati sti c al m o d el ar e e x pl ai n e d b el o w . 
8. 1. 2. 1.  
S e n siti vit y a n al y s e s f or mi s si n g d at a  
S e n siti vit y a n al y s e s f or mi s si n g d at a i n cl u d e s M A R pr e di cti v e m e a n m at c hi n g m ulti pl e i m p ut ati o n m et h o d, 
M N A R j u m p t o r ef er e n c e m ulti pl e i m p ut ati o n m et h o d , a n d M N A R ti p pi n g p oi nt a n al y si s. D et ail s f or t h e 
s e n siti vit y a n al y si s f or mi s si n g d at a ar e gi v e n b el o w:  
1)  M A R pr e di cti v e m e a n m at c hi n g m ulti pl e i m p ut ati o n m et h o d  
All mi s si n g d at a will b e i m p ut e d f or p ati e nt s mi s si n g d at a at w e e k 1 2 u si n g t h e pr e di cti v e m e a n m at c hi n g 
m ulti pl e i m p ut ati o n m et h o d (H eitj a n a n d Littl e 1 9 9 1 , S c h e n k er a n d T a yl or  1 9 9 6 ) f or a M A R d at a 
a s s u m pti o n u si n g f ull y c o n diti o n al s p e cifi c ati o n ( F C S) m et h o d. T h e i m p ut ati o n m o d el will i n cl u d e a g e 
gr o u p at b a s eli n e, r e gi o n, tr e at m e nt ar m, b a s eli n e Y G T S S -T T S , a n d Y G T S S -T T S  at all vi sit s u p t o w e e k 
1 2 w h er e t h e Y G T S S  i s s c h e d ul e d t o b e c oll e ct e d. T hi s i m p ut ati o n will b e p erf or m e d u si n g t h e S A S MI 
pr o c e d ur e wit h f c s s p e cifi c ati o n. T h e r e s ulti n g c o m pl et e, i m p ut e d d at a s et s will e a c h b e a n al y z e d u si n g 
t h e s a m e m o d el a s t h e pri m ar y a n al y si s m o d el, a n d t h e r e s ulti n g st ati sti c s c o m bi n e d u si n g m et h o d ol o g y 
pr o vi d e d b y R u bi n (1 9 8 7 ) a n d Littl e a n d R u bi n ( 2 0 0 2 ). T h e S A S c o d e  f or t h e m ulti pl e i m p ut ati o n 
m et h o d ol o g y  i s d et ail e d i n t h e A p p e n di x ( S e cti o n 1 4. 3).  
2)  M N A R j u m p t o r ef er e n c e  m ulti pl e i m p ut ati o n m et h o d 
D at a will b e i m p ut e d f or p ati e nt s mi s si n g d at a at w e e k 1 2 u si n g si mil ar pr e di cti v e m e a n m at c hi n g m ulti pl e 
i m p ut ati o n m et h o d.  U n d er a M N A R d at a a s s u m pti o n, p ati e nt s will h a v e t h eir mi s si n g d at a at w e e k 1 2 
i m p ut e d a s if t h e y b e h a v e d li k e pl a c e b o tr e at e d p ati e nt s aft er dr o p o ut. O nl y pl a c e b o p ati e nt s wit h 
c o m pl et e d at a will b e i n cl u d e d i n t h e i m p ut ati o n m o d el .  T h e i m p ut ati o n m o d el s will i n cl u d e a g e gr o u p at 
b a s eli n e, r e gi o n , b a s eli n e Y G T S S -T T S s c or e, a n d Y G T S S -T T S s c or e s at all vi sit s u p t o w e e k 1 2 w h er e 
t h e Y G T S S  i s  s c h e d ul e d t o b e c oll e ct e d. Aft er o bt ai ni n g c o m pl et e d at a s et s, t h e c o m pl et e d at a s et s will 
b e u s e d i n t h e a n al y si s.   T h e r e s ulti n g c o m pl et e, i m p ut e d d at a s et s will e a c h b e a n al y z e d u si n g t h e s a m e 
m o d el a s t h e pri m ar y a n al y si s m o d el, a n d t h e r e s ulti n g st ati sti c s c o m bi n e d u si n g m et h o d ol o g y pr o vi d e d 
b y R u bi n ( 1 9 8 7 ) a n d Littl e a n d R u bi n (2 0 0 2 ). T h e S A S c o d e  f or t h e m ulti pl e i m p ut ati o n m et h o d ol o g y i s 
d et ail e d i n t h e A p p e n di x ( S e cti o n  1 4. 4). 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2 2  of 4 8  
3)  Ti p pi n g p oi nt a n al y si s:  
I n t h e e v e nt t h at st ati sti c al si g nifi c a n c e i n f a v or of e c o pi p a m i s d et er mi n e d fr o m t h e pri m ar y a n al y si s, 
s u bj e ct s i n t h e e c o pi p a m gr o u p wit h a mi s si n g Y G T S S -T T S s c o r e ( c h a n g e fr o m b a s eli n e) will b e 
a s si g n e d s u c c e s si v el y m or e e xtr e m e v al u e s, w hil st s u bj e ct s i n t h e pl a c e b o gr o u p wit h a mi s si n g Y G T S S -
T S S s c or e ( c h a n g e fr o m b a s eli n e) will b e a s si g n e d s u c c e s si v el y l e s s e xtr e m e v al u e s, t o fi n d t h e p oi nt at 
w hi c h st ati sti c a l si g nifi c a n c e i s l o st (i. e. t h e 2-si d e d P -v al u e b e c o m e s gr e at er t h a n 0. 0 5)  
D et ail s f or ti p pi n g p oi nt a n al y si s ar e d e s cri b e d b el o w:  
a.  F or p ati e nt s t h at c o m pl et e d t h e st u d y, i nt er mitt e nt mi s si n g d at a ar e c o n si d er e d a s M A R a n d will 
b e i m p ut e d b y pr e di cti v e m e a n m at c hi n g m ulti pl e i m p ut ati o n m et h o d (H eitj a n a n d Littl e 
1 9 9 1 , S c h e n k er a n d T a yl or  1 9 9 6 ). T h e i m p ut ati o n m o d el will i n cl u d e a g e gr o u p at b a s eli n e, 
r e gi o n, tr e at m e nt ar m, b a s eli n e T T S s c or e, a n d T T S s c or e s at all vi sit s u p t o t h e i m p ut e d vi sit 
w h er e t h e T T S i s s c h e d ul e d t o b e c oll e ct e d.  
b.  F or p ati e nt s w h o di s c o nti n u e d d u e t o a n y r e a s o n, all  mi s si n g d at a will b e i m p ut e d u si n g t h e s a m e 
pr e di cti v e m e a n m at c hi n g m ulti pl e i m p ut ati o n m et h o d. T h e i m p ut e d v al u e s will b e a dj u st e d u n d er 
M N A R a s s u m pti o n:  
o  
P ati e nt s r a n d o mi z e d t o e c o pi p a m : t h e fir st mi s si n g v al u e aft er p ati e nt s dr o p o ut will b e 
a n al y z e d a s s u mi n g t h e u n o b s er v e d o ut c o m e i s o n a v er a g e w or s e n e d b y  δ 1 ( w h er e δ 1 = 
1 t o 1 0  or e sti m at e d tr e at m e nt eff e ct, w hi c h e v er i s hi g h er, i n st e p of 1) c o m p ar e d t o t h e 
p ati e nt s w h o h a v e n o mi s si n g v al u e;  
o  
P ati e nt s tr e at e d b y pl a c e b o: t h e fir st mi s si n g v al u e aft er p ati e nt s dr o p o ut will b e a n al y z e d 
a s s u mi n g t h e u n o b s er v e d o ut c o m e i s o n a v er a g e  b ett er b y δ 2 ( w h er e δ 2 =  1 t o 1 0  or 
e sti m at e d tr e at m e nt eff e ct, w hi c h e v er i s hi g h er, i n st e p of 1) c o m p ar e d t o t h e p ati e nt s 
w h o h a v e n o mi s si n g v al u e;  
T h e p e n alt y or r e w ar d will n ot b e a p pli e d t o t h e v al u e s fr o m l at er ti m e p oi nt s a s t h e s e v al u e s ar e 
p e n ali z e d or r e w ar d e d t hr o u g h c o n diti o n o n pr e vi o u s ti m e p oi nt s.  F or e a c h c o m bi n ati o n of ( δ 1, 
δ 2), 1 0 0 i m p ut e d d at a s et s will b e o bt ai n e d.  
c.  T h e r e s ulti n g c o m pl et e, i m p ut e d d at a s et s will e a c h b e a n al y z e d u si n g t h e s a m e m o d el a s t h e 
pri m ar y a n al y si s m o d el, a n d t h e r e s ulti n g st ati sti c s c o m bi n e d u si n g m et h o d ol o g y pr o vi d e d b y 
R u bi n ( 1 9 8 7) a n d Littl e a n d R u bi n (2 0 0 2 ). 
T h e c o m pl et e m ulti pl e i m p ut ati o n m et h o d ol o g y, al o n g wit h S A S c o d e, i s d et ail e d i n A p p e n di x 
( S e cti o n 1 4. 5 ). 
 
 
S e c o n d ar y Effi c a c y E n d p oi nt( s) a n d A n al y s e s  
A hi er ar c hi c al (fi x e d-s e q u e n c e) t e sti n g a p pr o a c h will b e u s e d f or t h e a n al y si s of t h e pri m ar y a n d 
s e c o n d ar y e n d p oi nt s t o m ai nt ai n t h e e x p eri m e nt -wi s e t y p e I err or r at e of 5 %  ( 2. 5 % f or o n e-si d e d t e st s) . If 
a n e n d p oi nt i s n ot st ati sti c all y si g nifi c a nt, c o nfir m at or y h y p ot h e si s t e sti n g will n ot b e c arri e d o ut o n t h e 
r e m ai ni n g h y p ot h e s e s, a n d r em ai ni n g h y p ot h e s e s t e sti n g will b e c o n si d er e d e x pl or at or y r at h er t h a n 
c o nfir m at or y .  T h e or d er of t e sti n g f oll o wi n g t h e pri m ar y effi c a c y e n d p oi nt i s o utli n e d b el o w : 
•  
C h a n g e i n Cli ni c al Gl o b al I m pr e s si o n of T o ur ett e S y n dr o m e S e v erit y ( C GI -T S -S) fr o m W e e k 4  to 
W e e k 1 2  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2 3  of 4 8  
•  
C h a n g e i n Cli ni c al Gl o b al I m pr e s si o n of T o ur ett e S y n dr o m e of I m pr o v e m e nt  ( C GI-T S -I) fr o m 
B a s eli n e t o W e e k 1 2  
•  
C h a n g e i n t h e Y G T S S -gl o b al S c or e fr o m B a s eli n e t o W e e k 1 2  
•  
C ar e gi v er Gl o b al I m pr e s si o n of C h a n g e ( C a GI -C) at  W e e k 1 2  
•  
C h a n g e i n Gill e s d e l a T o ur ett e S y n dr o m e -Q u alit y of Lif e S c al e f or C hil dr e n a n d A d ol e s c e nt s 
( C & A-G T S -Q O L) fr o m B a s eli n e t o W e e k 1 2  
•  
P er c e nt a g e of s u bj e ct s wit h a 2 5 %, 5 0 %  a n d  7 5 % i m pr o v e m e nt o n t h e Y G T S S-T T S  
•  
P er c e nt a g e of s u bj e ct s wit h c o m pl et e r e mi s si o n of ti c s o n t h e Y G T S S -T T S ( 1 0 0 % i m pr o v e m e nt) 
•  
C h a n g e i n t h e Y G T S S - T TS fr o m B a s eli n e t o W e e k s 4, 6, 8  
•  
C h a n g e i n t h e C GI -T S -S fr o m B a s eli n e t o W e e k s 4, 6, 8  
•  
C h a n g e i n t h e C GI -T S -I fr o m B a s eli n e t o W e e k s 4, 6, 8  
•  
C h a n g e i n t h e Y G T S S -G S fr o m B a s eli n e t o W e e k s 4, 6, 8  
•  
C h a n g e i n t h e C & A- G T S -Q O L fr o m B a s eli n e t o W e e k s 4, 6, 8  
E a c h e n d p oi nt a n d a n al y s e s ar e d efi n e d i n t h e f oll o wi n g s e cti o n s ( 8. 2. 1 -8. 2. 1 3). C o nti n u o u s e n d p oi nt s 
u si n g M M R M a n al y s e s will u s e t h e C H W m et h o d if t h e s a m pl e si z e i s a dj u st e d, a s d efi n e d i n s e cti o n 8. 1.  
 
C h a n g e i n Cli ni c al Gl o b al I m pr e s si o n of T o ur ett e S y n dr o m e S e v erit y ( C GI -T S -S) fr o m 
B a s eli n e t o W e e k 1 2 ( K e y S e c o n d ar y Effi c a c y E n d p oi nt)  
T h e  C GI  c o n si st s  of  t w o r eli a bl e a n d  v ali d   7-it e m Li k ert  s c al e s  u s e d  t o a s s e s s  s e v erit y  a n d  c h a n g e  
i n cli ni c al  s y m pt o m s.  T h e  i m pr o v e m e nt s c al e  will  b e  u s e d  at  e v er y  vi sit  aft er  t h e S cr e e ni n g  a n d  
B a s eli n e  Vi sit s.  T h e  s c al e  r a n g e s fr o m 1  = “ v er y m u c h  i m pr o v e d” t o  7  = v er y  m u c h  w or s e.”  T h e  C GI  
s e v erit y  s c al e  will  b e  u s e d  at  e a c h  st u d y  sit e  vi sit  a n d  r a n g e s fr o m 1 = “ n ot ill at  all”  t o 7 = “ a m o n g t h e 
m o st  e xtr e m el y  ill.” 
A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e c h a n g e i n C GI -T S -S fr o m B a s eli n e t o W e e k 1 2.  
St ati sti c al a n al y si s : 
T h e a n al y si s m et h o d will b e t h e s a m e a s t h e pri m ar y effi c a c y a n al y si s a s d e s cri b e d i n  S e cti o n 8. 1. 1 .  
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g b y tr e at m e nt gr o u p.  
 
