Clinical trial NCT04114539
Conditions: Tourette Syndrome in Children Tourette Syndrome in Adolescence
Keywords: Tourette Syndrome
Sponsor: Emalex Biosciences Inc.
Start date: 2019-10-04; Completion date: 2022-11-11
Enrollment: 124 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study was an international, multicenter, open-label, long term extension study evaluating the safety of ecopipam tablets for the treatment of children and adolescent subjects with Tourette Syndrome.

Detailed description:
This was an international, multicenter, open-label, long term extension study to evaluate the safety of ecopipam tablets for the treatment of pediatric subjects (aged ≥6 to ≤18 years at Baseline) with Tourette Syndrome. Participants who completed the Phase 2b, randomized, double-blind, efficacy and safety study (EBS-101-CL-001) without major reportable protocol deviations, and who met all the inclusion/exclusion criteria for this study were eligible to participate in this study. All participants were titrated to a target dose of 2 mg/kg/day as participants rolled over from the Phase 2b double-blind efficacy and safety study were tapered off study drug to maintain the blind from that study. Participants were to complete study visits every month for 1 year. Follow-up visits were conducted 7 and 14 days after the last dose of the study drug and a follow-up phone call was conducted 30 days after the last dose of study drug

Arms: arm 1: None
Interventions: intervention 1: Ecopipam
Intervention descriptions: intervention 1: Ecopipam HCl 12.5-, 37.5-. 50-, 75- and 100-mg tablets; 2 mg/kg/day target dose; oral administration daily in evenings.

Protocol documents:
Prot_000.pdf: 
 
ECOPIPAM (EBS-101) 
EBS-101-OL-001 
 
IND Number: 
109746 
 
 EudraCT Number: 
2019-000282-20 
 
Protocol Title:  
A Multicenter, Open-Label, Extension Study Intended to 
Evaluate the Long-term 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: 7.0, Amendment 6, 17 November 2021 
 
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 trial 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-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 2 of 76 
1. 
PROTOCOL AMENDMENT CHANGES 
Table 2: 
Study Design and Schedule of Assessments 
Existing Text 
Assessment4 
Baseline* 
(Titration) 
Treatment  
End of Study 
/ Early 
Termination 
Follow Up 
Visit 
Follow Up 
Phone Call  
Study Month 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
One and 
Two Weeks 
Post Last 
Dose 
30 Days 
After Last 
Dose  
Study Visit Number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 & 15 
 
Visit Window 
 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3days 
±3days 
±3days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric/ 
Medication History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Laboratory Tests 
(Hematology and 
Chemistry)2 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Urine Drug Screen 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Urine Pregnancy Test 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 3 of 76 
Assessment4 
Baseline* 
(Titration) 
Treatment  
End of Study 
/ Early 
Termination 
Follow Up 
Visit 
Follow Up 
Phone Call  
Study Month 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
One and 
Two Weeks 
Post Last 
Dose 
30 Days 
After Last 
Dose  
Study Visit Number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 & 15 
 
HbA1c  
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
YGTSS Score 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
CGI-TS-I 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
CGI-TS-S 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
C&A-GTS-QOL 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Columbia Suicide 
Severity Rating Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abnormal Involuntary 
Movement Scale 
(AIMS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Barnes Akathisia 
Ratings Scale (BARS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Children's Depression 
Rating Scale-Revised 
(CDRS-R) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pediatric Anxiety 
Ratings Scale (PARS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 4 of 76 
Assessment4 
Baseline* 
(Titration) 
Treatment  
End of Study 
/ Early 
Termination 
Follow Up 
Visit 
Follow Up 
Phone Call  
Study Month 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
One and 
Two Weeks 
Post Last 
Dose 
30 Days 
After Last 
Dose  
Study Visit Number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 & 15 
 
Dispense Study Drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
 
 
Collect Unused Study 
Drug/Assess Drug 
Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: BP = blood pressure, CGI = Clinician Global Impression, CGI-TS-I = CGI Tourette Syndrome of Improvement, CGI-TS-S = CGI Tourette 
Syndrome of Severity, ECG = electrocardiogram, HbA1c = Hemoglobin A1c 
* Baseline is to occur within 30 days of the EBS-101-CL-001 14 Day Follow Up Visit (or longer with the permission of the medical monitor).  All Baseline 
measurements can be taken from the Day 14 Follow Up Visit of the EBS-101-CL-001 study if performed less than 7 days prior to the Baseline visit.  In this 
case, the HbA1c and Urine Drug Screen from the Week 12/Completion Visit of the EBS-101-CL-001 study may be used.    
1 Vital signs will include heart rate, BP, orthostatic BP and heart rate (done supine and then 3 minutes after standing), height and weight. 
2 Subjects should be in a fasting state (8 hours) for laboratory tests.  
3 Study drug dispensation for down titration. 
4 Assessments for Study 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. 
 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 5 of 76 
Revised Text  
Assessment4 
Baseline* 
(Titration) 
Treatment  
End of Study 
/ Early 
Termination 
Follow Up 
Visit 
Follow Up 
Phone Call  
Study Month 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
One and 
Two Weeks 
Post Last 
Dose 
30 Days 
After Last 
Dose  
Study Visit Number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 & 15 
 
Visit Window 
 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3days 
±3days 
±3days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric/ 
Medication History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Laboratory Tests 
(Hematology,  
Chemistry and 
Urinalysis)2 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Urine Drug Screen 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Urine Pregnancy Test 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HbA1c  
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
YGTSS Score 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
CGI-TS-I 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 6 of 76 
Assessment4 
Baseline* 
(Titration) 
Treatment  
End of Study 
/ Early 
Termination 
Follow Up 
Visit 
Follow Up 
Phone Call  
Study Month 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
One and 
Two Weeks 
Post Last 
Dose 
30 Days 
After Last 
Dose  
Study Visit Number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 & 15 
 
CGI-TS-S 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
C&A-GTS-QOL 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Columbia Suicide 
Severity Rating Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abnormal Involuntary 
Movement Scale 
(AIMS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Barnes Akathisia 
Ratings Scale (BARS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Children's Depression 
Rating Scale-Revised 
(CDRS-R) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pediatric Anxiety 
Ratings Scale (PARS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense Study Drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
 
 
Collect Unused Study 
Drug/Assess Drug 
Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 7 of 76 
Abbreviations: BP = blood pressure, CGI = Clinician Global Impression, CGI-TS-I = CGI Tourette Syndrome of Improvement, CGI-TS-S = CGI Tourette 
Syndrome of Severity, ECG = electrocardiogram, HbA1c = Hemoglobin A1c 
* Baseline is to occur within 30 days of the EBS-101-CL-001 14 Day Follow Up Visit (or longer with the permission of the medical monitor).  All Baseline 
measurements can be taken from the Day 14 Follow Up Visit of the EBS-101-CL-001 study if performed less than 7 days prior to the Baseline visit.  In this 
case, the HbA1c and Urine Drug Screen from the Week 12/Completion Visit of the EBS-101-CL-001 study may be used.    
1 Vital signs will include heart rate, BP, orthostatic BP and heart rate (done supine and then 3 minutes after standing), height and weight. 
2 Subjects should be in a fasting state (8 hours) for laboratory tests.  
3 Study drug dispensation for down titration. 
4 Assessments for Study 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. 
 