C h a n g e i n Cli ni ci a n Gl o b al I m pr e s si o n T o ur ett e S y n dr o m e of I m pr o v e m e nt ( C GI -T S -I) fr o m 
B a s eli n e t o W e e k 1 2  
T h e C GI c o n si st s of t w o r eli a bl e a n d v ali d 7 -it e m Li k ert s c al e s u s e d t o a s s e s s s e v erit y a n d  c h a n g e i n 
cli ni c al s y m pt o m s.  T h e i m pr o v e m e nt s c al e ( C GI -T S -I) will b e u s e d at e v er y vi sit aft er t h e S cr e e ni n g a n d 
B a s eli n e Vi sit s. T h e s c al e r a n g e s fr o m 1 = “ v er y m u c h i m pr o v e d” t o 7 = v er y  m u c h w or s e.”  T h e C GI 
s e v erit y s c al e ( C GI -T S -S) will b e u s e d at e a c h st u d y sit e vi sit a n d r a n g e s fr o m  1 = “ n ot ill at all” t o 7 = 
“ a m o n g t h e m o st e xtr e m el y ill.” 
A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e C GI -T S -I at W e e k 1 2.  
St ati sti c al a n al y si s : 
T h e a n al y si s m et h o d will b e t h e s a m e a s t h e pri m ar y effi c a c y a n al y si s a s d e s cri b e d i n  S e cti o n 8. 1. 1 , wit h 
t h e e x c e pti o n of n o b a s eli n e s c or e will b e u s e d a s a c o v ari at e. 
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g b y tr e at m e nt gr o u p.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2 4  of 4 8  
 
C h a n g e i n Y G T S S -Gl o b al S c o r e ( G S) fr o m B a s eli n e t o W e e k 1 2 
A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e c h a n g e i n Y G T S S -Gl o b al S c or e ( Y G T S S -G S) fr o m 
B a s eli n e t o W e e k 1 2.  
St ati sti c al a n al y si s : 
T h e a n al y si s m et h o d will b e t h e s a m e a s t h e pri m ar y effi c a c y a n al y si s a s d e s cri b e d i n S e cti o n 8. 1. 1 .. 
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g b y tr e at m e nt gr o u p.  
 
C h a n g e i n C ar e gi v er Gl o b al I m pr e s si o n of C h a n g e ( C a GI -C) fr o m B a s eli n e t o W e e k 1 2  
T h e C a GI - C s c al e i s a  7 p oi nt Li k ert s c al e t h at a s k s t h e c ar e gi v er t h e f oll o wi n g q u e sti o n: o v er all, h o w 
h a v e t h e p ati e nt’ s s y m pt o m s c h a n g e d (if at all) si n c e t h e b e gi n ni n g of t h e st u d y ( b ef or e st arti n g 
tr e at m e nt) ? T h e C a GI - C i s r at e d a s f oll o w s: 1 ( v er y m u c h i m pr o v e d), 2 (m u c h  i m pr o v e d), 3 (mi ni m all y 
i m pr o v e d), 4 ( n o c h a n g e), 5 (mi ni m all y w or s e , 6 (m u c h w or s e ), a n d 7 ( v er y m u c h w or s e). 
A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e c h a n g e i n C a Gl -C fr o m B a s eli n e t o W e e k 1 2.  
St ati sti c al a n al y si s : 
T h e a n al y si s m et h o d will b e t h e s a m e a s t h e pri m ar y effi c a c y a n al y si s a s d e s cri b e d i n S e cti o n 8. 1. 1 , wit h 
t h e e x c e pti o n of n o b a s eli n e s c or e will b e u s e d a s a c o v ari at e. 
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g b y tr e at m e nt gr o u p.  
 
C h a n g e i n Gill e s d e l a T o ur ett e S y n dr o m e – Q u alit y of Lif e S c al e f or C hil dr e n a n d 
A d ol e s c e nt s ( C & A -G T S -Q O L) fr o m B a s eli n e t o W e e k 1 2  
Gill e s d e l a T o ur ett e S y n dr o m e – Q u alit y of Lif e S c al e f or C hil dr e n a n d A d ol e s c e nt s ( C & A -G T S -Q O L) i s a 
p ati e nt -r e p ort ed h e alt h r el at e d q u alit y of lif e m e a s ur e d e v el o p e d f or c hil dr e n a n d a d ol e s c e nt s . T h e C & A -
G T S -Q O L i s a 2 7 -it e m q u e sti o n n air e s p e cifi c t o T S p ati e nt s t h at a s k s t h e p ati e nt t o a s s e s s t h e e xt e nt t o 
w hi c h t h eir q u alit y of lif e i s i m p a ct e d b y t h eir s y m pt o m s. T h e  C & A -G T S -Q O L c o nt ai n s 6 s u b s c al e s 
( c o g niti v e, c o pr o p h e n o m e n a, p s y c h ol o gi c al, p h y si c al, o b s e s si v e-c o m p ul si v e, a n d A D L) a n d u s e s a 5 
p oi nt Li k ert s c al e r a n gi n g fr o m n o pr o bl e m t o e xtr e m e pr o bl e m. P ati e nt s will al s o b e a s k e d h o w s ati sfi e d 
t h e y f e el o v er all wit h t h eir lif e at t h at m o m e nt b y u si n g a V A S s c al e b et w e e n 0 a n d 1 0 0 ( S u et al 2 0 1 7). 
F oll o wi n g ar e t h e q u e sti o n s a s s e s s e d i n e a c h C & A G T S Q O L s u b s c al e:  
• 
C o g niti v e ( q u e sti o n s 1 1, 1 2, 1 3, 1 4, 1 8, 2 0, 2 1, 2 3) (r a n g e: 0 - 3 2)  
• 
P s y c h ol o gi c al ( q u e sti o n s 1 5, 1 6,  1 7, 1 9, 2 5, 2 7) (r a n g e: 0 – 2 4)  
• 
O b s e s si v e -c o m p ul si v e ( q u e sti o n s 7, 8, 9, 1 0) (r a n g e: 0 – 1 6)  
• 
P h y si c al ( q u e sti o n s 1, 3, 4) (r a n g e: 0 – 1 2)  
• 
C o pr o p h e n o m e n a ( q u e sti o n s 5, 6, 2 2) (r a n g e: 0 -1 2)  
• 
A D L ( q u e sti o n s 2, 2 4, 2 6) (r a n g e: 0 -1 2)  
S c or e s f or t h e si x  s u b s c al e s ar e g e n er at e d b y s u m mi n g it e m s a n d, f or e a s e of i nt er pr et ati o n, 
tr a n sf or m ati o n t o a r a n g e of 0 t o 1 0 0 ( 1 0 0 x [( o b s er v e d s c or e - mi n p o s si bl e s c or e)/ ( m a x p o s si bl e s c or e - 
mi n p o s si bl e s c or e)]). T h e t ot al s c or e, r e s ulti n g fr o m t h e s u m of t h e s u b s c al e s c or e s, i s al s o n or m ali z e d t o 
a 0 – 1 0 0 r a n g e. F or C & A G T S -Q O L, if a r e s p o n s e t o 1 q u e sti o n i s mi s si n g wit hi n t h e s u b s c al e, t h e 
mi s si n g r e s p o n s e will b e r e pl a c e d wit h t h e a v er a g e of t h e r e m ai ni n g r e s p o n s e s wit hi n t h e s u b s c al e; if 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2 5  of 4 8  
r e s p o n s e s t o 2 or m or e q u e sti o n s wit hi n a s u b s c al e ar e mi s si n g, t h e mi s si n g r e s p o n s e s will n ot b e 
r e pl a c e d a n d t h e s u b s c al e s c or e will b e s et t o mi s si n g; if at l e a st 1 s u b s c al e i s mi s si n g t h e n t h e t ot al 
s c or e will b e s et t o mi s si n g. F or all a n al y si s a n d s u m m ar y, tr a n sf or m e d s c or e s will b e u s e d.  
A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e c h a n g e i n C & A -G T S -Q O L t ot al s c or e a n d V A S fr o m 
B a s eli n e t o W e e k 1 2.  
St ati sti c al a n al y si s : 
T h e o v er all V A S s c or e, Q O L s u b s c al e s c or e s f or C o g niti v e, P s y c h ol o gi c al, O b s e s si v e -c o m p ul si v e, 
P h y si c al, C o pr o p h e n o m e n a, a n d A D L a n d t h e Q O L t ot al s c or e will b e a n al y z e d u si n g t h e s a m e m et h o d 
a s t h e pri m ar y effi c a c y a n al y si s a s d e s cri b e d i n 8. 1 a b o v e.  
F urt h er m or e, s u m m ar y st ati sti c s  f or t h e o v er all V A S s c or e, Q O L s u b s c al e s c or e s f or C o g niti v e, 
P s y c h ol o gi c al, O b s e s si v e -c o m p ul si v e, P h y si c al, C o pr o p h e n o m e n a, a n d A D L a n d Q O L t ot al s c or e will b e 
pr e s e nt e d al o n g wit h a f ull d at a li sti n g b y tr e at m e nt gr o u p.  
 
P er c e nt a g e of s u bj e ct s wit h a 2 5 %, 5 0 % or 7 5 %  i m pr o v e m e nt o n t h e Y G T S S-T T S  
T h e p er c e nt of s u bj e ct s wit h a 2 5 % i m pr o v e m e nt o n t h e Y G T S S -T T S at a n y ti m e b et w e e n t h e B a s eli n e 
vi sit a n d t h e W e e k 1 2 vi sit will b e c o n si d er e d a s a R e s p o n s e.  A n y s u bj e ct w h o h a s at l e a st 1 R e s p o n s e 
will b e c o n si d er e d a s a R e s p o n d er; ot h er wi s e t h e s u bj e ct will b e c o n si d er e d a N o n -R e s p o n d er.    
St ati sti c al a n al y si s : 
T h e p er c e nt a g e of s u bj e ct s wit h a 2 5 % i m pr o v e m e nt o n t h e Y G T S S -T T S will b e a n al y z e d t hr o u g h a 
l o gi sti c r e gr e s si o n m o d el t o o bt ai n a n e sti m at e of t h e p o p ul ati o n o d d s r ati o a n d a s s o ci at e d c o nfi d e n c e 
i nt er v al s b et w e e n e c o pip a m a n d m at c hi n g pl a c e b o.  T h e m o d el will i n cl u d e fi x e d eff e ct s f or tr e at m e nt, 
c e nt er, a n d c o v ari at e f or b a s eli n e Y G T S S -T T S s c or e.  
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g.  
Si mil ar a n al y s e s will b e p erf or m e d  f or 5 0 % a n d 7 5 % i m pr o v e m e nt. 
  
Su bj e ct s wit h c o m pl et e r e mi s si o n of ti c s o n t h e Y G T S S -T T S   
S u bj e ct s wit h c o m pl et e r e mi s si o n of ti c s o n t h e Y G T S S -T T S (i. e. Y G T S S -T T S = 0) at a n y ti m e b et w e e n 
t h e B a s eli n e vi sit a n d t h e W e e k 1 2 vi sit will b e c o n si d er e d a s R e s p o nd er s .  A n y s u bj e ct w h o h a s at l e a st 
1 R e s p o n s e will b e c o n si d er e d a s a R e s p o n d er; ot h er wi s e t h e s u bj e ct will b e c o n si d er e d a N o n -
R e s p o n d er.    
St ati sti c al a n al y si s : 
T h e p er c e nt a g e of s u bj e ct s wit h c o m pl et e r e mi s si o n of ti c s o n t h e Y G T S S -T T S will b e a n al y z e d  t hr o u g h a 
l o gi sti c r e gr e s si o n m o d el t o o bt ai n a n e sti m at e of t h e p o p ul ati o n o d d s r ati o a n d a s s o ci at e d c o nfi d e n c e 
i nt er v al s b et w e e n e c o pip a m a n d m at c hi n g pl a c e b o.  T h e m o d el will i n cl u d e fi x e d eff e ct s f or tr e at m e nt, 
c e nt er, a n d c o v ari at e f or b a s eli n e Y G T S S -T T S s c or e.  
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g.  
 
C h a n g e i n Y G T S S -T T S fr o m B a s eli n e t o W e e k s 4, 6, a n d 8  
A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e c h a n g e i n Y G T S S -T T S fr o m B a s eli n e t o W e e k s 4, 6 a n d 8.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2 6  of 4 8  
St ati sti c al a n al y si s : 
T h e a n al y si s m et h o d will b e t h e s a m e a s t h e pri m ar y effi c a c y a n al y si s a s d e s cri b e d i n S e cti o n 8. 1. 1 ., 
wit h t h e tr e at m e nt diff er e n c e at w e e k s 4, 6, a n d 8 e sti m at e d b a s e d o n M M R M . 
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g b y tr e at m e nt gr o u p.  
 
C h a n g e i n C GI -T S -S fr o m B a s eli n e t o W e e k s 4, 6, a n d 8  
A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e c h a n g e i n C GI -T S -S fr o m B a s eli n e t o W e e k s 4, 6 a n d 8.  
St ati sti c al a n al y si s : 
T h e a n al y si s m et h o d will b e t h e s a m e a s t h e pri m ar y effi c a c y a n al y si s a s d e s cri b e d i n S e cti o n 8. 1. 1 ., 
wit h t h e tr e at m e nt diff er e n c e at w e e k s 4, 6, a n d 8 e sti m at e d b a s e d o n M M R M . 
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g b y tr e at m e nt gr o u p.  
 
C GI -T S -I at  W e e k 4, 6, a n d 8 
A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e C GI -T S -I at  W e e k s 4, 6 a n d 8.  
St ati sti c al a n al y si s : 
T h e a n al y si s m et h o d will b e t h e s a m e a s t h e pri m ar y effi c a c y a n al y si s a s d e s cri b e d i n S e cti o n 8. 1. 1. , 
wit h t h e e x c e pti o n of n o b a s eli n e s c or e will b e u s e d a s a c o v ari at e .  T h e tr e at m e nt diff er e n c e at w e e k s 4, 
6, a n d 8 will b e e sti m at e d b a s e d o n M M R M . 
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g  wit h a f ull d at a li sti n g b y tr e at m e nt gr o u p.  
 
C h a n g e i n Y G T S S -G S fr o m B a s eli n e t o W e e k s 4, 6, a n d 8  
A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e c h a n g e i n Y G T S S -G S fr o m B a s eli n e t o W e e k s 4, 6 a n d 8.  
St ati sti c al a n al y si s : 
T h e a n al y si s m et h o d will b e t h e s a m e a s t h e pri m ar y effi c a c y a n al y si s a s d e s cri b e d i n S e cti o n 8. 1. 1 ., 
wit h t h e tr e at m e nt diff er e n c e at w e e k s 4, 6, a n d 8 e sti m at e d b a s e d o n M M R M . 
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g b y tr e at m e nt gr o u p.  
 
C h a n g e i n C a GI -C fr o m B a s eli n e t o W e e k s 4, 6 a n d 8  
S e e s e cti o n 8. 2. 4 f or a d e s cri pti o n of t h e C ar e gi v er Gl o b al I m pr essi o n of C h a n g e ( C a GI-C) . 
A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e C a GI -C at  W e e k s 4, 6 a n d 8.  
St ati sti c al a n al y si s : 
T h e a n al y si s m et h o d will b e t h e s a m e a s t h e pri m ar y effi c a c y a n al y si s a s d e s cri b e d i n  S e cti o n 8. 1. 1 , wit h 
t h e e x c e pti o n of n o b a s eli n e s c or e will b e u s e d a s a c o v ari at e.  T h e tr e at m e nt diff er e n c e at w e e k s 4, 6, 
a n d 8 will b e e sti m at e d b a s e d o n M M R M . 
S u m m ar y st ati sti c s will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g b y tr e at m e nt gr o u p.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2 7  of 4 8  
 
C h a n g e i n t h e C & A -G T S -Q O L fr o m B a s eli n e t o W e e k s 4, 6, a n d 8  
S e e s e cti o n 8. 2. 5 f or a d e s cri pti o n of t h e Gill e s d e l a T o ur ett e S y n dr o m e – Q u alit y of Lif e S c al e f or 
C hil dr e n a n d A d ol e s c e nt s ( C & A -G T S -Q O L) . A s e c o n d ar y a n al y si s will b e p erf or m e d o n t h e c h a n g e i n 
C & A -G T S -Q O L V A S a n d t ot al s c or e fr o m B a s eli n e t o W e e k s 4, 6 a n d 8.  
St ati sti c al a n al y si s : 
T h e a n al y si s m et h o d f or t h e V A S a n d t ot al s c or e will b e t h e s a m e a s t h e pri m ar y effi c a c y a n al y si s a s 
d e s cri b e d i n S e cti o n 8. 1. 1 ., wit h t h e tr e at m e nt diff er e n c e at w e e k s 4, 6, a n d 8 e sti m at e d b a s e d o n 
M M R M . 
S u m m ar y st ati sti c s f or t h e V A S, s u b s c al e s, a n d t ot al s c or e will b e pr e s e nt e d al o n g wit h a f ull d at a li sti n g 
b y tr e a t m e nt gr o u p. 
8. 3 C O VI D -1 9 A n al y s e s  
D u e t o C O VI D -1 9 p a n d e mic, a d diti o n al a n alys es will b e c o n d uct e d:  
•  
T h e a m o u nt of missi n g d at a by tr e at m e nt gr o u p a n d o v er all by e n d p oi nt f or d at a missi n g d u e t o 
C O VI D -1 9 will b e s u m m ariz e d i n a t a bl e.  
•  
Effic ac y e n d p oi nt  a n a l ys es will h a v e a d diti o n al a n al ysis m o d eli n g usi n g t h e t er ms R e m ot e  
( Y es/ N o) a n d Ty p e  ( A u di o/ Vi d e o), t o acc o u nt f or a ny bi as t h at t h es e d at a c oll ecti o n m et h o d s 
m a y h a v e i ntr o d uc e d.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2 8  of 4 8  
 
A n al y si s o f P h ar m a c o ki n eti c s 
Bl o o d s a m pl e s will b e c oll e ct e d t o m e a s ur e c o n c e ntr ati o n s of e c o pi p a m a n d/ or it s m aj or ( a cti v e) 
m et a b olit e s at W e e k s 4 a n d 1 2.  
F or t h e W e e k 4 vi sit, a m or ni n g a p p oi nt m e nt i s s u g g e st e d.  P ar e nt s/ c ar e gi v er s will b e i n str u ct e d n ot t o 
a d mi ni st er t h e st u d y m e di c ati o n t o t h e s u bj e ct o n t h e e v e ni n g pri or t o t h e W e e k 4 vi sit a n d t o r e c or d t h e 
ti m e of a d mi ni str ati o n of t h e l a st d o s e of st u d y m e di c ati o n t a k e n.  T h e st u d y dr u g a d mi ni str ati o n will o c c ur 
o n t h e d a y of t h e W e e k 4 vi sit at t h e sit e u n d er t h e s u p er vi si o n of t h e st u d y i n v e sti g at or.  A n i ntr a v e n o u s 
c at h et er will b e pl a c e d, a n d t h e s u bj e ct will h a v e s a m pl e s c oll e ct e d at t h e f oll o wi n g ti m e wi n d o w s: o n e 
s a m pl e at pr e d o s e ( 3 4 t o 4 4 h o ur s si n c e t h e l a st d o s e), o n e s a m pl e b et w e e n 0. 5 a n d 1. 5  h o ur aft er 
a d mi ni str at i o n of st u d y m e di c ati o n, a n d o n e s a m pl e b et w e e n 2 a n d 4 h o ur s aft er st u d y dr u g 
a d mi ni str ati o n.  A n y s a m pl e s s h o ul d b e c oll e ct e d at l e a st 3 0 mi n a p art.   
F or t h e W e e k 1 2 vi sit, p ar e nt s/ c ar e gi v er s will b e a s k e d t o r e c or d t h e ti m e of st u d y dr u g a d mi ni str ati o n  o n 
t h e e v e ni n g pri or t o t h e vi sit.  A n a p p oi nt m e nt i s s u g g e st e d t o b e m a d e f or t h e m or ni n g of t h e W e e k 1 2 
vi sit.  A bl o o d s a m pl e will b e c oll e ct e d at t h e e n d of t h e vi sit. T h e ti m e of s a m pl e c oll e cti o n will b e 
r e c or d e d.  Bl o o d s a m pl e s will b e pr o c e s s e d a s o utli n e d i n t h e pr ot o c ol a n d s er u m/ pl a s m a will b e fr o z e n, 
s hi p p e d a n d a n al y z e d f or e c o pi p a m a n d S C H 4 0 8 5 3.  
Pl a s m a c o n c e ntr ati o n -ti m e d at a will b e s u m m ari z e d i n t h e Cli ni c al St u d y R e p ort ( C S R).  P o p ul ati o n 
p h ar m a c o ki n eti c a n al y si s will b e c o n d u ct e d a n d s u m m ari z e d s e p ar at el y, u si n g d at a fr o m t hi s st u d y al o n g 
wit h d at a fr o m a d ult s u si n g t h e s a m e t a bl et f or m ul ati o n (if a v ail a bl e).  T h e m et h o d ol o g y f or t h e s e 
p h ar m a c o ki n eti c a n al y s e s will b e r e p ort e d i n a s e p ar at e a n al y si s pl a n.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 2 9  of 4 8  
 
S af et y  
T h e p o p ul ati o n u s e d f or s af et y a n al y s e s will b e t h e S af et y S et ( S S).  S af et y will b e a s s e s s e d b y 
m o nit ori n g a n d r e c or di n g all a d v er s e e v e nt s ( A E s) a n d S eri o u s A d v er s e E v e nt s ( S A E s) ( all Vi sit s), r e g ul ar 
m o nit ori n g of h e m at ol o g y, bl o o d c h e mi str y, a n d uri n e v al u e s ( S cr e e ni n g, B a s eli n e, W e e k 1 2 a n d 7 -d a y 
a n d 1 4 -d a y F oll o w U p vi sit s).  H b A 1 c will al s o b e m e a s ur e d d uri n g t h e s e vi sit s e x c e pt o n t h e 1 4 d a y 
F oll o w U p vi sit.  R e g ul ar m e a s ur e m e nt of vit al si g n s a n d t h e p erf or m a n c e of a p h y si c al e x a mi n ati o n a n d 
a n E C G will o c c ur at S cr e e ni n g , B a s eli n e a n d W e e k s 4, 6, 8 a n d 1 2 a n d 7 d a y a n d 1 4 d a y F oll o w U p 
vi sit s. A n a d diti o n al a s s e s s m e nt will i n cl u d e t h e C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S) ( all 
Vi sit s e x c e pt 3 0 d a y F oll o w u p vi sit). A d diti o n al s af et y o ut c o m e s ( B a s eli n e a n d W e e k s 4, 6, 8 a n d 1 2) will 
i n cl u d e t h e A b n or m al I n v ol u nt ar y M o v e m e nt S c al e ( AI M S), t h e B ar n e s A k at hi si a R ati n g S c al e ( B A R S), 
t h e S w a n s o n, N ol a n a n d P el h a m ( S N A P-I V) q u e sti o n n air e, t h e C hil dr e n' s Y al e-Br o w n O b s e s si v e 
C o m p ul si v e S c al e ( C Y -B O C S), t h e C hil dr e n' s D e pr e s si o n R ati n g S c al e -R e vi s e d ( C D R S -R), a n d t h e 
P e di atri c A n xi et y R ati n g S c al e ( P A R S).  
All s af et y d at a will b e s u m m ari z e d i n S af et y S et  a c c or di n g t o t h e a ct u al tr e at m e nt.  
Tr e at m e nt -e m er g e nt a d v er s e e v e nt s ( T E A E s) ar e d efi n e d a s a d v er s e e v e nt s t h at ar e n e wl y o c c urri n g or 
w or s e ni n g aft er t h e fir st d o s e of st u d y m e di c ati o n.  T h e i n ci d e n c e of T E A E s will b e s u m m ari z e d b y 
tr e at m e nt gr o u p, b y s e v erit y a n d b y r el ati o n s hi p t o st u d y m e di c ati o n. S eri o u s T E A E s a n d T E A E s l e a di n g 
t o t h e st u d y t er mi n ati o n will b e s u m m ari z e d b y tr e at m e nt gr o u p. L a b or at or y d at a, vit al si g n, p h y si c al 
e x a mi n ati o n a n d E C G will b e s u m m ari z e d b y tr e at m e nt a n d vi sit.    
Ti mi n g s p e cifi c a d v er s e e v e nt s ar e d efi n e d a s a n y a d v er s e e v e nt s t h at o c c ur or i n cr e a s e i n i nt e n sit y 
d uri n g a n y s p e cifi c all y d efi n e d st u d y mil e st o n e s: tr e at m e nt p h a s e ( T P A E), t a p er d o w n ( T D A E) a n d off 
st u d y dr u g ( O D A E). Tr e at m e nt p h a s e a d v er s e e v e nt s ( T P A E s) will b e a d v er s e e v e nt s t h at st art or 
i n cr e a s e i n i nt e n sit y b et w e e n t h e fir st d a y of d o si n g a n d e n d of t h e 8-w e e k tr e at m e nt p h a s e ( d a y b ef or e 
t a p er d o w n). T a p er d o w n a d v er s e e v e nt s ( T D A E s) will b e a d v er s e e v e nt s t h at st art or i n cr e a s e i n i nt e n sit y 
b et w e e n t h e fir st d a y of d o s e t a p eri n g ( aft er 8 -w e e k tr e at m e nt p h a s e) a n d l a st d o si n g d at e. Off st u d y dr u g 
a d v er s e e v e nt s ( O D A E) will b e a d v er s e e v e nt s t h at st art or i n cr e a s e i n i nt e n sit y b et w e e n t h e fir st d a y off 
st u d y dr u g ( d a y aft er l a st d o si n g d at e) a n d e n d of st u d y. T h e i n ci d e n c e of T P A E s, T D A E s a n d O D A E s will 
b e s u m m ari z e d b y tr e at m e nt gr o u p, b y s e v erit y a n d b y r el ati o n s hi p t o st u d y m e di c ati o n a n d will b e 
di s pl a y e d s u c h t h at c o m p ari s o n s c a n b e m a d e. T h e C -S S R S, AI M S, S N A P -I V q u e sti o n n air e, C Y-B O C S, 
C D R S -R a n d P A R S will al s o b e s u m m ari z e d d e s cri pti v el y.  
 
E xt e nt of E x p o s ur e  
D ur ati o n of e x p o s ur e will b e s u m m ari z e d u si n g d e s cri pti v e st ati sti c s b y tr e at m e nt gr o u p. T h e d ur ati o n of 
e x p o s ur e will al s o b e c at e g ori z e d ( < 7, 7 -< 1 4, 1 4 -< 2 8, 2 8 -< 4 2, 4 2 -< 5 6, 5 6 -< 7 0, 7 0 -< 8 4, ≥8 4), a n d 
t a b ul at e d b y tr e at m e nt gr o u p. D ur ati o n of e x p o s ur e ( w e e k s) will b e c al c ul at e d a s ( D at e of L a st D o s e – 
D at e of Fir st D o s e) + 1. If d at e of l a st d o s e i s u n k n o w n t h e n t h e d at e of l a st cli ni c al  vi sit will b e u s e d.  
A li sti n g i n cl u di n g st u d y dr u g a d mi ni str ati o n i nf or m ati o n fr o m t h e e C R F will b e pr e s e nt e d.  
 
Tr e at m e nt C o m pli a n c e  
S u bj e ct s ar e e x p e ct e d t o t a k e 1 t a bl et of st u d y m e di c ati o n o n c e p er d a y .  
Tr e at m e nt c o m pli a n c e, a s a p er c e nt a g e, will b e c al c ul at e d a s c o m pli a n c e ( %) = ( S u m of St u d y dr u g 
t a k e n = Y e s) / ( n u m b er of d a y s i n st u d y) x 1 0 0. T h e n u m b er of a ct u al d o s e s t a k e n will b e r e c or d e d o n t h e 
e C R F.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 3 0  of 4 8  
S u bj e ct s will b e c o n si d er e d c o m pli a nt o v er all f or st u d y m e di c ati o n if t h e c o m pli a n c e i s ≥8 0 %. D e s cri pti v e 
st ati sti c s ( n u m b er of s u bj e ct s, m e a n, S D, mi ni m u m, m e di a n, a n d m a xi m u m) f or n u m b er of a ct u al t a bl et s 
t a k e n, n u m b er of e x p e ct e d t a bl et s t a k e n, a n d tr e at m e nt c o m pli a n c e will b e s u m m ari z e d b y tr e at m e nt 
gr o u p.  
 
A d v er s e E v e nt s / A d v er s e Dr u g R e a cti o n s  
A n a d v er s e e v e nt ( A E) i s a n y u nt o w ar d m e di c al c o n diti o n t h at o c c ur s i n a p ati e nt w hil e p arti ci p ati n g i n 
t hi s cli ni c al st u d y. A d v er s e e v e nt s will b e c o d e d a c c or di n g t o t h e M e di c al Di cti o n ar y f or R e g ul at or y 
A cti viti e s ( M e d D R A 2 2 . 0) t er mi n ol o g y a n d t h e s e v erit y of t h e t o xi citi e s will b e gr a d e d a c c or di n g t o t h e 
N ati o n al C a n c er I n stit ut e ( N CI) C o m m o n T o xi cit y Crit eri a f or A d v er s e E v e nt s ( C T C A E), v 4. 0 3, w h er e 
a p pli c a bl e. A n a d v er s e dr u g r e a cti o n ( A D R) m e a n s a n y A E c a u s e d b y a dr u g or bi ol o gi c.   
 