Rationale for Amendment 
Urinalysis is being added.   
 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 8 of 76 
Section: 12.1 Safety Parameters  
Existing Text 
 
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) 
 
 
Revised Text 
 
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 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential  
Page 9 of 76 
Other 
Glucose, calcium, albumin, cholesterol, 
triglycerides, phosphorus, lactate 
dehydrogenase (LDH), total protein, 
globulin 
Urinalysis 
Complete urinalysis includes color, 
appearance, specific gravity, pH, protein, 
glucose, ketones, and blood with 
microscopic examination for positive 
protein or blood results 
Pregnancy Test 
Urine test (for women of childbearing 
potential only) 
Special Parameters - Hemoglobin 
A1c (HbA1c) 
 
 
Rationale for Amendment 
Urinalysis is being added.   
 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential  
Page 10 of 76 
SIGNATURE PAGE 
 
Sponsor’s Approval 
The protocol has been approved by Emalex Biosciences, Inc. 
This program will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical protocol and also in accordance with the 
following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonization (ICH) Tripartite: Harmonized Guideline for 
Good Clinical Practice E6. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 
 
Drug 
Development 
Emalex Biosciences, Inc. 
 
 
 
 
 
 
Date 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential  
Page 11 of 76 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for Ecopipam.  I have read the protocol 
EBS-101-OL-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 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential  
Page 12 of 76 
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Clinical Study Leader 
 
 
 
Drug Safety Physician 
Syneos Medical Physician 
1 877-462-0134 
24-Hour emergency contact 
Syneos Medical Physician 
1 877-462-0134 
 
PPD
PPD
PPD


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential  
Page 13 of 76 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Emalex Biosciences, Inc. 
Name of Investigational Product: 
Ecopipam Tablets 
Protocol Number: EBS-101-OL-001 
Title of Study:  
A Multicenter, Open-Label, Extension Study Intended to Evaluate the Long-term Safety of Ecopipam 
Tablets in Children and Adolescent Subjects with Tourette’s Syndrome 
Study center(s): Approximately 60 sites in US, Canada and EU 
Principal Investigator: TBD 
Investigators: TBD 
Studied period (years):  
Estimated date first patient enrolled: 3Q2019 
Estimated date last patient completed:  2Q2023, or until NDA 
approval or until development is discontinued by the 
Sponsor, whichever is sooner 
Phase of development:  
2b 
Objectives:  
The primary objective of this study is to evaluate the long-term safety and tolerability of ecopipam 
tablets in pediatric subjects (aged ≥6 to ≤18 years at Baseline) with Tourette’s Syndrome (TS) that 
were previously enrolled in the EBS-101-CL-001 study (Phase 2b) and completed the Phase 2b study.  
The secondary objective is to evaluate the durability of effect of ecopipam in pediatric subjects (aged 
≥6 to ≤18 years at Baseline) with TS. 
Methodology:  
This is an international, multicenter, open-label, long-term extension study evaluating the safety of 
ecopipam tablets for the treatment of children and adolescent subjects with TS.  Subjects who 
completed the Phase 2b, randomized double-blind efficacy and safety study (EBS-101-CL-001) and 
who continue to meet the inclusion/exclusion criteria for this study will be eligible to participate in 
this study.  All subjects will be titrated to a target dose of 2 mg/kg/day as subjects participating from 
previous studies will be tapered off of study medication to maintain the blind. Subjects will complete 
study visits every month for 1 year.  Follow Up visits will be conducted 7 and 14 days after the last 
dose of study medication and a Follow Up phone call will be conducted 30 days after the last dose of 
study medication.  Study Visits 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.   
Safety will be monitored throughout the study at all visits by repeated adverse event (AE) monitoring, 
vital signs, the Columbia-Suicide Severity Rating Scale (C-SSRS), the Abnormal Involuntary 
Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), the Pediatric Anxiety Rating 
Scale (PARS) and Children's Depression Rating Scale-Revised (CDRS-R).  In addition to these 
assessments, at Baseline, Months 1, 3, 6, 9 and 12 safety will also be monitored by clinical and 
laboratory evaluations, and electrocardiogram (ECG) monitoring.  In addition to the scales 
aforementioned, the Yale Global Tic Severity Scale (YGTSS), Clinician Global Impression of 
Tourette Syndrome of Severity (CGI-TS-S), the Clinician Global Impression Tourette Syndrome of 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential  
Page 14 of 76 
Improvement (CGI-TS-I) and the Gilles de la Tourette Syndrome–Quality of Life Scale for Children 
and Adolescents (C&A-GTS-QOL) will also be assessed at Baseline, Months 1, 3, 6, 9 and 12.  At the 
Follow Up visits, AE monitoring, the C-SSRS, clinical and laboratory evaluations and vital signs will 
be assessed.  A Follow Up phone call will be conducted 30 days after the last dose of study 
medication to assess AEs. 
Number of subjects (planned):  
The actual number of subjects that are enrolled will depend on the final number of subjects who 
complete the Phase 2b, randomized double-blind efficacy and safety study (EBS-101-CL-001)and 
who continued to meet the inclusion and exclusion criteria for this study.   . 
Diagnosis and main criteria for inclusion:  
Inclusion Criteria: 
1) Subjects must have completed the EBS-101-CL-001 study through the Day 14 Follow Up Visit 
within the last 30 days (or longer with permission of the medical monitor) and must be who the 
Investigator feels would benefit from continued participation.   
2) 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.  
3) 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.  
4) Parents or legal guardians of subjects <18 years of age at Baseline must execute a written 
informed consent.  Subjects ≥18 years of age must execute a written informed consent.   
5) Subjects <18 years of age at Baseline must execute a written informed assent according to the 
requirements of the site’s IRB/EC.  
Exclusion Criteria: 
1) Subjects with a clinical presentation 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). 
2) History of schizophrenia, bipolar disorder, or other psychotic disorders. 
3) Any unstable primary mood disorder (DSM-5 criteria) at time of Baseline. 
4) Subjects who have unstable medical illness or clinically significant abnormalities on laboratory 
tests or ECG at Baseline as determined by the Principal Investigator.  
5) Subjects who have moderate to severe renal insufficiency at Screening. 
6) Subjects with a major depressive episode in the past 2 years.  
7) Subjects with a history of attempted suicide.  
8) 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. 
9) Subjects with a history of seizures (excluding febrile seizures that occurred <2 years prior to 
Baseline). 
10) Subjects with a myocardial infarction within 6 months.  
11) Female subjects who are currently pregnant or lactating or planning to get pregnant during the 
course of the study.  


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential  
Page 15 of 76 
12) 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. 
13) Subjects with current or recent (past 3 months) DSM-5 substance use disorder (with the exception 
of nicotine).  
14) Subjects with positive urine drug screen for cocaine, amphetamine, methamphetamine, 
benzodiazepines, barbiturates, phencyclidine (PCP) or opiates at Baseline, except those receiving 
stable, prescribed treatment for attention deficit/hyperactivity disorder.  Subjects with urine 
positive only for benzodiazepines will be exclusionary unless medically prescribed.   
15) Subjects with a lifetime history of bipolar disorder type I or II, dementia, schizophrenia, or any 
other psychotic disorder.    
16) Inability to swallow tablets. 
17) Subjects with a known hypersensitivity to ecopipam or any of its excipients. 
18) 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 will be supplied as 12.5-, 37.5-, 50-, 75-, and 100-mg tablets.  The target dose is 
2 mg/kg via oral administration. 
 
Subjects will be dosed according to 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.   
 
During the 4-week titration period, the following ecopipam HCl doses 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 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 52-week treatment phase, the following ecopipam doses 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 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. 
At the end of the 52-week treatment phase, subjects will titrate off therapy and receive ecopipam HCl 
doses that will be reduced by 25 mg/day until off drug. 