Tr e at m e nt -E m er g e nt A d v er s e E v e nt s ( T E A E s) ar e t h o s e a d v er s e e v e nt s/ a d v er s e dr u g r e a cti o n s t h at ar e 
r e c or d e d d uri n g or f oll o wi n g t h e i niti ati o n of st u d y tr e at m e nt a d mi ni str ati o n, a n d d o n ot n e c e s s aril y h a v e a 
c a u s al r el ati o n s hi p t o t h e u s e of t h e st u d y m e di c ati o n. Tr e at m e nt -E m er g e nt A d v er s e E v e nt s ( si m pl y 
r ef err e d t o a s a d v er s e e v e nt s i n s u m m ar y t a bl e s) will b e s u m m ari z e d.  
T h e f oll o wi n g a d v er s e e v e nt s u m m ar y t a bl e s will b e s u m m ari z e d b y tr e at m e nt gr o u p:  
1)  A n o v er all s u m m ar y wit h t h e n u m b er a n d p er c e nt a g e of p ati e nt s r e p orti n g A E s, s eri o u s A E s, 
gr a d e 3 or hi g h er A E s, tr e at m e nt -r el at e d A E s, s eri o u s T E A E s, A E s l e a di n g t o st u d y tr e at m e nt 
di s c o nti n u ati o n a n d A E s wit h o ut c o m e of d e at h s.  
2)  A E s o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m.  
I n t hi s s u m m ar y, a p ati e nt i s c o u nt e d o n c e at t h e s y st e m or g a n cl a s s a n d o n c e at e a c h pr ef err e d t er m 
wit hi n t h e s y st e m or g a n cl a s s.  
3)  A E s o v er all a n d b y s y st e m or g a n cl a s s, pr ef err e d t er m a n d i niti al d ail y d o s e l e v el.  
4)  A E s o v er all a n d b y s y st e m or g a n cl a s s, pr ef err e d t er m a n d r e gi o n.  
5)  A E s o v er all a n d b y s y st e m or g a n cl a s s, pr ef err e d t er m a n d w ei g ht b a n d . 
6)  A E s o v er all a n d b y s y st e m or g a n cl a s s, pr ef err e d t er m i n s u bj ects o v er 1 0 0 K g i n w ei g ht. 
7)    A E s o v er all a n d b y s y st e m or g a n cl a s s, pr ef err e d t er m a n d w e e k wit hi n t h e titr ati o n p h a s e.  
8)    A E s o v er all a n d b y s y st e m or g a n cl a s s, pr ef err e d t er m a n d vi sit wit hi n t h e m ai nt e n a n c e p h a s e.  
9)    A E s o v er all a n d b y s y st e m or g a n cl a s s, pr ef err e d t er m a n d vi sit wit hi n t h e d o w n titr ati o n p h a s e 
a n d f oll o w u p.  
1 0)  A E s o v er all a n d b y s y st e m or g a n cl a s s, pr ef err e d t er m a n d hi g h e st C T C A E gr a d e.  
I n t hi s s u m m ar y, a p ati e nt i s c o u nt e d o n c e at t h e hi g h e st gr a d e f or w hi c h t h e e v e nt o c c urr e d i n t h e 
s y st e m or g a n cl a s s a n d t h e hi g h e st gr a d e f or e a c h u ni q u e pr ef err e d t er m wit hi n t h at s y st e m or g a n 
cl a s s. T h er ef or e, p ati e nt s m a y o nl y c o ntri b ut e o n c e t o e a c h pr ef err e d t er m a n d o n c e t o e a c h s y st e m 
or g a n cl a s s. T h e mi s si n g s e v erit y gr a d e will b e r e p ort e d i n a s e p ar at e c at e g or y.  
1 1)  St u d y -tr e at m e nt-rel at e d A E s o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 3 1  of 4 8  
All t h o s e A E s wit h r el ati o n s hi p t o tr e at m e nt m ar k e d a s “ P o s si bl y R el at e d” or “ Pr o b a bl y R el at e d” or 
mi s si n g will b e r e p ort e d i n t h e t a bl e.  
1 2)  St u d y -tr e at m e nt r el at e d A E s b y s y st e m or g a n cl a s s, pr ef err e d t er m a n d Hi g h e st C T C A E gr a d e  
1 3)  A E s l e a di n g t o st u d y tr e at m e nt t er mi n ati o n b y s y st e m or g a n cl a s s a n d pr ef err e d t er m.  
1 4)  A E s l e a di n g t o st u d y tr e at m e nt t er mi n ati o n b y s y st e m or g a n cl a s s, pr ef err e d t er m a n d hi g h e st 
C T C A E gr a d e  
1 5)  C T C A E Gr a d e 3 or hi g h er A E s, o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m  
1 6)   A E s b y m a xi m u m s e v erit y, m a xi m u m r el at e d n e s s a n d mil e st o n e s  (titr ati o n p h a s e, m ai nt e n a n c e 
p h a s e, t a p er d o w n, a n d off st u d y dr u g) . 
 
A S eri o u s A d v er s e E v e nt ( S A E) i s a n A E w hi c h f all s i nt o o n e or m or e of t h e f oll o wi n g c at e g ori e s:  
a.  R e s ult s i n d e at h  
b.  I s lif e-t hr e at e ni n g 
c.  R e q uir e s i n p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali z ati o n   
d.  R e s ult s i n p er si st e nt or si g nifi c a nt di s a bilit y or i n c a p a cit y  
e.  I s a c o n g e nit al a n o m al y/ birt h d ef e ct  
f. 
I s a n y ot h er i m p ort a nt m e di c al e v e nt  
 
S eri o u s a d v er s e e v e nt s will b e s u m m ari z e d b y tr e at m e nt gr o u p a n d c o m bi n e d o v er b ot h tr e at m e nt 
gr o u p s.   A s u m m ar y b y a g e gr o u p ( c hil dr e n 6-1 1 a n d a d ol e s c e nt s 1 2 -1 7) will al s o b e pr o vi d e d.  
1 7)  S A E s o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m.  
I n t hi s s u m m ar y, a p ati e nt i s c o u nt e d o n c e at t h e s y st e m or g a n cl a s s a n d o n c e at e a c h pr ef err e d t er m 
wit hi n t h e s y st e m or g a n cl a s s.  
A d v er s e E v e nt s of S p e ci al I nt er e st ( A E SI) f or e c o pi p a m i n cl u d e C o n v ul si o n s, D e pr e s si o n a n d 
S ui ci d e/ S elf I nj ur y, Dr u g A b u s e, D e p e n d e n c e a n d Wit h dr a w al, D y sli p e d a e mi a, H e p ati c Di s or d er s, 
H y p er gl y c a e mi a/ N e w O n s et Di a b et e s M ellit u s, N M S, a n d P s y c h o si s a n d P s y c h oti c Di s or d er s.  
A E SI f or P ar ki n s o ni s m i n cl u d e At a xi a, C o nf u si o n al st at e, C o or di n ati o n a b n or m al, S o m n ol e n c e, 
Di st ur b a n c e i n att e nti o n, D y s ki n e si a, H y p er ki n e si a, G ait di st ur b a n c e, M e m or y i m p air m e nt, Tr e m or, 
V erti g o, A git ati o n, A n xi et y, Di st ur b a n c e i n att e nti o n, D y st o ni a, Br a d y ki n e si a, M u s c ul o s k el et al stiff n e s s, 
D y s st a si a, G ait di st ur b a n c e, P o st ur e a b n or m al, B al a n c e di s or d er, M o v e m e nt di s or d er, M o v e m e nt 
di s or d er, D y s ki n e si a, M u s cl e ri gi dit y, C o or di n ati o n a b n or m al, M u s cl e c o ntr a ct ur e, Br a d y ki n e si a, G ait 
di st ur b a n c e, T er mi n al i n s o m ni a, Ni g ht m ar e, P o or q u alit y sl e e p, Sl e e p di s or d er, F ati g u e, Di z zi n e s s , 
B al a n c e di s or d er, R e stl e s s n e s s, A m n e si a, C o nf u si o n al st at e, D e m e nti a, M e nt al i m p air m e nt, S p e e c h 
di s or d er, D y s p h o ni a, V o c al c or d d y sf u n cti o n, P ar o s mi a, A n o s mi a, Uri n ar y i n c o nti n e n c e, A n xi et y, A p at h y, 
J oi nt stiff n e s s, R e d u c e d f a ci al e x pr e s si o n, C o nf u si o n al  st at e, Fl at aff e ct, C o n sti p ati o n, D e pr e s si o n, 
D y s p h a gi a, Dr o oli n g, F all, F e ar of f alli n g, L o s s of vi s u al c o ntr a st s e n siti vit y, M u s cl e ti g ht n e s s, D y s gr a p hi a, 
D y s ki n e si a, a n d W ei g ht d e cr e a s e d.  
A E SI s u m m ar y t a bl e s ar e li st e d b el o w:  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 3 2  of 4 8  
1)  A E SI f or e c o pi p a m o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m  
2)  A E SI f or P ar ki n s o n i s m o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m.  
I n t hi s s u m m ar y, a p ati e nt i s c o u nt e d o n c e at t h e s y st e m or g a n cl a s s a n d o n c e at e a c h pr ef err e d t er m 
wit hi n t h e s y st e m or g a n cl a s s.   
 
 
L a b or at or y E v al u ati o n s  
Bl o o d s a m pl e s f or h e m at ol o g y, bi o c h e mi str y, a n d uri n e s a m pl e s f or uri n al y si s ar e t o b e c oll e ct e d at 
s cr e e ni n g, B a s eli n e, W e e k s 1 2 a n d 7 d a y a n d 1 4 d a y F oll o w U p vi sit s. All r e s ult s will b e pr o vi d e d u si n g 
I nt er n ati o n al S y st e m of U nit s ( SI).  H b A 1 c will b e m e a s ur e d at t h e b a s eli n e a n d c o m pl eti o n/ e arl y 
t er mi n ati o n vi sit s. 
D e s cri pti v e st ati sti c s f or h e m at ol o g y, bi o c h e mi str y a n d H b A 1 c will b e pr o vi d e d f or e a c h t e st p ar a m et er 
a n d f or c h a n g e fr o m b a s eli n e tr e at m e nt b y vi sit a n d f or e a c h tr e at m e nt gr o u p  ( sp e cifi c e m p h a si s will b e 
pl a c e d o n m e a n c h a n g e s b et w e e n e c o pi p a m a n d pl a c e b o i n f a sti n g gl u c o s e l e v el s  a n d bl o o d li pi d 
p ar a m et er s ). S hift t a bl e s (i. e., l o w -n or m al -hi g h at B a s eli n e v er s u s l o w -n or m al -hi g h at e a c h p o st -b a s eli n e 
vi sit i n a 3 -b y -3 c o nti n g e n c y t a bl e) will b e pr o vi d e d f or h e m at ol o g y, bi o c h e mi str y, H b A 1 c a n d uri n e t o 
a s s e s s c h a n g e s fr o m B a s eli n e i n l a b or at or y v al u e s b y vi sit f or e a c h tr e at m e nt gr o u p .  
S e p ar at e  li sti n g s  will  b e  pr o vi d e d  f or  all  l a b or at or y  e v al u ati o n s  ( h e m at ol o g y,  bi o c h e mi str y,  H b A 1 c  a n d 
uri n al y si s.  
 
Vit al Si g n s  
Vit al si g n m e a s ur e m e nt s i n cl u di n g sitti n g s y st oli c bl o o d pr e s s ur e, sitti n g di a st oli c bl o o d pr e s s ur e, sitti n g 
p ul s e r at e, s u pi n e ort h o st ati c s y st oli c bl o o d pr e s s ur e, s u pi n e ort h o st ati c di a st oli c bl o o d pr e s s ur e, s u pi n e  
p ul s e r at e, st a n di n g ort h o st ati c s y st oli c bl o o d pr e s s ur e, st a n di n g ort h o st ati c di a st oli c bl o o d pr e s s ur e, a n d 
st a n di n g p ul s e r at e at e a c h s c h e d ul e d ti m e a n d c h a n g e s fr o m b a s eli n e i n vit al si g n m e a s ur e m e nt s will b e 
s u m m ari z e d wit h d e s cri pti v e st ati sti c s at e a c h s c h e d ul e d ti m e p oi nt b y tr e at m e nt gr o u p.  
B o d y h ei g ht will b e m e a s ur e d at S cr e e ni n g o nl y a n d will b e s u m m ari z e d b y tr e at m e nt gr o u p.  W ei g ht will 
b e m e a s ur e d at e a c h s c h e d ul e vi sit a n d, al o n g wit h c h a n g e s fr o m b a s eli n e, will b e s u m m ari z e d wit h  
d e s cri pti v e st ati sti c s at e a c h s c h e d ul e d ti m e p oi nt b y tr e at m e nt gr o u p. W ei g ht g ai n ≥ 7 % of b o d y w ei g ht  
will b e t a b ul at e d . W ei g ht will b e di s pl a y e d i n kil o gr a m s; h ei g ht will b e di s pl a y e d i n c e nti m et er s.   
B o d y m a s s i n d e x ( B MI) will b e d eri v e d fr o m t h e w ei g ht at e a c h vi sit a n d fr o m h ei g ht ( at s cr e e ni n g), al o n g 
wit h c h a n g e s fr o m b a s eli n e, will b e s u m m ari z e d wit h d e s cri pti v e st ati sti c s at e a c h s c h e d ul e ti m e p oi nt b y 
tr e at m e nt gr o u p.  B MI will b e di s pl a y e d i n kil o gr a m s p er m et er s q u ar e d.   
All vit al si g n s d at a will b e pr e s e nt e d i n a li sti n g.  
 
E C G  
T h e f oll o wi n g E C G d at a will b e c oll e ct e d at t h e S cr e e ni n g, B a s eli n e, W e e k 4, W e e k 6, W e e k 8, W e e k 1 2, 
7 D a y F oll o w U p a n d 1 4 d a y F oll o w U p vi sit s:  
•  
P R i nt er v al ( m s e c)  
•  
Q R S i nt er v al ( m s e c)  
•  
Q T i nt er v al  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 3 3  of 4 8  
•  
Q T c i nt er v al ( m s e c)  
•  
O v er all E C G r e s ult ( N or m al; A b n or m al, N ot Cli ni c all y Si g nifi c a nt; A b n or m al, Cli ni c all y 
Si g nifi c a nt).  
A n E C G i s o pti o n al at u n s c h e d ul e d vi sit s, p er t h e i n v e sti g at or’ s di s cr eti o n.   
T h e a ct u al E C G r e s ult s al o n g wit h c h a n g e fr o m b a s eli n e will b e s u m m ari z e d at e a c h vi sit b y tr e at m e nt 
gr o u p . All E C G d at a will b e pr e s e nt e d i n a li sti n g.  
 
P h y si c al E x a mi n ati o n  
A P h y si c al e x a mi n ati o n will b e p erf or m e d at t h e S cr e e ni n g, B a s eli n e, W e e k 4, W e e k 6, W e e k 8, W e e k 1 2, 
7 D a y F oll o w U p a n d 1 4 d a y F oll o w U p vi sit s. T hi s will i n cl u d e p h y si c al e x a mi n ati o n of t h e f oll o wi n g b o d y 
ar e a s a n d s y st e m s: H e a d, E y e s, E ar s, N o s e, M o ut h, T hr o at, N e c k (i n cl u di n g T h yr oi d); T h or a x; A b d o m e n; 
Ur o g e nit al; E xtr e miti e s; N e ur ol o gi c al; S ki n a n d M u c o s a e; a n d Ot h er.  
A p h y si c al e x a m i s o pti o n al at u n s c h e d ul e d vi sit s, p er t h e i n v e sti g at or’ s di s cr eti o n.  
T h e P h y si c al e x a mi n ati o n r e s ult s will b e s u m m ari z e d at e a c h vi sit b y tr e at m e nt gr o u p.  All p h y si c al 
e x a mi n ati o n d at a will b e pr e s e nt e d i n a li sti n g.  
 