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Duration of treatment:  
52-weeks, until New Drug Application (NDA) approval, or until development of the study drug is 
discontinued by the Sponsor, whichever is sooner. 
Criteria for evaluation: 
Safety:  Study Visits 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.  Safety will be 
monitored throughout the study at every visit by repeated adverse event (AE) monitoring, vital signs, 
the Columbia-Suicide Severity Rating Scale (C-SSRS), the Abnormal Involuntary Movement Scale 
(AIMS), the Barnes Akathisia Rating Scale (BARS), the Pediatric Anxiety Rating Scale (PARS) and 
Children's Depression Rating Scale-Revised (CDRS-R).  In addition to these assessments, at Baseline, 
Months 1, 3, 6, 9 and 12 safety will also be monitored by clinical and laboratory evaluations and 
electrocardiogram (ECG) monitoring.  At the Follow Up visits, AE monitoring, the C-SSRS, 
clinical and laboratory evaluations and vital signs will be assessed.  Laboratory evaluations will 
include hematology, chemistry, urine values and HbA1c.  A Follow Up phone call will be conducted 
30 days after the last dose of study medication to assess AEs.  Subjects will be monitored for signs of 
abuse, and withdrawal or dependence. 
 
Efficacy: The YGTSS, CGI-TS-S and C&A-GTS-QOL will be conducted at Baseline and Months 1, 
3, 6, 9 and 12.  The CGI-TS-I will be conducted at Months 1, 3, 6, 9, and 12. 
All safety and efficacy variables will be summarized descriptively.   
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, these additional analyses will be specified in the SAP.  
 
 


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3. 
TABLE OF CONTENTS 
1. 
PROTOCOL AMENDMENT CHANGES ..................................................................2 
SIGNATURE PAGE .....................................................................................................................10 
INVESTIGATOR’S AGREEMENT .............................................................................................11 
PROCEDURES IN CASE OF EMERGENCY .............................................................................12 
2. 
SYNOPSIS .................................................................................................................13 
3. 
TABLE OF CONTENTS ...........................................................................................17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Background on Tourette’s Syndrome .........................................................................21 
5.1.1. 
Disrupted Dopamine Systems in Tourette’s Syndrome..............................................22 
5.2. 
Background on Ecopipam ...........................................................................................23 
5.2.2. 
Clinical Data ...............................................................................................................23 
5.2.2.1. 
Safety in Humans ........................................................................................................23 
5.3. 
Risk-Benefit Assessment ............................................................................................27 
5.3.1. 
Assessment of Risk .....................................................................................................27 
5.3.2. 
Assessment of Benefit ................................................................................................28 
5.3.3. 
Methods to Minimize Risks ........................................................................................29 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................31 
6.1. 
Primary Objective .......................................................................................................31 
6.2. 
Secondary Objectives .................................................................................................31 
7. 
INVESTIGATIONAL PLAN .....................................................................................32 
7.1. 
Overall Study Design ..................................................................................................32 
7.2. 
Number of Subjects ....................................................................................................32 
7.3. 
Treatment Assignment ................................................................................................32 
7.4. 
Dose Adjustment Criteria ...........................................................................................32 
7.5. 
Criteria for Subject Study Discontinuation .................................................................33 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................37 
8.1. 
Subject Inclusion Criteria ...........................................................................................37 
8.2. 
Subject Exclusion Criteria ..........................................................................................37 
8.3. 
Subject Withdrawal Criteria .......................................................................................38 
CCI


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9. 
TREATMENT OF SUBJECTS ..................................................................................39 
9.1. 
Description of Study Drug ..........................................................................................39 
9.2. 
Concomitant Medications ...........................................................................................39 
9.3. 
Prohibited Therapies ...................................................................................................39 
9.4. 
Treatment Compliance ................................................................................................40 
9.5. 
Randomization and Blinding ......................................................................................40 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................41 
10.1. 
Study Drug ..................................................................................................................41 
10.2. 
Study Drug Packaging and Labeling ..........................................................................41 
10.3. 
Study Drug Storage .....................................................................................................41 
10.4. 
Study Drug Preparation ..............................................................................................41 
10.5. 
Administration ............................................................................................................41 
10.6. 
Dosing Rationale ........................................................................................................43 
10.7. 
Study Drug Accountability .........................................................................................45 
10.8. 
Study Drug Handling and Disposal ............................................................................45 
11. 
ASSESSMENT OF EFFICACY ................................................................................46 
11.1 
Efficacy Assessments .................................................................................................46 
12. 
ASSESSMENT OF SAFETY .....................................................................................47 
12.1. 
Safety Parameters .......................................................................................................47 
12.2. 
Adverse and Serious Adverse Events .........................................................................48 
12.2.1. 
Definition of Adverse Events .....................................................................................48 
12.2.1.1. 
Treatment-Emergent Adverse Event ..........................................................................49 
12.2.1.2. 
Serious Adverse Event ................................................................................................49 
12.2.1.3. 
Other Adverse Event ...................................................................................................49 
12.3. 
Relationship to Study Drug ........................................................................................50 
12.4. 
Recording Adverse Events .........................................................................................50 
12.5. 
Reporting Adverse Events ..........................................................................................51 
13. 
STATISTICS ..............................................................................................................52 
13.1. 
Analysis Populations ..................................................................................................52 
13.2. 
Planned Analyses ........................................................................................................52 
13.2.1. 
Safety Analysis ...........................................................................................................52 
13.2.2. 
Efficacy Analysis ........................................................................................................53 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................54 
14.1. 
Study Monitoring ........................................................................................................54 
14.2. 
Audits and Inspections ................................................................................................54 
14.3. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................55 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
16. 
ETHICS ......................................................................................................................57 
16.1. 
Ethics Review .............................................................................................................57 
16.2. 
Ethical Conduct of the Study ......................................................................................57 
16.3. 
Written Informed Consent ..........................................................................................57 
16.4. 
Subject Confidentiality ...............................................................................................57 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................59 
17.1. 
Inspection of Records .................................................................................................59 
17.2. 
Retention of Records ..................................................................................................59 
18. 
PUBLICATION POLICY ..........................................................................................60 
19. 
LIST OF REFERENCES ............................................................................................61 
20. 
REFERENCES FOR QUESTIONNAIRES AND SCALES .....................................62 
21. 
APPENDICES ............................................................................................................63 
WMA DECLARATION OF HELSINKI – ETHICAL PRINCIPLES FOR MEDICAL 
RESEARCH INVOLVING HUMAN SUBJECTS ....................................................63 
CONTRACEPTION GUIDELINES .............................................................................................69 
PROHIBITED MEDICATIONS LIST ..........................................................................................70 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information .................................................................................12 
Table 2: 
Study Design and Schedule of Assessments ..............................................................34 
Table 3: 
Investigational Product ...............................................................................................39 
Table 4: 
Proposed Dosing Regimen .........................................................................................43 
Table 5: 
Animal:Human Exposure Ratios with the Proposed Dosage Regimen of 
Ecopipam HCl to 7 to 16 Year Olds ...........................................................................44 
 
 


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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 
AE 
adverse event 
AESI 
adverse event of special interest 
AIMS 
Abnormal Involuntary Movement Scale 
CDRS-R 
Children’s Depression Rating Scale-Revised 
CGI 
Clinician Global Impression 
CGI-TS-I 
Clinician Global Impression Tourette’s Syndrome of Improvement 
CGI-TS-S 
Clinician Global Impression Tourette’s Syndrome of Severity 
CI 
confidence interval 
COVID-19 
SARS-CoV-2 (coronavirus) 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CY-BOCS 
Child Yale-Brown Obsessive Compulsive  
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – 5th 
Edition 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HCl 
Hydrochloride 
HbA1c 
Hemoglobin A1c 
ITT 
Intent-to-treat 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LND 
Lesch-Nyhan Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
OAE 
other adverse event 
OCD 
obsessive-compulsive disorder 
PARS 
Pediatric Anxiety Rating Scale 
PO 
oral (per os) 
SAE 
serious adverse event 
SCH 
Schering-Plough drug code indicator 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TS 
Tourette’s Syndrome 
US 
United States 
YGTSS 
Yale Global Tic Severity 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.1,2  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.2  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 
appear several years after the onset of motor tics.  For most subjects, the period of worst-ever tic 
severity is between 7 and 15 years old, 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.3  
 
DSM-V 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 (attention deficit disorder [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 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 
patients.  Many patients eventually discontinue due to adverse events (AEs), including 
extrapyramidal disorders, somnolence, blood glucose changes, weight gain, and effects on lipids.  
A selective D1 dopamine receptor blocking agent may mitigate against some of these AEs and 
has the 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.4  Research to date has 
indicated that dopamine circuits in the central nervous system (CNS) are intimately involved 
based on the following observations.5,6,7 
• Dopamine-rich areas of the brain (e.g., striatum) are believed to control motor tics. 
• Clinical neuroimaging studies of TS patients implicate dopamine-rich brain areas. 
• Dopamine antagonists can ameliorate tics.  


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• 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 earlier 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.  
The Phase 1 studies examined ecopipam's pharmacokinetics, pharmacodynamics, bioavailability, 
distribution, food-effects on absorption, interactions with other drugs, bioequivalence of different 
CCI


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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 AEs were mild to moderate in intensity.  The most commonly reported AE 
in Phase 1 clinical studies were somnolence.  Other commonly reported AEs in Phase 1 clinical 
studies were headache, fatigue, nausea, and insomnia. 
In a Phase 2 study (C197-184), 279 subjects with cocaine dependence in 3 dose groups (10-, 25-, 
and 100 mg/day) were exposed to ecopipam HCl for 8 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 AEs 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 6 weeks.  Ecopipam, when administered to 
subjects with schizophrenia, did not demonstrate efficacy in these studies.  The most commonly 
reported AEs 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 AEs 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, 
once daily [QD]) for 52 weeks.  Subjects receiving ecopipam HCl showed a dose-dependent 
weight loss.  These Phase 3 studies were discontinued because of unexpected psychiatric AEs 
(ecopipam 31% vs. placebo 15%), including depression, anxiety, and suicidal ideation, thereby 
excluding its projected use in weight management.  The most frequently reported AEs 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), and nausea 7% (107/1482).  
The frequencies of insomnia, depression, somnolence, and anxiety were about twice as frequent 
in subjects receiving ecopipam HCl than placebo.  The frequencies of upper respiratory tract 
infection, headache, fatigue, pharyngitis, back pain and nausea were similar in frequencies in 
subjects receiving ecopipam and placebo.   


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Clinical Summary: 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 (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 Phase1 LND study (PSY101), in which 4 of 5 subjects were children, the most commonly 
reported AEs 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 pathological gambling (PSY201) received placebo (1-2 tablets/day orally 
depending on their urge to gamble) for 1 week and then ecopipam HCl (1-2 50-mg tablets/day 
orally depending on their urge to gamble) for 6 weeks.  The most commonly reported AEs 
(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 done.  A total of 9 pediatric subjects were enrolled before the study was terminated 
for non-safety related reasons.  Ecopipam HCl was administered at either 50 mg/day (<20 kg 
body weight) or 100 mg/day (>20 kg body weight).  In the PSY102 LND study, 1 subject aged 
10 years old experienced dystonia, swallowing difficulty, and depressed mood which involved 
persistence or significant disability or incapacity.  The same subject experienced renal calculus, 
dystonia, and bronchospasm which involved persistence or significant disability or incapacity, 
and the relationship to study drug was not related.  Another subject aged 6 years old experienced 
dysphagia, somnolence, and depressed mood which involved persistence or significant disability 
or incapacity, and the relationship to study drug was possibly related.  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 these AEs 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 Score (YGTSS).  After ecopipam treatment, 
YGTSS total score, motor tics score, phonic tics score, and overall impairment were all 
significantly decreased from baseline to endpoint, which indicated that the severity of tics was 
decreased.  The most commonly reported AEs (incidence≥20%) were sedation (33%), insomnia 
(33%), fatigue (33%), somnolence (28%), headache (22%), muscle twitching (22%), and anxiety 
(22%).  


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Study PSY302 
In a Phase 2b multicenter, double blind, randomized, crossover study (PSY302), 40 children/ 
adolescents (ages 7-17 years) were given ecopipam HCl up to 50 mg/day (if <75 lbs) or 
100 mg/day (if >75lbs) for 4 weeks.  The primary endpoint was the YGTSS Total (MP) Scores 
which were the sum of the motor and phonic subscales of YGTSS.  In the Intent-to-treat (ITT) 
population, the mean (± standard deviation [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 by 5.1 (±8.5) points on ecopipam 
and 2.1 (±4.7) points on placebo.  On Day 30, YGTSS Total (MP) Scores decreased by 5.6 
(±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, least square (LS) means (±standard error [SE]) of the difference between 
ecopipam and placebo treatment were -2.8885±1.5282 (95% confidence interval [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 days 
(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.  The secondary endpoints were not ranked in a hierarchical order and 
multiplicity was not taken into account.  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 days of 
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 the Evaluable population. 
In the ITT population, after 30 days of treatment, Clinician Global Impression (CGI) Severity 
Scores decreased by 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%, 
respectively; while the percentages on placebo were 20.00%, 27.50%, 32.50%, and 12.50%, 
respectively.  Similar results were observed in the 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 by 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 the 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 by 0.8 (±3.3) points on ecopipam and 0.9 (±4.1) points on placebo.  The results 
of the obsession and compulsion subscales were similar to the total scores. 


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The results from the Safety population were the same as the ITT population. 
A total of 149 treatment-emergent adverse events (TEAEs) were reported in 35 of the 40 treated 
subjects (87.50%).  There was 1 serious TEAE during placebo treatment and 1 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 (50.00%) reporting TEAEs related to study drug during ecopipam treatment and 
10 subjects (25.00%) during placebo treatment.  Forty percent (40.00%) of TEAEs were mild 
and 37.50% were moderate.  One subject decreased the dosage due to fatigue one day after 
starting ecopipam.  Another subject in the ecopipam group was discontinued from the study due 
to rash starting at Day 0 of the second treatment phase. 
The most common TEAEs during ecopipam treatment were headache (6 of 40), abdominal pain 
upper (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), abdominal pain upper (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, Children’s Depression 
Inventory (CDI) scores or Columbia Suicide Severity Rating Scale (C-SSRS) in the subjects.  
There were no clinically significant laboratory abnormalities, changes in vital signs, ECG, or 
physical examination findings after ecopipam administration.  There were no AEs related to 
extrapyramidal reactions.  
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-OL-001 is outlined below.  
5.3.1. 
Assessment of Risk 
As 2651 human subjects have been exposed to single and multiple doses 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 


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depression, anxiety and suicidal ideation) and the gastrointestinal system (e.g., nausea and 
vomiting). 
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 extrapyramidal 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 on 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.  