C ol u m bi a S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S)  
T h e C -S S R S i s a l o w b ur d e n ( a p pr o xi m at el y 5 mi n ut e s f or c o m pl eti o n) i n str u m e nt t o a s s e s s b ot h  s ui ci d al 
b e h a v i or a n d i d e ati o n. T h e s c al e i s a p pr o pri at e f or s u bj e ct s fr o m a g e 6 t hr o u g h t o a n el d erl y p o p ul ati o n . 
T h e n u m b er a n d p er c e nt a g e of s u bj e ct s wit h s ui ci d al b e h a vi or a n d i d e ati o n  will b e s u m m ari z e d b y 
tr e at m e nt gr o u p at t h e B a s eli n e, W e e k 4, W e e k 6, W e e k 8 a n d W e e k 1 2  vi sit s  a n d all q u e sti o n n air e d at a 
will b e di s pl a y e d i n a li sti n g.  
 
Ot h er S af et y  
 
A b n or m al I n v ol u nt ar y M o v e m e nt S c al e ( AI M S)  
A b n or m al I n v ol u nt ar y M o v e m e nt S c al e ( AI M S) r e c or d s t h e o c c urr e n c e s of t ar di v e d y s ki n e si a ( T D) i n 
s u bj e ct s r e c ei vi n g n e ur ol e pti c m e di c ati o n s. T h e t e st i s u s e d t o d et e ct T D a n d t o f oll o w t h e s e v erit y o v er 
ti m e.  It c o n si st s of r ati n g t h e pr e s e n c e a n d s e v erit y of m o v e m e nt di s or d er s i n v ol vi n g t h e f a c e, m o ut h, 
e xtr e miti e s, a n d tr u n k a s w ell a s t hr e e it e m s of gl o b al j u d g m e nt fr o m a s c al e of 0 ( n o n e) t o 4 ( s e v er e).   
T h e AI M S t ot al s c or e will b y c al c ul at e d b y s u m mi n g t h e s e v erit y of t h e 1 0 it e m s t h at ar e r at e d o n a s c al e 
of 0 t o 4.  T h e t ot al s c or e will b e s u m m ari z e d b y tr e at m e nt gr o u p at t h e B a s eli n e, W e e k 4, W e e k 6, W e e k 
8 a n d W e e k 1 2  vi sit s  a n d all q u e sti o n n air e d at a will b e di s pl a y e d i n a li sti n g.  
 
B ar n e s A k at hi si a R ati n g S c al e ( B A R S)  
T h e B ar n e s A k at hi si a R ati n g S c al e ( B A R S) i s u s e d t o a s s e s s t h e s e v erit y of dr u g -i n d u c e d a k at hi si a. 
O bj e cti v e a n d s u bj e cti v e it e m s i n t h e s c al e m e a s ur e t h e l e v el of s u bj e ct’ s r e stl e s s n e s s, r a n gi n g fr o m z er o 
( n or m al) t o 3 ( m o st s e v er e).  T h e B A R S al s o i n cl u d e s a gl o b al a s s e s s m e nt of a k at hi si a, r a n gi n g fr o m z er o 
( a b s e nt) t o 5 ( s e v er e).  
T h e  o bj e cti v e, s u bj e cti v e, a n d gl o b al s c or e s  will b e s u m m ari z e d b y tr e at m e nt gr o u p at t h e B a s eli n e, 
W e e k 4, W e e k 6, W e e k 8 a n d W e e k 1 2  vi sit s  a n d all q u e sti o n n air e d at a will b e di s pl a y e d i n a li sti n g.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 3 4  of 4 8  
 
S w a n s o n, N ol a n a n d P el h a m ( S N A P -I V) q u e sti o n n air e 
S w a n s o n, N ol a n a n d P el h a m ( S N A P -I V) q u e sti o n n air e m e a s ur e d e si g n e d a s s e s s A D H D a n d o p p o siti o n al 
d efi a nt di s or d er ( O D D) s y m pt o m s i n c hil dr e n a n d a d ol e s c e nt s.   T h e S N A P -I V i s b a s e d o n a 0 t o 3 r ati n g 
s c al e: N ot at All = 0, J u st A Littl e = 1, Q uit e A Bit = 2, a n d V er y M u c h = 3. S u b s c al e s c or e s o n t h e S N A P -
IV ar e  c al c ul at e d b y s u m mi n g t h e s c or e s o n t h e it e m s i n t h e s u b s et a n d di vi di n g b y t h e n u m b er of it e m s 
i n t h e s u b s et. T h e s c or e f or a n y s u b s et i s e x pr e s s e d a s t h e A v er a g e R ati n g -P er -It e m.  
T h e it e m s fr o m t h e D S M -I V ( 1 9 9 4) crit eri a f or Att e nti o n-D efi cit/ H y p e r a cti vit y Di s or d er ( A D H D) ar e 
i n cl u d e d f or t h e t w o s u b s et s of s y m pt o m s: i n att e nti o n (it e m s # 1-# 9) a n d h y p er a cti vit y/i m p ul si vit y (it e m s 
# 1 1 -# 1 9). Al s o, it e m s ar e i n cl u d e d fr o m t h e D S M -I V crit eri a f or O p p o siti o n al D efi a nt Di s or d er (O D D, it e m s 
# 2 1 -# 2 8) si n c e it oft e n i s pr e s e nt i n  c hil dr e n wit h A D H D.  
I n a d diti o n t o t h e D S M-I V it e m s f or A D H D a n d O D D, t h e S N A P-I V c o nt ai n s it e m s fr o m t h e C o n n er s I n d e x 
Q u e sti o n n air e ( C o n n er s, 1 9 6 8) a n d t h e I O W A  C o n n er s Q u e sti o n n air e ( L o n e y a n d Mili c h, 1 9 8 5). T h e 
I O W A w a s d e v el o p e d u si n g di v er g e nt v ali dit y t o s e p ar at e it e m s w hi c h m e a s ur e i n att e nti o n/ o v er a cti vit y 
(I/ O — it e m s # 4, # 8, # 1 1, # 3 1, # 3 2) fr o m t h o s e it e m s w hi c h m e a s ur e a g gr e s si o n/ d efi a n c e ( A/ D — it e m s 
# 2 1, # 2 3, # 2 9, # 3 4, # 3 5). T h e C o n n er s I n d e x (it e m s # 4, # 8,  # 1 1, # 2 1, # 3 2,  # 3 3, # 3 6, # 3 7, # 3 8, # 3 9) w a s 
d e v el o p e d b y s el e cti n g t h e it e m s w hi c h l o a d e d hi g h e st o n t h e m ulti pl e f a ct or s of t h e C o n n er s 
Q u e sti o n n air e, a n d t h u s  r e pr e s e nt s a g e n er al i n d e x of c hil d h o o d pr o bl e m s. 
T h e S N A P -I V al s o  i n cl u d e s t h e 1 0 it e m s of t h e S w a n s o n, K ot ki n, A gl er, M yl n n, a n d P el h a m ( S K A M P) 
R ati n g S c al e. T h e s e it e m s ar e cl a s sr o o m  m a nif e st ati o n s of i n att e nti o n, h y p er a cti vit y, a n d i m p ul si vit y (i. e., 
g etti n g st art e d, st a yi n g o n t a s k, i nt er a cti o n s wit h ot h er s, c o m pl eti n g w or k, a n d s hifti n g a cti viti e s).   T h e 
s u b s c al e s of t h e S K A M P i n cl u d e a c a d e mi c (it e m s # 8 1 -8 6) a n d d e p ort m e nt (it e m s # 8 7 -9 0).  
T h e s u b s c al e s c or e s  will b e s u m m ari z e d b y tr e at m e nt gr o u p at t h e B a s eli n e, W e e k 4, W e e k 6, W e e k 8 
a n d W e e k 1 2  vi sit s  a n d all q u e sti o n n air e d at a will b e di s pl a y e d i n a li sti n g.  
 
C hil dr e n' s Y al e -Br o w n O b s e s si v e C o m p ul si v e S c al e ( C Y -B O C S)  
C hil dr e n' s Y al e -Br o w n O b s e s si v e C o m p ul si v e S c al e ( C Y -B O C S) i s a r eli a bl e a n d  v ali d  s c al e  t o b ot h  
d et er mi n e  s e v erit y  of  O C D  a n d  t o m o nit or  i m pr o v e m e nt d uri n g tr e at m e nt. T h e  s c al e  i s a cli ni ci a n -r at e d, 1 0 -
it e m s c al e  t h at i n cl u d e s q u e sti o n s  a b o ut  t h e a m o u nt  of  ti m e s p e nt  o n  o b s e s si o n s/ c o m p ul si o n s,  l e v el of  
i m p air m e nt or  di str e s s,  a n d  h o w  m u c h  r e si st a n c e a n d  c o ntr ol  s u bj e ct s  h a v e  o v er  t h e s e t h o u g ht s.   
S e v erit y of c o m p ul si o n s a n d o b s e s si o n s ar e r at e d o n a fi v e -p oi nt s c al e fr o m 0 t o 4.   C Y B O C S t ot al s c or e 
i s c o m p ut e d a s t h e s u m of t h e 1 0 it e m s, r a n gi n g fr o m 0 t o 4 0, wit h hi g h er s c or es i n di c ati n g m or e s e v er e 
c o m p ul si o n s a n d o b s e s si o n s.  
T h e t ot al s c or e will b e s u m m ari z e d b y tr e at m e nt gr o u p at t h e B a s eli n e, W e e k 4, W e e k 6, W e e k 8 a n d 
W e e k 1 2  vi sit s  a n d all q u e sti o n n air e d at a will b e di s pl a y e d i n a li sti n g.  
 
C hil dr e n' s D e pr e s si o n R ati n g S c al e -R e vi s e d ( C D R S -R)  
C hil dr e n' s D e pr e s si o n R ati n g S c al e -R e vi s e d ( C D R S -R) i s a cli ni c all y  v ali d at e d  r ati n g s c al e  d e si g n e d  t o 
a s s e s s  p s y c hi atri c  si g n s  a n d  s y m pt o m s  of  d e pr e s si o n s.   F o urt e e n si g n s a n d s y m pt o m s ar e r at e d fr o m 1 
( n or m al) t o 7 ( m o st s e v er e), a n d 3 si g n s a n d s y m pt o m s ar e r at e d fr o m 1 ( n or m al) t o 5 ( m o st s e v er e).  T h e 
r a w s u m m ar y s c or e i s t h e s u m of all 1 7 it e m s, r a n gi n g fr o m 1 7 t o 1 1 3.   
T h e r a w s u m m ar y s c or e will b e s u m m ari z e d b y tr e at m e nt gr o u p at t h e B a s eli n e, W e e k 4, W e e k 6, W e e k 
8 a n d W e e k 1 2  vi sit s  a n d all q u e sti o n n air e d at a will b e di s pl a y e d i n a li sti n g.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 3 5  of 4 8  
 
P e di atri c A n xi et y R ati n g S c al e ( P A R S)  
P e di atri c A n xi et y R ati n g S c al e ( P A R S) i s a cli ni ci a n -r at e d i n str u m e nt f or a s s e s si n g t h e s e v erit y of a n xi et y 
s y m pt o m s a s s o ci at e d wit h c o m m o n a n xi et y di s or d er s a n d g e n er ali z e d a n xi et y i n c hil dr e n a n d 
a d ol e s c e nt s.  T h e P A R S h a s t w o s e cti o n s: t h e s y m pt o m c h e c kli st a n d t h e s e v erit y it e m s.  T h e s y m pt o m 
c h e c kli st i s u s e d t o  d et er mi n e t h e c hil d’ s r e p ert oir e of s y m pt o m s d uri n g t h e p a st w e e k.  T h e 7 -s e v erit y 
it e m i s u s e d t o d et er mi n e s e v erit y of s y m pt o m s a n d t h e P A R S t ot al s c or e.  E a c h s e v erit y it e m i s c o d e d 
fr o m z er o ( n o n e) t o 5 ( m o st e xtr e m e).  N ot a p pli c a bl e i s c o d e d t o 8, a n d d o e s n ot k n o w i s c o d e d t o 9.  
T h e t ot al s c or e f or t h e P A R S i s t ot al of t h e 7 s e v erit y it e m s.  T h e t ot al s c or e r a n g e s fr o m 0 t o 3 5.  C o d e s 
“ 8” a n d “ 9” ar e n ot i n cl u d e d i n t h e s u m m ati o n. 
T h e t ot al s c or e will b e s u m m ari z e d b y tr e at m e nt gr o u p at t h e B a s eli n e, W e e k 4, W e e k 6, W e e k 8 a n d 
W e e k 1 2  vi sit s  a n d all q u e sti o n n air e d at a will b e di s pl a y e d i n a li sti n g.  
 