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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 
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 this study 
• All subjects will be evaluated for safety at monthly visits for one year.  Follow-up 
visits will be conducted 7 and 14 days after the last dose of study medication and a 
follow-up phone call will be conducted 30 days after the last dose of study 
medication. 
• 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 
− Columbia Suicide Severity Rating Scale 
− Children’s Depression Rating Scale-Revised 
− Gilles de la Tourette Syndrome Quality of Life Scale 


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− Pediatric Anxiety Scale 
− Clinical Global Impression Tourette Syndrome of Severity 
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, extrapyramidal 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 long-term safety and tolerability of 
ecopipam tablets in pediatric subjects (aged ≥6 to ≤18 years at Baseline) with TS that were 
previously enrolled in study EBS-101-CL-001 within the time period specified for this protocol. 
6.2. 
Secondary Objectives 
The secondary objective of this study is to evaluate the durability of effect of ecopipam in 
pediatric subjects (aged ≥6 to ≤18 years at Baseline) with TS. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an international, multicenter, open-label, long-term extension study evaluating the safety 
of ecopipam tablets for the treatment of pediatric subjects (aged ≥6 to ≤18 years at Baseline) 
with TS.  Subjects who completed the Phase 2b, randomized, double-blind, efficacy and safety 
study (EBS-101-CL-001) and who meet all the inclusion/exclusion criteria for this study will be 
eligible to participate in this study.  All subjects will be titrated to a target dose of 2 mg/kg/day as 
participants rolling over from the Phase 2b double-blind efficacy and safety study will be tapered 
off of study medication to maintain the blind from that study.  Subjects will complete study visits 
every month for 1 year.  A Follow Up visits will be conducted 7 and 14 days after the last dose 
of study medication and a Follow Up phone call will be conducted 30 days after the last dose of 
study medication.  Study Visits 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.   
Safety will be monitored throughout the study at every visit by repeated adverse event (AE) 
monitoring, vital signs, the Columbia-Suicide Severity Rating Scale (C-SSRS), the Abnormal 
Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), the Pediatric 
Anxiety Rating Scale (PARS) and Children's Depression Rating Scale-Revised (CDRS-R).  In 
addition to these assessments, at Baseline, Months 1, 3, 6, 9 and 12 safety will also be monitored 
by clinical and laboratory evaluations, and electrocardiogram (ECG) monitoring.  In addition to 
the scales aforementioned, the YGTSS, CGI Tourette Syndrome of Severity (CGI-TS-S), and 
Gilles de la Tourette Syndrome–Quality of Life Scale for Children and Adolescents (C&A-GTS-
QOL) will also be assessed at Baseline, Months 1, 3, 6, 9 and 12.  The CGI-TS-I will be 
conducted at Months 1, 3, 6, 9, and 12.  At the Follow Up visits, AE monitoring, the C-SSRS, 
clinical and laboratory evaluations and vital signs will be assessed.  A Follow Up phone call will 
be conducted 30 days after the last dose of study medication to assess AEs. 
7.2. 
Number of Subjects 
The actual number of subjects that are enrolled will depend on the final number of subjects who 
complete study EBS-101-CL-001. 
7.3. 
Treatment Assignment 
Since this is an open-label study, all subjects that have cleared the inclusion/exclusion criteria 
will be administered ecopipam HCl at a target dose of 2 mg/kg/day. 
7.4. 
Dose Adjustment Criteria 
Doses will be adjusted based on the following weight bands to better achieve the 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.  
Dosing adjustments would be allowed down one dose level based on titration for safety reasons 
at the discretion of the Principal Investigator.  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 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 discontinued 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 1 or more 
of these reasons as secondary reasons for discontinuation.  Study disposition information will be 
collected on the case report form (CRF). 
 


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Table 2: 
Study Design and Schedule of Assessments 
Assessment4  
Baseline* 
(Titration) 
Treatment  
End of Study 
/ Early 
Termination 
Follow Up 
Visit 
Follow Up 
Phone Call  
Study Month 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
One and 
Two Weeks 
Post Last 
Dose 
30 Days 
After Last 
Dose  
Study Visit Number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 & 15 
 
Visit Window 
 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3
days 
±3days 
±3days 
±3days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric/ 
Medication History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Laboratory Tests 
(Hematology, 
Chemistry and 
Urinalysis)2 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Urine Drug Screen 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Urine Pregnancy Test 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HbA1c  
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
YGTSS Score 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
CGI-TS-I 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 


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Assessment4  
Baseline* 
(Titration) 
Treatment  
End of Study 
/ Early 
Termination 
Follow Up 
Visit 
Follow Up 
Phone Call  
Study Month 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
One and 
Two Weeks 
Post Last 
Dose 
30 Days 
After Last 
Dose  
Study Visit Number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 & 15 
 
CGI-TS-S 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
C&A-GTS-QOL 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Columbia Suicide 
Severity Rating Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abnormal Involuntary 
Movement Scale 
(AIMS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Barnes Akathisia 
Ratings Scale (BARS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Children's Depression 
Rating Scale-Revised 
(CDRS-R) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pediatric Anxiety 
Ratings Scale (PARS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense Study Drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
 
 
Collect Unused Study 
Drug/Assess Drug 
Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Abbreviations: BP = blood pressure, CGI = Clinician Global Impression, CGI-TS-I = CGI Tourette Syndrome of Improvement, CGI-TS-S = CGI Tourette 
Syndrome of Severity, ECG = electrocardiogram, HbA1c = Hemoglobin A1c 
* Baseline is to occur within 30 days of the EBS-101-CL-001 14 Day Follow Up Visit (or longer with the permission of the medical monitor).  All Baseline 
measurements can be taken from the Day 14 Follow Up Visit of the EBS-101-CL-001 study if performed less than 7 days prior to the Baseline visit.  In this 
case, the HbA1c and Urine Drug Screen from the Week 12/Completion Visit of the EBS-101-CL-001 study may be used.    
1 Vital signs will include heart rate, BP, orthostatic BP and heart rate (done supine and then 3 minutes after standing), height and weight. 
2 Subjects should be in a fasting state (8 hours) for laboratory tests.  
3 Study drug dispensation for down titration. 
4 Assessments for Study 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. 
 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
 
1) Subjects must have completed the EBS-101-CL-001 study through the Day 14 Follow Up 
Visit within the last 30 days (or with permission of the medical monitor) and must be 
who the Investigator feels would benefit from continued participation. 
2) 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 contraception for 30 days after 
their last dose of study drug.  
3) 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.  
4) Parents or legal guardians of subjects <18 years of age at Baseline must execute a written 
informed consent.  Subjects ≥18 years of age must execute a written informed consent.   
5) Subjects <18 years of age at Baseline must execute a written informed assent according to 
the requirements of the site’s IRB/EC.  
8.2. 
Subject Exclusion Criteria 
 
1) Subjects with a clinical presentation 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). 
2) History of schizophrenia, bipolar disorder, or other psychotic disorders. 
3) Any unstable primary mood disorder (DSM-5 criteria) at time of Baseline. 
4) Subjects who have unstable medical illness or clinically significant abnormalities on 
laboratory tests or ECG at Baseline as determined by the Principal Investigator.  
5) Subjects who have moderate to severe renal insufficiency at Screening. 
6) Subjects with a major depressive episode in the past 2 years.  
7) Subjects with a history of attempted suicide.  
8) 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. 
9) Subjects with a history of seizures (excluding febrile seizures that occurred <2 years prior 
to Baseline). 
10) Subjects with a myocardial infarction within 6 months.  


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11) Female subjects who are currently pregnant or lactating or planning to become pregnant 
during the course of the study.  
12) 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. 
13) Subjects with current or recent (past 3 months) DSM-5 substance use disorder (with the 
exception of nicotine).  
14) Subjects with positive urine drug screen for cocaine, amphetamine, methamphetamine, 
benzodiazepines, barbiturates, phencyclidine (PCP) or opiates at Baseline, except those 
receiving stable, prescribed treatment for ADHD.  Subjects with urine positive only for 
benzodiazepines will be exclusionary unless medically prescribed.   
15) Subjects with a lifetime history of bipolar disorder type I or II, dementia, schizophrenia, 
or any other psychotic disorder. 
16) Inability to swallow tablets. 
17) Subjects with a known hypersensitivity to ecopipam or any of its excipients. 
18) Any subject who in the opinion of the investigator is not a suitable candidate for the study. 
8.3. 
Subject Withdrawal Criteria 
The Investigator or subject themselves may stop study treatment at any time for safety or 
personal reasons. 
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. 
Where possible, a subject who discontinues treatment will undergo the protocol-specified end-of 
study procedures at the time of discontinuation.  Date and reason(s) of premature discontinuation 
will be described on the CRF.  In addition, the date of last dose of study treatment will be 
recorded on the Study Treatment Dosing CRF.   


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
 
Table 3: 
Investigational Product 
 
Investigational Product 
Product Name: 
Ecopipam  
Active Pharmaceutical 
Ingredient: 
Ecopipam hydrochloride 
Dosage Form: 
Tablets 
Unit Dose (expressed as 
the free base) 
12.5-, 37.5-, 50-, 75-, and 100 mg 
Route of Administration 
Oral 
Physical Description 
Round, biconvex, light blue film-coated tablet, plain on both 
sides 
Manufacturer 
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.  Non-dopaminergic 
blocking tic treatment could be allowed in consultation with the PI.  The Investigator will record 
any AE on the Adverse Events CRF for which a 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 medications which would 
have unfavorable interactions with ecopipam: 
• Dopamine antagonists or agonists (including bupropion) 


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• Tetrabenazine 
• Monoamine oxidase inhibitors 
• St. John’s Wort 
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 to determine if the subject may continue the study. 
9.5. 
Randomization and Blinding 
No blinding will be needed as this is an open-label study. 


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Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 41 of 76 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Ecopipam 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 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:  
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. “Keep out of reach of children”  
10. Storage Conditions  
11. 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. 
10.5. 
Administration 
Ecopipam HCl will be supplied as 12.5-, 37,5-, 50-, 75-, and 100-mg tablets.  The target dose is 
2 mg/kg via oral administration. 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 42 of 76 
During the 4-week titration period, the following ecopipam HCl doses 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 (two 12.5-mg tablets) 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 (two 12.5-mg tablets) 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 (two 12.5-mg tablets) 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 (two 
12.5-mg tablets) 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 (two 
12.5-mg tablets) during Week 1, 50 mg during Week 2, 100 mg during Week 3, and 
150 mg (two 75-mg tablets) during Week 4. 
• Those who weigh >83 kg will titrate from 25 mg daily to 200 mg daily: 25 mg (two 
12.5-mg tablets) during Week 1, 50 mg during Week 2, 100 mg during Week 3, and 
200 mg (two 100-mg tablets) during Week 4. 
During the treatment phase, the following ecopipam HCl doses 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. 
At the end of the open-label treatment phase, subjects will titrate off therapy and receive 
ecopipam HCl doses that will be reduced by 25 mg/day until off of drug; signs of symptoms of 
withdrawal will be monitored. 
Subjects with weight changes during the course of the study resulting in change in weight band 
may titrate to the dosing of the new weight band at the discretion of the Investigator and with the 
approval of the Medical Monitor.  If approved, the dose of study medication should be increased 
according to the titration scheme noted for the new weight band.   


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
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10.6. 
Dosing Rationale 
An ecopipam HCl dose of 2 mg/kg/day with titration is targeted in pediatric subjects >6 to 
≤18 years of age at Baseline using the dosage regimen proposed in Table 4. 
Table 4: 
Proposed Dosing Regimen  
Weight (kg) 
Dose (mg) 
Week 1 
Dose (mg) 
Week 2 
Dose (mg) 
Week 3  
Dose (mg) 
Week 4 onwards 
>18 to ≤23 
12.5 
25 (2×12.5) 
37.5  
37.5  
>23 to ≤34 
12.5 
25 (2×12.5) 
37.5  
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: 
• In 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, a post-hoc analysis showed that t ecopipam HCl likely has modest 
efficacy (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 95th percentile from Study PSY302; 
• The predicted plasma concentration-time curves for the median, 5th percentile, and 95th 
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-OL-001). 
• In Study PSY302, the 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 2-week titration which has the potential to improve 
tolerability.   


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
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• 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 25th 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.   
 
Table 5: 
Animal:Human Exposure Ratios with the Proposed Dosage Regimen of 
Ecopipam HCl 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 
17.2× 
2.1× 
5.9× 
2.1× 
10.6× 
2 
289 
8.7× 
1.1× 
3.0× 
1.1× 
5.3× 
Full 
Dose 
535 
4.7× 
0.6× 
1.6× 
0.6× 
2.9× 
Combined Cmaxa (ng/mL) 
1 
17.1 
16.9× 
1.4× 
3.4× 
1.5× 
8.7× 
2 
34.3 
8.4× 
0.7× 
1.7× 
0.8× 
4.3× 
Full 
Dose 
62.6 
4.6×c 
0.4× 
0.92× 
0.4× 
2.4×c 
a Animal: human ratios were calculated based on combined unconjugated parent ecopipam HCl 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 Study 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 times where noted.   


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
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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 as required by local regulations) 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).  
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 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 Good Clinical Practices (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 
• 
That study drug is handled and stored safely and properly 
• 
That study drug is only dispensed to study subjects in accordance with the protocol 
• 
That 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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Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
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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 
Efficacy Assessments 
The YGTSS, CGI-TS-S, and C&A-GTS-QOL will be assessed at Baseline, Months 1, 3, 6, 9 and 
12.  The CGI-TS-I will be assessed at Months 1, 3, 6, 9 and 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.  Efficacy will be analyzed for both the YGTSS-TTS and 
Global YGTSS. 
The CGI consists of 2 reliable and valid 7-item Likert scales used to assess severity and 
change in clinical symptoms.  The scale ranges from 1 = “very much improved” to 7 = very 
much worse” for the CGI-TS-I.  The CGI severity scale (C GI-TS -S ) 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.  Versions of the scale appropriate for subjects 6-12 years of age and 13-18 years of 
age will be provided.  Subjects who turn 13 during the course of the study should continue to be 
assessed using the version of the scale initially administered.   
 


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Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Study Visits may be completed in locations other than clinic and/or via remote administration due 
to restrictions as a consequence of the COVID-19 pandemic or other qualifying event.  Safety 
will be monitored throughout the study at all visits by repeated adverse event (AE) monitoring, 
vital signs, the Columbia-Suicide Severity Rating Scale (C-SSRS), the Abnormal Involuntary 
Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), the Pediatric Anxiety 
Rating Scale (PARS) and Children's Depression Rating Scale-Revised (CDRS-R).  In addition to 
these assessments, at Baseline, Months 1, 3, 6, 9 and 12 safety will also be monitored by clinical 
and laboratory evaluations and electrocardiogram (ECG) monitoring.  At the Follow Up visit, 
AE monitoring, the C-SSRS, clinical and laboratory evaluations and vital signs will be assessed.  
Laboratory evaluations will include hematology, chemistry, urine values and HbA1c.  A Follow 
Up phone call will be conducted 30 days after the last dose of study medication to assess AEs.  
Additional assessments (all visits except the follow up visit) will include the AIMS, the BARS, 
the CDRS-R and the PARS.  C-SSRS will also be assessed (all visits including the 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.  
The 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. 
Children's Depression Rating Scale-Revised (CDRS-R) is a clinically validated rating scale 
designed to assess psychiatric signs and symptoms of depressions in children and adolescents. 
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. 
Vital Signs: 
Vital signs will be collected each clinic visit.  They include heart rate, blood pressure, orthostatic 
blood pressure and heart rate (after being supine for 5 minutes and 3 minutes after standing), 
height and weight. 
Clinical Laboratory Assessments: 
The following clinical laboratory tests will be performed in a fasting state at Baseline, Months 1, 
3, 6, 9 and 12: 