C O VI D -1 9 A n al y s e s  
D u e t o C O VI D -1 9 p a n d e mic, a d diti o n al a n alys es will b e c o n d uct e d:  
•  
Listi n gs of C O VI D -1 9 r el at e d st u dy disr u pti o n s by s u bj ect a n d by sit e, i ncl u di n g d escri pti o n s of 
t h e disr u pti o n. 
•  
T h e a m o u nt of missi n g d at a by tr e at m e nt gr o u p a n d o v er all by e n d p oi nt f or d at a missi n g d u e t o 
C O VI D -1 9 will b e s u m m ariz e d i n a t a bl e.  
•  
Pr ot oc ol d e vi ati o ns d u e t o C O VI D -1 9 will b e s u m m ariz e d by ty p e a n d tr e at m e nt i n a t a bl e.  
 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 3 6  of 4 8  
 
I nt eri m A n al y s e s 
A n u n bli n d e d i nt eri m a n al y si s will b e c o n d u ct e d w h e n a p pr o xi m at el y 5 0 % of t h e 1 5 0 pl a n n e d s u bj e ct s 
h a v e b e e n  r a n d o mi z e d ( 1: 1 r ati o b et w e e n e c o pi p a m a n d pl a c e b o) a n d c o m pl et ed tr e at m e nt or ar e 
t er mi n at e d e arl y. T h e i nt eri m a n al y si s will b e p erf or m e d b y a n i n d e p e n d e nt st ati sti ci a n a n d g o v er n e d b y 
a n e xt er n al D at a S af et y M o nit ori n g B o ar d ( D S M B). T h e c o n diti o n al p o w er will b e c al c ul at e d t o h el p t h e 
D S M B a s s e s s t h e pr o b a bilit y of a  s u c c e s sf ul st u d y b a s e d o n o b s er v e d d at a.  
T h e pri m ar y effi c a c y e n d p oi nt of t h e st u d y i s t h e Y G T S S -T T S.  A s m all er Y G T S S -T T S s c or e i n di c at e s a 
b ett er c o n diti o n i n s u bj e ct s wit h T o ur ett e’ s s y n dr o m e, a n d w e m a y e x p e ct t h at t h e e c o pi p a m gr o u p h a s a 
l ar g er r e d u cti o n t h a n t h e pl a c e b o gr o u p. L et µ 𝑇𝑇 b e t h e m e a n c h a n g e Y G T S S -T T S s c or e fr o m B a s eli n e t o 
W e e k 1 2 f or t h e e c o pi p a m gr o u p, a n d µ 𝐶𝐶 b e t h e m e a n c h a n g e Y G T S S -T T S s c or e fr o m B a s eli n e t o W e e k 
1 2 f or t h e pl a c e b o gr o u p. T h e n, gi v e n 𝐶𝐶0 : µ 𝐶𝐶≥ µ 𝑛𝑛≡ ∆𝑁𝑁−𝑇𝑇≥0  v s. 𝑛𝑛1 : µ 𝑁𝑁< µ 𝑇𝑇≡ ∆𝑒𝑒−𝑝𝑝< 0  . Si n c e t h e 
ori gi n al s a m pl e si z e c al c ul ati o n i s b a s e d o n t w o -si d e d t e st at a si g nifi c a n c e l e v el of α = 5 %, w e will u s e 
α/ 2 = 2. 5 % t o m at c h t h e o n e -si d e d t e st.  
T h e pri m ar y e n d p oi nt will b e a n al y z e d wit h a Mi x e d M o d el f or R e p e at e d M e a s ur e s ( M M R M) m o d el u si n g 
t h e S A S MI X E D pr o c e d ur e wit h R E P E A T E D st at e m e nt. T h e m o d el will i n cl u d e fi x e d eff e ct s f or tr e at m e nt, 
vi sit, vi sit i nt er a cti o n b et w e e n tr e at m e nt a n d vi sit, r e gi o n, a g e gr o u p ( 0 = c hil dr e n 6 -1 1, 1 = a d ol e s c e nt s 
1 2 -1 7 ) a n d c o v ari at e f or b a s eli n e Y G T S S -T T S.  
T o d et er mi n e if t h e t ot al s a m pl e si z e s h o ul d b e i n cr e a s e d fr o m N (t o 𝛿𝛿∗), t h e c o n diti o n al p o w er b a s e d o n 
t h e M M R M will b e c al c ul at e d at t h e i nt eri m a n al y si s u si n g t h e o b s er v e d eff e ct s ( w h er e n = 7 5) a n d t h e 
pl a n n e d s a m pl e si z e ( N = 1 5 0).  
If it i s d et er mi n e d t h at t h e s a m pl e si z e s h o ul d b e i n cr e a s e d, t h e C H W ( C ui-H u n g -W a n g) st ati sti c, w hi c h 
c o ntr ol s t h e t y p e I err or, will b e u s e d. T h e C H W st ati sti c i s a w ei g ht e d st ati sti c d efi n e d a s:  
𝐿𝐿𝐿𝐿𝐿𝐿𝑒𝑒= �𝐿𝐿1
𝐿𝐿𝐿𝐿1 + �𝑝𝑝2
𝑣𝑣𝑣𝑣2
∗ 
T h e v ali dit y of t h e C H W t e st s t ati sti c r e q uir e s t h at pr e -i nt eri m ( St a g e 1) a n d p o st -i nt eri m ( St a g e 2) 
st ati sti c s T 1  a n d 𝑣𝑣2
∗ b e  st o c h a sti c all y i n d e p e n d e nt of e a c h ot h er. U n d er t h e v ari o u s s c e n ari o s d e s cri b e d 
b el o w, t h e T 1  st ati sti c will b e b a s e d  t h e l e a st-s q u ar e m e a n s fr o m t h e St a g e 1 M M R M m o d el . S p e cifi c all y, 
a t S t a g e 1 t h e m e a n diff er e n c e ∆𝛿𝛿−𝛿𝛿 (tr e at m e nt eff e ct of e c o pi p a m v er s u s pl a c e b o) i s t h e diff er e n c e i n 
l e a st-s q u ar e m e a n s of c h a n g e fr o m b a s eli n e at W e e k 1 2 fr o m t h e M M R M. T h e L S M E A N S st at e m e nt wit h 
C O V o pti o n will r e p ort t h e c o v ari a n c e of L S m e a n s  a n d  t h e v ari a n c e 𝑣𝑣𝑣𝑣𝑣𝑣(𝛿𝛿1 ) of t h e diff er e n c e c a n b e 
c al c ul at e d . T h er e b y, t h e t-st ati sti c 𝑇𝑇1  at t h e i nt eri m a n al y si s c a n b e c al c ul at e d a s : 
𝑇𝑇1 =
𝛿𝛿1
�𝑣𝑣𝑣𝑣𝑣𝑣(𝛿𝛿1 ), w h er e 𝛿𝛿1 = 𝐿𝐿𝐿𝐿𝐿𝐿𝑒𝑒−𝐿𝐿𝐿𝐿𝐿𝐿𝑝𝑝 
T h e  𝑇𝑇2
∗ st ati sti c will b e d efi n e d i n t w o w a y s  t o pr o d u c e t hr e e c o n diti o n al p o w er c al c ul ati o n s, a s f oll o w s: 
Fir stl y, 𝑇𝑇2
∗ will b e b a s e d o n St a g e 2  s a m pl e m e a n s a s s u mi n g all St a g e 2 s u bj e ct s c o m pl et e t h e We e k 1 2 
a s s e s s m e nt.  T h e n t h e St a g e 2 ( p o st-i nt eri m a n al y si s) t-st ati sti c 𝑇𝑇2
∗ at t h e i nt eri m a n al y si s c a n b e 
c al c ul at e d a s:  
𝑇𝑇2
∗=
𝛿𝛿�2
𝜎𝜎�2 / 𝑘𝑘2
∗
 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 3 7  of 4 8  
w h er e 𝑇𝑇�2  i s t h e o b s er v e d tr e at m e nt m e a n diff er e n c e i n t h e c h a n g e of Y G T S S-T T S fr o m b a s eli n e t o W e e k 
1 2 w h e n  t h e 𝐶𝐶2
∗ s u bj e ct s i n St a g e 2 c o m pl et e W e e k 1 2 of st u d y f or e a c h gr o u p.  
Gi v e n t h e i nf or m ati o n at S t a g e 1, 
𝐶𝐶(𝐶𝐶𝑛𝑛𝑁𝑁𝑇𝑇|𝑛𝑛1 ) =  �𝑁𝑁1
𝑇𝑇𝑒𝑒1 + �𝑝𝑝2
𝛿𝛿
𝐿𝐿
𝐿𝐿�2 / 𝐿𝐿2
∗=
�𝑒𝑒1
𝐿𝐿𝐿𝐿1 + �𝐿𝐿2 𝑝𝑝2
∗
2 𝑣𝑣
𝑣𝑣
𝑣𝑣 
𝛿𝛿𝛿𝛿𝑣𝑣(𝑣𝑣𝑣𝑣𝛿𝛿𝑇𝑇|𝑇𝑇1 ) =  𝛿𝛿2
𝑣𝑣𝑣𝑣𝑣𝑣𝛿𝛿(𝛿𝛿2
∗) = 𝐿𝐿2
𝐿𝐿 
T h u s , t h e c o n diti o n al p o w er i s: 
𝐿𝐿𝑒𝑒= 𝐿𝐿�𝐿𝐿𝐿𝐿𝑝𝑝𝑇𝑇< −𝑇𝑇𝑇𝑇2
⁄ �𝑇𝑇1 �≈1 − Φ (�𝛿𝛿
𝜎𝜎2 𝑘𝑘𝛼𝛼2
⁄ + �
𝑛𝑛1
𝑛𝑛2 𝑇𝑇1 + �𝑘𝑘2
∗
2
𝛿𝛿
𝜎𝜎)  
T h e c o n diti o n  p o w er will t h e n b e c al c ul at e d u n d er t h e f oll o wi n g s c e n ari o s f or t h e tr e at m e nt diff er e n c e 𝛿𝛿 
a n d st a n d ar d d e vi ati o n 𝜎𝜎: 
1)  U si n g t h e v al u e s h y p ot h e si z e d i n t h e pr ot o c ol. Tr e at m e nt diff er e n c e 𝛿𝛿= 3  a n d st a n d ar d d e vi ati o n 
𝜎𝜎= 6. 1  
2)  U si n g t h e e sti m at e s fr o m t h e S t a g e 1 d at a. Tr e at m e nt diff er e n c e 𝛿𝛿 i s t h e St a g e 1 o b s er v e d 
s a m pl e m e a n diff er e n c e  i n c h a n g e fr o m b a s eli n e b et w e e n t h e t w o tr e at m e nt gr o u p s, a n d 
st a n d ar d d e vi ati o n 𝜎𝜎 i s t h e p o ol e d st a n d ar d d e vi ati o n of t h e c h a n g e fr o m b a s eli n e, b ot h b a s e d o n 
t h e c o m pl et er s i n t h e r e s p e cti v e tr e at m e nt gr o u p s. 
If t h e dr o p-o ut  r at e b a s e d o n t h e fir st st a g e i s f, t h e c orr e s p o n di n g s a m pl e si z e at 2 n d  st a g e s h o ul d b e 
𝑛𝑛2
∗= 𝑘𝑘2
∗/( 1 − 𝑓𝑓), a n d t h e n e w t ot al s a m pl e si z e i s 𝑁𝑁∗= 𝑛𝑛1 + 𝑛𝑛2
∗. 
S e c o n dl y, 𝑇𝑇2
∗ will b e b a s e d o n St a g e 2  l e a st-s q u ar e s m e a n diff er e n c e a s s u mi n g all S t a g e 2 s u bj e ct s will 
h a v e  t h e s a m e tr e n d i n tr e at m e nt diff er e n c e a n d v ari a bilit y,  a s d o e s  St a g e 1. T h e tr e at m e nt diff er e n c e δ 
will b e e sti m at e d b y t h e l e a st -s q u ar e s m e a n s diff er e n c e b et w e e n tr e at m e nt s o b s er v e d i n St a g e 1. A s 
a b o v e, d efi n e 𝑇𝑇2
∗=
𝛿𝛿�2
�𝑣𝑣𝑣𝑣𝑣𝑣(𝛿𝛿�2 )
, w h er e 𝛿𝛿̂2  i s t h e f ut ur e e sti m at e of tr e at m e nt eff e ct fr o m S t a g e 2. T h e 
i n e q u alit y 𝑇𝑇𝐶𝐶𝐶𝐶𝐶𝐶< −𝑍𝑍𝛼𝛼 2⁄  c a n b e writt e n a s:  
𝛿𝛿̂2 − 𝛿𝛿
�𝑣𝑣𝑣𝑣𝑣𝑣(𝛿𝛿̂2 )
< �𝑁𝑁
𝑛𝑛2
�−𝑍𝑍𝛼𝛼 2⁄
−�𝑛𝑛1
𝑁𝑁𝑇𝑇1 � −
𝛿𝛿
�𝑣𝑣𝑣𝑣𝑣𝑣(𝛿𝛿̂2 )
 
A s a b o v e, 𝑛𝑛1 , 𝑛𝑛2 , N, a n d 𝑇𝑇1  ar e k n o w n at t h e ti m e of t h e i nt eri m a n al y si s, a n d t h e tr e at m e nt eff e ct, 𝛿𝛿, i s 
h y p ot h e si z e d a s t h at e sti m at e d i n St a g e 1. T h e r e m ai ni n g t er m, 𝑣𝑣𝑣𝑣𝑣𝑣(𝛿𝛿̂2 ), i s e sti m at e d a s:  
𝑣𝑣𝑣𝑣𝑣𝑣�𝛿𝛿̂2 �= 𝑛𝑛1 𝑉𝑉𝑣𝑣𝑣𝑣(𝛿𝛿1�) 𝑘𝑘2
∗
⁄
 
T o j u stif y t hi s e q u ati o n, n ot e t h at t h e v ari a n c e of a n M M R M e sti m at e of tr e at m e nt eff e ct d e p e n d s o n 
s a m pl e si z e, ot h er a s p e ct s of st u d y d e si g n i n c or p or at e d i n t h e m o d el ( e. g., c o v ari at e, str atifi c ati o n f a ct or s, 
et c.), a n d u n d erl yi n g p o p ul ati o n v ari a bilit y. D efi n e D  
Rt o b e t h e c o m p o n e nt of 𝑣𝑣𝑣𝑣𝑣𝑣(𝛿𝛿̂1 ) t h at i n c or p or at e s all 
d e si g n a n d c o v ari at e f e at ur e s b ut s a m pl e si z e, i. e., 𝑣𝑣𝑣𝑣𝑣𝑣�𝛿𝛿̂1 �= 𝐷𝐷
𝑛𝑛1
�
, s o t h at D = n1 𝑣𝑣𝑣𝑣𝑣𝑣�𝛿𝛿̂1 �. A s s u mi n g t h at 
t h e m o d el c o m p o n e nt s a n d u n d erl yi n g p o p ul ati o n v ari a bilit y i n St a g e 2 ar e t h e s a m e a s i n St a g e 1, w e 
h a v e 𝑣𝑣𝑣𝑣𝑣𝑣�𝛿𝛿̂2 �=
𝐷𝐷
𝑘𝑘2∗. 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 3 8  of 4 8  
It f oll o w s t h at 𝑇𝑇𝐶𝐶𝐶𝐶�𝐶𝐶̂2 �=  𝑛𝑛1 𝑁𝑁𝑇𝑇𝑛𝑛(𝑁𝑁1�) 𝑇𝑇2
∗
⁄
.  T h er ef or e, t h e c o n diti o n al p o w er i s : 
𝑒𝑒𝑝𝑝= Φ
⎝
⎛�𝛿𝛿
𝐿𝐿2
�−𝐿𝐿𝐿𝐿 2⁄
−�𝑒𝑒1
𝐿𝐿𝐿𝐿1 � −
𝐿𝐿
�𝑝𝑝1 𝑣𝑣𝑣𝑣𝑣𝑣(𝛿𝛿1�) 𝛿𝛿2
∗
�
⎠
⎞ 
T h e c o n diti o n p o w er will t h e n b e c al c ul at e d u n d er t h e f oll o wi n g f or t h e tr e at m e nt diff er e n c e 𝑣𝑣 a n d 
st a n d ar d err or  𝑣𝑣𝑣𝑣𝛿𝛿(𝑇𝑇1�): 
3)  U si n g t h e e sti m at e s fr o m t h e st a g e 1 d at a. Tr e at m e nt diff er e n c e 𝑇𝑇 i s t h e St a g e 1 M M R M 
tr e at m e nt eff e ct �𝛿𝛿1�� a n d  𝑣𝑣𝑣𝑣𝑣𝑣�𝛿𝛿1�� i s t h e v ari a n c e of t hi s e sti m at e  of tr e at m e nt diff er e n c e b a s e d o n 
t h e c o v ari a n c e m atri x of t h e L S m e a n s. 
U si n g t h e s e r e s ult s, t h e D S M B m a y m a k e o n e of t h e f oll o wi n g r e c o m m e n d ati o n s:   
1)  If t h e c o n diti o n al p o w er at t h e pl a n n e d s a m pl e si z e ( 1 5 0) i s l e s s t h a n 3 0 % t h e n t h e D S M B m a y 
r e c o m m e n d t h at t h e st u d y b e t er mi n at e d f or f utilit y. 
2)  If t h e c o n diti o n al p o w er at t h e pl a n n e d s a m pl e si z e ( 1 5 0) i s gr e at er t h a n 3 0 % a n d l e s s t h a n 8 0%, 
t h e n t h e pl a n n e d s a mpl e si z e will b e i n cr e a s e d u p t o 2 0 0 t o tr y t o a c hi e v e a c o n diti o n al p o w er of 
at l e a st 8 0 %. If t h e c o n diti o n al p o w er at t h e m a xi m u m s a m pl e si z e ( 2 0 0) i s still l e s s t h a n 8 0 %, t h e 
D S M B m a y  r e c o m m e n d c o nti n ui n g t h e st u d y at t h e m a xi m u m s a m pl e si z e ( 2 0 0). 
3)  If th e c o n diti o n al p o w er i s at l e a st 8 0 %, t h e n t h e D S M B m a y  r e c o m m e n d c o nti n ui n g t hi s st u d y 
wit h t h e pl a n n e d s a m pl e si z e ( 1 5 0).  
F ull d et ail s of t h e D S M B i n cl u di n g pri m ar y r e s p o n si biliti e s, it s r el ati o n s hi p wit h ot h er st u d y c o m p o n e nt s, 
it s m e m b er s hi p, a n d t h e p ur p o s e a n d ti mi n g s of it s m e eti n g s ar e  d o c u m e nt e d i n a D S M B c h art er. T h e s e 
d et ail s will al s o i n cl u d e pr o c e d ur e s t o e n s ur e c o nfi d e nti alit y a n d pr o p er c o m m u ni c ati o n, t h e g ui d eli n e s t o 
b e i m pl e m e nt e d b y t h e D S M B a n d a n o utli n e of t h e c o nt e nt of t h e cl o s e d r e p ort s ( u n bli n d e d) a n d o p e n 
r e p ort s ( bli n d e d) t h at will b e pr o vi d e d t o t h e D S M B. 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 3 9  of 4 8  
 