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Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
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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 
Urinalysis 
Complete urinalysis includes color, 
appearance, specific gravity, pH, protein, 
glucose, ketones, and blood with 
microscopic examination for positive 
protein or blood results 
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.  
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 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 


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Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
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drug.  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. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, 
physical examination) 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 
 
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 the Sponsor or its representative. 
12.2.1.1. Treatment-Emergent Adverse Event  
A TEAE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product.  
12.2.1.2. Serious Adverse Event  
An SAE 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: 
• It results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• 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 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 representative. 
12.2.1.3. Other Adverse Event  
Other AEs (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 AEs of particular clinical importance, other than SAEs and those AEs leading to 
discontinuation of the subject from the study, will be classified as OAEs.  For each OAE, a 


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Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
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narrative may be written and included in the clinical study report.  Adverse events of special 
interest (AESI) are listed in Section 13.2.1. 
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 to be 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 rate need not 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 and SAEs will be collected from the 
signing of the informed consent form until 30 days following the last dose of study drug.  The 
S/AE term should be reported in standard medical terminology when possible.  For each S/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/study treatment. 
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) 
• 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 the 
Sponsor or its representatives’ pregnancy form.  Pregnancy in itself is not regarded as an AE 
unless there is a suspicion that the 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  


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Ecopipam  
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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 1 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 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) of all SAEs that occur 
at his or her site.  Investigators will also be notified of all unexpected and 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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Protocol EBS-101-OL-001 
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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 or higher.  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, these additional analyses will be specified in 
the SAP. 
13.1. 
Analysis Populations 
The Safety Population will include all subjects who received at least one dose of study drug from 
the open labeled study.  The Safety Population will be used for the analysis of the safety 
endpoints. 
The Intent-to-Treat (mITT) Population will consist of all subjects who receive at least one dose 
of study drug.  All efficacy analyses will be conducted using the mITT population.  
13.2. 
Planned Analyses 
13.2.1. 
Safety Analysis 
Adverse Events: 
AEs, which include clinical laboratory test variables, will be documented from the time of the 
first study medication administration from the open label study until the subject’s study 
participation is complete (study discontinuation and up to 30-days follow-up).  All AEs that 
occur after the first study medication application and up to 30 days after the subject’s last study 
medication application will be considered TEAEs. 
Each AE will be reported with severity (mild, moderate, severe), seriousness, duration, 
resolution, action taken, and its relationship with the study medication (related or not related). 
Adverse events will be summarized using system organ classification (SOC) defined by Medical 
Dictionary for Regulatory Activities (MedDRA); the following AEs will be categorized as 
AESIs in this study (AEs fitting under these categories to be fully described in the SAP): 
• Extrapyramidal reactions (i.e. tardive dyskinesia, akathisia) 
• Metabolic changes (hyperglycemia/diabetes mellitus, dyslipidemia, weight gain) 
• Orthostatic hypotension 
• Suicidality 
• Leukopenia, neutropenia, agranulocytosis 
TEAEs and AESIs will be summarized by severity and by relationship to study medication.  
Serious TEAEs and TEAEs leading to study termination will be summarized separately. 
Other Safety Assessments: 
Laboratory values, vital signs, ECG, and physical examination will be summarized descriptively 
by visit. 


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13.2.2. 
Efficacy Analysis 
The efficacy outcome measures will be measured at Baseline, Months, 1, 3, 6, 9, and 12 which is 
end of study or early termination; and include:  
• YGTSS-TTS, which is the combined score from the motor and phonic tic score,  
• YGTSS Impairment score and global YGTSS (YGTSS-TTS + Impairment score),  
• CGI-TS-S  
• CGI-TS-I (not measured at Baseline) 
The observed YGTSS-TTS, YGTSS-Global and CGI values and their changes from baseline will 
be summarized by visit.  The paired t-test may be used for analyzing the change from baseline 
within treatment. 
The CGI-TS-S, CGI-TS-I and C&A-GTS-QOL values will also be summarized descriptively by 
visit as continuous and categorical variables.   
 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of the Sponsor 
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 Emalex or its representative 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 CRFs 
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 the applicable CRFs and 
confirm any SAEs have been forwarded to Emalex 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 Emalex, a regulatory authority, or an IEC/IRB 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, ICH GCP, and any applicable 
regulatory requirements.  The Investigator should contact Emalex immediately if contacted by a 
regulatory agency about an inspection. 


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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 informed 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 1 year.  The Investigator shall make an accurate and 
adequate final report to the IRB/IEC within 90 days after the close-out visit or within 1 year after 
last patient out (LPO) or termination of the study, whichever is earlier. 
 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, Emalex or its 
designee may conduct a quality assurance audit.  Please see Section 14.2 for more details 
regarding the audit process. 
The Sponsor implements and maintains quality assurance and quality control systems in 
accordance 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). 
The Sponsor or its representative may arrange to inspect/audit the clinical study at any or all 
investigational sites.  The auditor is independent from the Sponsor’s clinical monitoring and 
project management team.  The audit may include on-site review of regulatory documents, 
CRFs, and source documents. Direct access to these documents will be required by the auditors. 
 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the informed consent form, must be 
approved or given a favorable opinion in writing by an IRB or IEC, as appropriate.  The 
Investigator must submit written approval to Emalex before he or she can enroll any subject into 
the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment(s) to 
the protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit 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.  Sponsor or its representative 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 and are consistent with ICHGCP, applicable regulatory requirements, 
and Sponsor’s policy on Bioethics. 
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the subject and his/her parents or 
legal guardian is given full and adequate oral and written information about the nature, purpose, 
possible risk and benefit of the study.  Subjects and their parents or legal guardian must also be 
notified that subjects are free to discontinue from the study at any time.  The subject and his/her 
parents or legal guardian 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/EC.  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 and 


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his/her parents’ or legal guardian’s 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 trial 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 representative will be allowed to conduct site visits at 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 Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved, 2 years following the 
discontinuation of the test article for investigation.  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 treating physician 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 principles outlined in Good Publication Practices. 
Data from all sites participating in the program will be pooled and analyzed by Emalex 
Biosciences or its representatives.  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.   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 
2.   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  
3.   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 
4.   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 
5.   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 
6.   Barnes T.R. A rating scale for drug-induced akathisia.  British Journal of Psychiatry. 
1989;154:672-676. 
7.   Poznanski EO, Freeman LN, Mokros HB. Children's Depression Rating Scale Revised 
(September 1984). Psychopharmacol Bull 1985; 21:979-989. 
 
8. 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. 
9.   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 patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient’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 patients, 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 patients 
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 patients 
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 patients 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 patients, 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 patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never adversely affect the patient-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 patients 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 patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient 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, 
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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 
− Vasectomized 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 vasectomized 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 
Baseline is also prohibited. 
• Other medications used to treat TS are prohibited. 
• Dopamine depleting medications are prohibited. 
• D2 receptor antagonists are 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 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 71 of 76 
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 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 72 of 76 
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 
 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 73 of 76 
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 
Bictegravir 
PGP substrates 
Buprenorphine 
PGP substrates 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 74 of 76 
PGP substrates: dose of these PGP substrates should  be adjusted 
based on their respective labels 
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 
Ivosidenib 
PGP substrates 
Lapatinib 
PGP substrates 
Larotrectinib 
PGP substrates 
Ledipasvir 
PGP substrates 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 75 of 76 
PGP substrates: dose of these PGP substrates should  be adjusted 
based on their respective labels 
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 
Ranolazine 
PGP substrates 
Rivaroxaban 
PGP substrates 
Rosuvastatin (acid) 
PGP substrates 
Saquinavir 
PGP substrates 
Selexipag 
PGP substrates 
Simeprevir 
PGP substrates 


Emalex Biosciences, Inc. 
 