C h a n g e s fr o m A n al y si s Pl a n n e d i n Pr ot o c ol  
T h er e ar e n o c h a n g e s fr o m t h e a n al y si s pl a n n e d i n pr ot o c ol.  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 4 0  of 4 8  
 
R ef er e n c e Li st  
1.  R o b ert s o n, M. M., B a n erj e e, S., K url a n, R., C o h e n, D. J., L e c k m a n, J. F., M c M a h o n, W., P a ul s, 
D. L., S a n d or, P., v a n d e W et eri n g, B. J. M. T h e T o ur ett e S y n dr o m e Di a g n o sti c C o nfi d e n c e I n d e x: 
D e v el o p m e nt a n d Cli ni c al A s s o ci ati o n s. N e ur ol o g y D e c 1 9 9 9, 5 3 ( 9) 2 1 0 8 -2 1 1 2.  
2.    L e c k m a n J F, Ri d dl e M A, H ar di n M T, Ort SI, S w art z K L, St e v e n s o n J, et al. T h e Y al e Gl o b al Ti c 
S e v erit y S c al e: i niti al t e sti n g of a cli ni ci a n -r at e d s c al e of ti c s e v erit y. J A m A c a d C hil d A d ol e s c 
P s y c hi atr y 1 9 8 9; 2 8( 4): 5 6 6 -7 3  
3.    P o s n er K, Br o w n G K, St a nl e y B, Br e nt D A, Y er s h o v a K V, O q u e n d o M A, C urri er G W, M el vi n G A, 
Gr e e n hill L, S h e n S, M a n n J J. T h e C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e: i niti al v ali dit y a n d 
i nt er n al  c o n si st e n c y  fi n di n g s  fr o m  t hr e e  m ulti sit e  st u di e s  wit h  a d ol e s c e nt s  a n d  a d ult s.  A m  J 
P s y c hi atr y. 2 0 1 1 D e c; 1 6 8( 1 2): 1 2 6 6 -7 7  
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Cli ni c al Tri al s V er si o n ( S CI D - 5-C T). Arli n gt o n, V A, A m eri c a n P s y c hi atri c A s s o ci ati o n, 2 0 1 5  
5.    L e c k m a n  J F,  T o w bi n  K E,  Ort  SI,  C o h e n  D J.  Cli ni c al  a s s e s s m e nt  of  ti c  di s or d er s  s e v erit y.  I n: 
C o h e n  D J,  Br u u n  R D,  L e c k m a n  J F,  e dit or s.  T o ur ett e’ s  S y n dr o m e  a n d  Ti c  Di s or d er s:  Cli ni c al 
U n d er st a n di n g a n d Tr e at m e nt. N e w Y or k: J o h n Wil e y & S o n s; 1 9 8 8  
6.    G u y,  Willi a m  ( 1 9 7 6).  " Cli ni c al  Gl o b al  I m pr e s si o n s".  E C D E U  A s s e s s m e nt  M a n u al  f or 
P s y c h o p h ar m a c ol o g y — R e vi s e d.  R o c k vill e,  M D:  U. S.  D e p art m e nt  of  H e alt h,  E d u c ati o n,  a n d 
W elf ar e; P u bli c H e alt h S er vi c e, Al c o h ol; Dr u g A b u s e, a n d M e nt al H e alt h A d mi ni str ati o n; N ati o n al 
I n stit ut e of  M e nt al  H e alt h;  P s y c h o p h ar m a c ol o g y  R e s e ar c h  Br a n c h;  Di vi si o n  of  E xtr a m ur al 
R e s e ar c h Pr o gr a m s  
7.    A b n or m al  i n v ol u nt ar y  m o v e m e nt  s c al e  [ AI M S]  ( 1 9 7 6).  N ati o n al  I n stit ut e  of  M e nt al  H e alt h 
P s y c h o p h ar m a c ol o g y  R e s e ar c h  Br a n c h.  G u y,  W.  ( 1 9 7 6).  E C D E U  a s s e s s m e nt  m a n u al  f or 
p s y c h o p h ar m a c ol o g y.  
R e v.  
R o c k vill e,  
M D:  
U. S.  
N ati o n al  
I n stit ut e  
of  
H e alt h, 
P s y c h o p h ar m a c ol o g y R e s e ar c h Br a n c h. P g. 5 3 4 -5 3 7  
8.    B ar n e s  T. R.  A  r ati n g  s c al e  f or  dr u g -i n d u c e d  a k at hi si a.  Briti s h  J o ur n al  of  P s y c hi atr y. 
1 9 8 9; 1 5 4: 6 7 2 -6 7 6.  
9.    S w a n s o n  J M,  Kr a e m er  H C,  Hi n s h a w  S P,  Ar n ol d  L E,  C o n n er s  C K,  A bi k off  H B,  Cl e v e n g er W, 
D a vi e s M, Elli ott G R, Gr e e n hill L L, H e c ht m a n L, H o z a B, J e n s e n P S, M ar c h J S, N e w c or n J H, 
O w e n s E B, P el h a m W E, S c hill er E, S e v er e J B, Si m p s o n S, Viti ell o B, W ell s K, Wi g al T, W u M. 
Cli ni c al  r el e v a n c e of t h e pri m ar y fi n di n g s of t h e M T A: s u c c e s s r at e s b a s e d o n s e v erit y of A D H D 
a n d  O D D  s y m pt o m s  at  t h e  e n d  of  tr e at m e nt.  J  A m  A c a d  C hil d  A d ol e s c  P s y c hi atr y. 
2 0 0 1; 4 0( 2): 1 6 8 -7 9  
1 0.  S c a hill L, Ri d dl e M A, M c S wi g gi n -H ar di n M, Ort SI, Ki n g R A, G o o d m a n W K, Ci c c h etti D, L e c k m a n 
J F. C hil dr e n' s Y al e -Br o w n O b s e s si v e C o m p ul si v e S c al e: r eli a bilit y a n d v ali dit y. J A m A c a d C hil d 
A d ol e s c P s y c hi atr y. 1 9 9 7 J u n; 3 6( 6): 8 4 4 -5 2  
1 1.  P o z n a n s ki  E O,  Fr e e m a n  L N,  M o kr o s  H B.  C hil dr e n' s  D e pr e s si o n  R ati n g  S c al e  R e vi s e d 
( S e pt e m b er 1 9 8 4). P s y c h o p h ar m a c ol B ull 1 9 8 5; 2 1: 9 7 9-9 8 9.  
 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 4 1  of 4 8  
1 2.  S u M, M c F arl a n e F, C a v a n n a A, et al. T h e E n gli s h V er si o n of t h e Gill e s d e l a T o ur ett e  
S y n dr o m e – Q u alit y of Lif e S c al e f or C hil dr e n a n d A d ol e s c e nt s ( C & A -G T S -Q O L). J C hil d N e ur ol 
2 0 1 7; 3 2( 1): 7 6 -8 3.  
1 3.  R e s e ar c h U nit s o n P e di atri c P s y c h o p h ar m a c ol o g y A n xi et y St u d y Gr o u p. T h e P e di atri c A n xi et y 
R ati n g  S c al e  ( P A R S):  d e v el o p m e nt  a n d  p s y c h o m etri c  pr o p erti e s.  J  A m  A c a d  C hil d  A d ol e s c 
P s y c hi atr y 2 0 0 2; 4 1; 1 0 6 1 -9.  
1 4.  H eitj a n,  D a ni el  F.,  a n d  R o d eri c k  J.  A.  Littl e.  “ M ulti pl e  I m p ut ati o n  f or  t h e  F at al  A c ci d e nt 
R e p orti n g  S y st e m.”  J o ur n al of t h e R o y al St ati sti c al S o ci et y. S eri e s C ( A p pli e d St ati sti c s) , 
v ol. 4 0, n o. 1, 1 9 9 1, p p. 1 3 – 2 9.  J S T O R , w w w.j st or. or g/ st a bl e/ 2 3 4 7 9 0 2 . 
1 5.  S c h e n k er,  N at h a ni el  a n d  T a yl or,  J er e m y  M.  G.,  ( 1 9 9 6),  P arti all y  p ar a m etri c  t e c h ni q u e s  f or 
m ulti pl e i m p ut ati o n, C o m p ut ati o n al St ati sti c s & D at a A n al y si s, 2 2, i s s u e 4, p. 4 2 5 -4 4 6.  
1 6.  R u bi n, D o n al d B. ( 1 9 8 7) M ulti pl e I m p ut ati o n f or N o nr e s p o n s e i n S ur v e y s. N e w Y or k: J o h n Wil e y 
& S o n s.  
1 7.  Littl e, R. J., & R u bi n, D. B. ( 2 0 0 2). St ati sti c al A n a l y si s wit h Mi s si n g D at a, 2 n d. e d. U N C 2 0 1 1 S SI L 
Wil e y  
 
 
C CI


 
 
 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 4 2  of 4 8  
 
A p p e n di c e s  
 
S c h e d ul e of A s s e s s m e nt s  
Assess me nt  
Scree ni n g a B aseli ne  
Titr ati o n  
Tre at me nt  
C o m pleti o n/  
E arl y 
Ter mi n ati o n  
 
7 D a y 
F oll o w -u p  
1 4 D a y 
F oll o w -
u p  
 
3 0 d a y 
F oll o w U p *  
St u d y Wee k  
U p t o - 4 
0 
2 * 
4  g 
6  g 
8  g 
1 0 * 
1 2  g 
1 3/ 1 4 g 
1 4/ 1 5 g 
1 6/ 1 7 
St u d y D a ys  
U p t o - 2 8 
0 
1 4 + 3 
2 8 + 3 
4 2 + 3 
5 6 + 3 
7 0 + 3 
8 4 + 3 
7 D a ys 
P ost L ast 
D ose + 3     
1 4 D a ys 
P ost L ast 
D ose + 3  
3 0 D a ys 
P ost L ast 
D ose + 3  
St u d y Visit N u m ber  
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0 
1 1 
I nf or me d C o nsent  
X  
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ E xcl usi o n 
X  
X  
 
 
 
 
 
 
 
 
 
Me dical/ Ps yc hiatric/ me d
icati o n Hist or y  
X 
X 
 
 
 
 
 
 
 
 
 
Ra n d o mizati o n  
 
X 
 
 
 
 
 
 
 
 
 
P h ysical E xa m/ Vital 
Si g ns b 
X 
X 
 
X 
X 
X 
 
X 
X 
X  
 
E C G  
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
La b orat or y tests 
( He mat ol o g y a n d 
C he mistr y )c 
X 
X 
 
 
 
 
 
X 
X 
X  c 
 
Uri ne Dr u g Scree n  
X  
X  
 
 
 
 
 
X  
 
 
 
Uri ne Pre g na nc y T est  
X 
X 
 
 
 
 
 
X 
 
X 
 
D S M -5 Criteria f or T S  
X  
 
 
 
 
 
 
 
 
 
 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 4 3  of 4 8  
Assess me nt  
Scree ni n g a B aseli ne  
Titr ati o n  
Tre at me nt  
C o m pleti o n/  
E arl y 
Ter mi n ati o n  
 
7 D a y 
F oll o w -u p  
1 4 D a y 
F oll o w -
u p  
 
3 0 d a y 
F oll o w U p *  
St u d y Wee k  
U p t o - 4 
0 
2 * 
4  g 
6  g 
8  g 
1 0 * 
1 2  g 
1 3/ 1 4 g 
1 4/ 1 5 g 
1 6/ 1 7 
St u d y D a ys  
U p t o - 2 8 
0 
1 4 + 3 
2 8 + 3 
4 2 + 3 
5 6 + 3 
7 0 + 3 
8 4 + 3 
7 D a ys 
P ost L ast 
D ose + 3     
1 4 D a ys 
P ost L ast 
D ose + 3  
3 0 D a ys 
P ost L ast 
D ose + 3  
St u d y Visit N u m ber  
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0 
1 1 
Y ale G l o bal T ic S e verit y 
Sc ale 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
Cli nical Gl o bal 
I m pressi o n - T o urette’s 
S y n dr o me of Se verit y  
 
X 
 
X 
X 
X 
 
X 
 
 
 
Cli nical Gl o bal 
I m pressi o n - T o urette’s 
S y n dr o me of 
I m pr o ve me nt 
 
 
 
X 
X 
X 
 
X 
 
 
 
C are gi ver Gl o bal 
I m pressi o n of C ha n ge 
 
 
 
X 
X 
X 
 
X 
 
 
 
C ol u m bia S uici de 
Se verit y Rati n g Sca le 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
A b n or mal I n v ol u ntar y 
M o ve me n td 
 
X 
 
X 
X 
X 
 
X 
 
 
 
B ar nes A k at hisia Rati n g 
Scale  
 
X 
 
X 
X 
X 
 
X 
 
 
 
S wa ns o n, N ola n, a n d 
P el ha m Q uesti o n naire  
 
X 
 
X 
X 
X 
 
X 
 
 
 
C hil dre n’s Yale -Br o w n 
O bsessi ve C o m p ulsi ve 
Scale  
 
X 
 
X 
X 
X 
 
X 
 
 
 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 4 4  of 4 8  
Assess me nt  
Scree ni n g a B aseli ne  
Titr ati o n  
Tre at me nt  
C o m pleti o n/  
E arl y 
Ter mi n ati o n  
 
7 D a y 
F oll o w -u p  
1 4 D a y 
F oll o w -
u p  
 
3 0 d a y 
F oll o w U p *  
St u d y Wee k  
U p t o - 4 
0 
2 * 
4  g 
6  g 
8  g 
1 0 * 
1 2  g 
1 3/ 1 4 g 
1 4/ 1 5 g 
1 6/ 1 7 
St u d y D a ys  
U p t o - 2 8 
0 
1 4 + 3 
2 8 + 3 
4 2 + 3 
5 6 + 3 
7 0 + 3 
8 4 + 3 
7 D a ys 
P ost L ast 
D ose + 3     
1 4 D a ys 
P ost L ast 
D ose + 3  
3 0 D a ys 
P ost L ast 
D ose + 3  
St u d y Visit N u m ber  
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0 
1 1 
C hil dre n’s De pressi o n 
Rati n g Scale - Re vise d  
 
X 
 
X 
X 
X 
 
X 
 
 
 
Gilles de la T o urette 
S y n dr o me Q ualit y of 
Life Scale  
 
X 
 
X 
X 
X 
 
X 
 
 
 
P e diatric A n xiet y Scale  
 
X 
 
X 
X 
X 
 
X 
 
 
 
P K Bl o o d Dra w se, h 
 
 
 
X  
 
 
 
X  
 
 
 
A d verse E ve nts  
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X *  
C o nc o mita nt 
Me dicati o ns  
X 
X 
 
X 
X 
X 
 
X 
X 
X  
 
Dis pe nse St u d y Dr u g  
 
X 
 
X 
X 
X 
 
X f 
 
 
 
C ollect U n use d St u d y 
Dr u g/ Assess dr u g 
c o m plia nce  
 
 
 
X 
X 
X 
 
X 
X 
 
 
A b bre viati o ns: A E = a d verse e ve nt; B P = bl o o d press ure; E C G = electr ocar di o gra m; H R = heart rate; P K = p har mac o ki netic(s)  
a 
I nf or me d c o nse nt m ust be perf or me d pri or t o a n y scree ni n g pr oce d ures.  All scree ni n g pr oce d ures are t o occ ur after was h o ut of a n y a p plica ble me dicati o ns.  
Rescree ni n g is all o we d  after a p pr o val b y t he Me dical A d vis or .   
b 
Vital si g ns will i ncl u de, p ulse, B P , ort h ostatic B P ( d o ne 5 mi n utes after bei n g s u pi ne a n d t he n 3 mi n utes after sta n di n g), hei g ht a n d wei g ht. 
c 
S u bj ects s h o ul d be i n a fasti n g state ( 8 h o urs) f or la b orat or y t ests. H b A 1c will be meas ure d at t he baseli ne a n d c o m pleti o n/earl y ter mi nati o n visit s. 
d 
E ver y atte m pt s h o ul d be ma de t o perf or m t his assess me nt at t he sa me ti me at eac h visit.  
e 
At W ee k 4 St u d y d ose s h o ul d n ot be ta ke n u ntil after pre -d ose bl o o d dra w at t he site. P K dra ws s h o ul d be pre -d ose, bet wee n 0. 5 a n d 1. 5 h o urs after st u d y 
dr u g a d mi nistrati o n, a n d bet wee n 2 a n d 4 h o urs after st u d y dr u g a d mi nistrati o n. B ot h W ee k 4 a n d W ee k 1 2, visits s h o ul d be sc he d ule d f or t he m or ni n g. At 
W ee k 1 2, bl o o d sa m ple will b e c ollecte d i n t he after n o o n at t he e n d of t he visit.  
f 
St u d y dr u g will be dis pe nse d f or d ose d o w n titrati o n.   
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 4 5  of 4 8  
*    W ee ks 2 a n d 1 0 will be tel e p h o ne visits. If t here are a n y a b n or mal fi n di n gs, t he s u bj ect will be br o u g ht t o t he site f or f ull  assess me nt. A tele p h o ne call will be 
ma de t o t he s u bj ect 3 0 da ys after t he last visit t o assess a n y a d verse e ve nts t hat ma y ha ve occ urre d.  
g Assess me nts f or t hese visits ma y be c o m plete d i n l ocati o ns ot her t ha n st u d y cli nic a n d/ or safet y a n d efficac y assess me nts re q uire d at t hese visits will b e ma de 
a vaila ble f or re m ote a d mi nistr ati o n d ue t o restricti o ns as a c o nse q ue nce of t he C O VI D -1 9 pa n de mic or ot her q ualif yi n g e ve nt.  
h If visits at W ee ks 4 a n d 1 2 are c o m plete d i n l ocati o ns ot her t ha n st u d y cli nic d ue t o restri cti o ns as a c o nse q ue nce of t he C OVI D -1 9 pa n de mic or ot her 
q ualif yi n g e ve nt, t he n c ollecti o n of la bs f or P K assess me nts are o pti o nal  
 
I n str u m e nt s 
Ex act c o pi es of i nstr u m e nts a n d sc ori n g al g orit h ms ar e pr ovi d e d i n a d diti o n al d oc u m e nt ati o n, lit er at ur e r ef er e nc es ar e st at e d i n S e cti o n 1 3. 
 
M A R m ulti pl e i m p ut ati o n m et h o d ol o g y  
T h e F C S m et h o d will b e u s e d t o i m p ut e missi n g v al u es f or T T S of t h e Y G T S S c h a n g e v al u es a n d will us e a g e gr o u p at b as eli n e,  r e gi o n, tr e at m e nt 
ar m , b as eli n e Y G T S S -T T S sc or e a n d Y G T S S -T T S  s c or e s at all vi sit s u p t o w e e k 1 2  t o d et er mi n e t h e sc or es ( 1 0 0  i m p ut ati o ns will b e cr e at e d). 
T h e S A S c o d e f or t h e i m p ut ati o n is as f oll o ws:  
pr oc mi d at a =fi n al o ut = mi 1 s e e d = 1 2 3 ni m p ut e = 1 0 0 ;    
 cl ass a g e gr p r e gi o n ar m ;  
 v ar a g e gr p r e gi o n ar m b as e _ 4 _ 6 _ 8 _ 1 2;  
 fcs r e g p m m; r u n; 
 
M N A R j u m p t o r ef er e n c e m ulti pl e i m p ut ati o n m et h o d ol o g y  
T h e m o n ot o n e m et h o d  will b e us e d t o i m p ut e missi n g v al u es f or T T S of t h e Y G T S S c h a n g e v al u es a n d will us e a g e gr o u p at b as eli n e , r e gi o n, a n d 
b as eli n e T T S sc or e t o d et er mi n e t h e sc or es ( 1 0 0 i m p ut ati o ns will b e cr e at e d).   O nl y pl ac e b o p ati e nts wit h c o m pl et e d at a will b e i ncl u d e d i n t h e 
i m p ut ati o n m o d el. 
T h e S A S c o d e f or t h e i m p ut ati o n is as f oll o ws:  
pr oc mi d at a = fi n al o ut = mi 2 s e e d = 1 2 3  ni m p ut e = 1 0 0 ;  
cl ass a g e gr p r e gi o n  ar m ; 
   m o n ot o n e r e g;  
   m n ar m o d el( _ 4  / m o d el o bs =(ar m =’ Pl ac e b o’ )); 
   m n ar m o d el( _ 6  / m o d el o bs =( ar m =’ Pl ac e b o’ )); 
   m n ar m o d el( _ 8  / m o d el o bs =( ar m =’ Pl ac e b o’ ));  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 4 6  of 4 8  
   m n ar m o d el( _ 1 2  / m o d el o bs =( ar m =’ Pl ac e b o’ )); 
   v ar a g e gr p r e gi o n b as e _ 4 _ 6 _ 8 _ 1 2 ; 
r u n; 
 
Ti p pi n g P oi nt A n al y si s  
L et d elt a 1 a n d d elt a 2 b e t h e p e n alt y t o e c o pi p a m gr o u p a n d r e w ar d f or pl a c e b o gr o u p, r e s p e cti v el y. D elt a 1 a n d d elt a 2 = 1 t o 1 0  ( or e sti m at e d 
tr e at m e nt eff e ct fr o m pri m ar y a n al y si s if it i s l ar g er t h a n 1 0) i n st e p of 1. G e n er al st e p s f or t hi s a n al y si s i n cl u d e s:  
St e p 1:  
F or e a c h c o m bi n ati o n of ( d elt a 1, d el t a 2), 1 0 0 i m p ut ati o ns will b e cr e at e d.  
I n or d er t o i n d u c e m o n ot o ni cit y, a n i m p ut ati o n m o d el will fir st b e u s e d t o i m p ut e mi s si n g v al u e s f or T T S of t h e Y G T S S w e e k 4 c h a n g e v al u e s a n d 
will u s e a g e gr o u p at b a s eli n e, tr e at m e nt ar m, a n d b a s eli n e T T S s c or e t o d et er mi n e t h e s c or e s.  
T h e S A S c o d e f or t h e i m p ut ati o n i s a s f oll o w s:  
pr o c mi d at a =fi n al o ut = mi s e e d = 6 6 6  ni m p ut e = 1 0 0;  
 cl a s s a g e gr p r e gi o n 1 ar m;  
 v ar a g e gr p r e gi o n 1 ar m b a s e _ 4 ; 
 m o n ot o n e r e g p m m; r u n;  
* Cr e at e d elt a 1, d elt a 2 i n t h e d at a s et; 
d at a mit v 1;  
 s et mi;  
 d o i = 1 t o 1 0 ; 
  d o j = 1 t o 1 0 ; 
     d elt a 1 =i; d elt a 2 =j; o ut p ut;  
  e n d;  
 e n d;  
r u n; 
 
d at a mit v 1;  
 s et mit v 1;  
 if fir st dr p = 4 a n d mi s s d m i n ('' M N A R') a n d i n d e x(ar m , ’ e c o pi p a m’) t h e n _ & c v = _ & c v +d elt a 1;  
el s e if fir st dr p = 4  a n d mi s s d m i n ('' M N A R') a n d ar m =’ Pl a c e b o’ t h e n _ & c v = _ & c v -d elt a 2;  
r u n; 
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 4 7  of 4 8  
 
F or e a c h vi sit aft er w e e k 4 :  
% m a cr o ti p pi m p ( c v, p v, p v s, s e e d);  
 
pr o c mi d at a = mit v & p v o ut = mit v & c urr e nt v s e e d = & s e e d ni m p ut e = 1;  
 cl a s s a g e gr p  r e gi o n 1 ar m;  
 v ar a g e gr p r e gi o n 1 ar m b a s e _ & c v & p v s;  
 m o n ot o n e r e g p m m;  
 b y _I m p ut ati o n _ & d elt a 1 & d elt a 2; r u n;  
d at a mit v & c v;  
if fir st dr p = & c v a n d mi s s d m i n ('' M N A R') a n d i n d e x( ar m, ’ e c o pi p a m’) t h e n _ & c v = _ & c v +d elt a 1;  
el s e if fir st dr p = & c v a n d mi s s d m i n ('' M N A R') a n d ar m =’ Pl a c e b o’ t h e n _ & c v = _ & c v -d elt a 2;  
r u n; 
% m e n d;  
 
 
% ti p pi m p ( 6,  4, _ 4  , 2 6 2 6 ); 
% ti p pi m p ( 8 , 6, 4, % st r( _ 4 _ 6), 2 8 2 8); 
% ti p pi m p ( 1 2, 8, 6, 4 % str( _ 4 _ 6 _ 8 ), 2 9 2 9 ); 
St e p 2  
T h e r e s ult a nt c o m pl et e d at a s et s will b e a n al y z e d u si n g t h e s a m e m o d el a s t h e pri m ar y a n al y si s. T h e S A S c o d e i s a s f oll o w s:  
pr o c s ort d at a = mit v 1 2 ; b y d elt a 1 d elt a 2 _i m p ut ati o n _ d e s c e n di n g ar m a vi sit n; r u n;  
pr o c mi x e d d at a = all or d er = d at a; b y d elt a 1 d elt a 2 _i m p ut ati o n _;  
   cl a s s u s u bji d ar m a vi sit n a g e gr p  re gi o n 1 ; 
   m o d el c h g = ar m a vi sit n ar m* a vi sit n a g e gr p  re gi o n 1  b a s e / d df m = s at;  
   r e p e at e d a vi sit n / t y p e = u n s u bj e ct = u s u bji d; 
   l s m e a n s ar m* a vi sit n / diff cl; 
   o d s o ut p ut diff s = diff( w h er e =( a vi sit n = _ a vi sit n) l s m e a n s =l s m; r u n;  
St e p 3  
C CI


St ati sti c al A n al y si s Pl a n  f or I nt er v e nti o n al St u di e s  
S p o n s or: E m al e x Bi o s ci e n c e s, I n c. ; Pr ot o c ol N o.: E B S -1 0 1 -C L -0 0 1  
 
 
T hi s d o c u m e nt i s c o nfi d e nti al.  
S A P V er si o n: V 3 . 0 2 3 S e p -2 0 2 1  
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 2 9-O ct -2 0 1 8  
Fili n g r e q uir e m e nt s: T M F  
P a g e 4 8  of 4 8  
T h e r e s ult s fr o m t h e i m p ut e d d at a a n al y si s will b e c o m bi n e d u si n g P R O C MI A N A L Y Z E w hi c h will pr o vi d e t h e L S m e a n a n d st a n d ar d err or of t h e 
L S m e a n f or e a c h tr e at m e nt gr o u p at e a c h vi sit a s w ell a s t h e L S m e a n diff er e n c e, 9 5 % CI a n d r e s ult a nt p -v al u e b et w e e n t h e e c o pi p a m  a n d 
pl a c e b o gr o u p s at e a c h vi sit. T h e S A S c o d e i s a s f oll o w s:  
pr o c s ort d at a = diff; b y d elt a 1 d elt a 2 a vi sit n ar m; r u n;  
pr o c s ort d at a =l s m; b y d elt a 1 d elt a 2 a vi sit n ar m; r u n;  
pr o c mi a n al y z e d at a = diff;   b y d elt a 1 d elt a 2 a vi sit n ar m;  
 m o d el eff e ct s e sti m at e;  
 st d err st d err;  
 o d s o ut p ut P ar a m et er E sti m at e s = e st diff; r u n;  
pr o c mi a n al y z e d at a =l s m; b y d elt a 1 d elt a 2 a vi sit n ar m;  
 m o d el eff e ct s e sti m at e;  
 st d err st d err;  
 o d s o ut p ut P ar a m et er E sti m at e s = e stl s m; r u n;  
 
 
C CI