Protocol EBS-101-OL-001 
Ecopipam  
Version 7.0, Amendment 6, 17 November 2021 
 
Confidential 
Page 76 of 76 
PGP substrates: dose of these PGP substrates should  be adjusted 
based on their respective labels 
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 
 
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: 
 
 
 
 
 
This document is confidential. 
SAP Version V2.0 11-Jul-2023 
Controlled Document ID:
 Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 1 of 44 
Statistical Analysis Plan for Interventional Studies 
 
 
 
Sponsor Name: Emalex Biosciences, Inc. 
 
 
Protocol Number: EBS-101-OL-001 
 
 
Protocol Title:  
A Multicenter, Open-Label, Extension Study Intended to Evaluate the Long-term Safety of Ecopipam 
  
 
 
Protocol Version and Date: (DD-Mmm-YYYY):  
1.0, 24-Dec-2018 
2.0, Amendment 1, 12-Feb-2019 
3.0, Amendment 2, 14-Mar-2019 
4.0, Amendment 3, 13-Jun-2019 
4.1, Amendment 3, 11-Jul-2019 
4.2, Amendment 3, 16-Jul-2019 
5.0, Amendment 4, 20-Nov-2019 
6.0, Amendment 5, 17-Apr-2020 
7.0, Amendment 6, 17-Nov-2021 
 
 
 
Syneos Health Project Code: 7001931 
 
 
Author: 
 
 
 
 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Emalex Biosciences, Inc. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Emalex Biosciences, 
Inc. However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the condition that 
they are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly. 
PPD
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
SAP Version: V2.0 11-Jul-2023 
Controlled Document ID: 
 Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 2 of 44 
Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
1.0 
17-Nov-2022 
 
Initial Final Version 
2.0 
11-Jul-2023 
 
Updated to include ad-hoc analysis after Data Base Lock 
PPD
PPD
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
SAP Version: V2.0 11-Jul-2023 
Controlled Document ID: 
 Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 3 of 44 
I confirm that I have reviewed this document and agree with the content. 
Approvals 
Syneos Health Approval 
 
 
 
Name, Title  
Lead Biostatistician  
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
 
 
Name, Title 
Senior Reviewing Biostatistician 
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
Emalex Biosciences, Inc. Approval 
 
 
 
 
 
 
 
 
 
 
Name, Title 
Sponsor Contact  
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
PPD
PPD
PPD
PPD
PPD
PPD
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PPD
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
SAP Version: V2.0 11-Jul-2023 
Controlled Document ID: 
 Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 4 of 44 
Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................. 3 
1. 
Glossary of Abbreviations ................................................................................................... 7 
2. 
Purpose .............................................................................................................................. 9 
2.1. 
Responsibilities ...................................................................................................... 9 
2.2. 
Timings of Analyses ............................................................................................... 9 
3. 
Study Objectives .............................................................................................................. 10 
3.1. 
Primary Objective .................................................................................................10 
3.2. 
Secondary Objective(s) .........................................................................................10 
3.3. 
Brief Description ...................................................................................................10 
3.4. 
Subject Selection ..................................................................................................10 
3.4.1. 
Inclusion Criteria .................................................................................................. 10 
3.4.2. 
Exclusion Criteria ................................................................................................. 10 
3.5. 
Determination of Sample Size ...............................................................................11 
3.6. 
Treatment Assignment ..........................................................................................11 
3.7. 
Administration of Study Medication .......................................................................11 
3.8. 
Study Procedures and Flowchart ..........................................................................12 
4. 
Endpoints ......................................................................................................................... 13 
4.1. 
Efficacy Endpoints ................................................................................................13 
4.2. 
Safety Endpoints ...................................................................................................13 
4.3. 
Other Safety Endpoints .........................................................................................13 
5. 
Analysis Sets .................................................................................................................... 14 
5.1. 
Enrolled Set ..........................................................................................................14 
5.2. 
Safety Set .............................................................................................................14 
5.3. 
Modified Intent-to-Treat Set ..................................................................................14 
5.4. 
Intention-to-Treat Set ............................................................................................14 
6. 
General Aspects for Statistical Analysis ........................................................................... 15 
6.1. 
General Methods ..................................................................................................15 
6.2. 
Key Definitions ......................................................................................................15 
6.3. 
Missing Data .........................................................................................................15 
6.4. 
Visit Windows .......................................................................................................15 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
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Filing requirements: TMF 
Page 5 of 44 
6.5.
Pooling of Centers ................................................................................................16
6.6. 
Subgroups ............................................................................................................16 
7. 
Demographic, Other Baseline Characteristics and Medication ......................................... 17 
7.1. 
Subject Disposition and Withdrawals ....................................................................17 
7.2. 
Demographic and Other Baseline Characteristics .................................................17 
7.3. 
Medical History .....................................................................................................17 
7.4. 
Medication ............................................................................................................18 
7.4.1. 
Prior Medication ................................................................................................... 18 
7.4.2. 
Concomitant Medication ...................................................................................... 18 
8. 
Efficacy ............................................................................................................................ 19 
8.1. 
Yale Global Tic Severity Scale (YGTSS)...............................................................19 
8.2. 
-
TS-I &S) ................................................................................................................19 
8.3. 
Gilles de la Tourette Syndrome Quality of Life Scale for Children and Adolescents 
(C&A-GTS-QOL) ...................................................................................................19 
9. 
Safety ............................................................................................................................... 21 
9.1. 
Extent of Exposure ...............................................................................................21 
9.2. 
Treatment Compliance ..........................................................................................21 
9.3. 
Adverse Events (AEs) ...........................................................................................21 
9.4. 
Laboratory Evaluations .........................................................................................23 
9.5. 
Vital Signs .............................................................................................................24 
9.6. 
ECG ......................................................................................................................24 
9.7. 
Physical Examination ............................................................................................24 
9.8. 
Other Safety .........................................................................................................25 
9.8.1. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................ 25 
9.8.2. 
Abnormal Involuntary Movement Scale (AIMS) ................................................... 25 
9.8.3. 
Barnes Akathisia Rating Scale (BARS) ............................................................... 25 
9.8.4. 
Children's Depression Rating Scale-Revised (CDRS-R) ..................................... 25 
9.8.5. 
Pediatric Anxiety Rating Scale (PARS) ............................................................... 25 
9.9. 
COVID-19 Analyses ..............................................................................................26 
10. 
Changes from Analysis Planned in Protocol ..................................................................... 27 
11. 
Reference List .................................................................................................................. 29 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
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Filing requirements: TMF 
Page 6 of 44 
12.
Programming Considerations ...........................................................................................30
12.1. 
General Considerations ........................................................................................30 
12.2. 
Table, Listing, and Figure Format .........................................................................30 
12.2.1. 
General ................................................................................................................ 30 
12.2.2. 
Headers ................................................................................................................ 30 
12.2.3. 
Display Titles ........................................................................................................ 31 
12.2.4. 
Column Headers .................................................................................................. 31 
12.2.5. 
Body of the Data Display ..................................................................................... 31 
12.2.6. 
Footnotes ............................................................................................................. 33 
13. 
Quality Control ................................................................................................................. 34 
14. 
Index of Tables ................................................................................................................. 35 
15. 
Index of Listings ............................................................................................................... 39 
16. 
Index of Figures................................................................................................................ 41 
17. 
Appendices ...................................................................................................................... 42 
17.1. 
Schedule of Assessments .....................................................................................42 
 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
SAP Version: V2.0 11-Jul-2023 
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Filing requirements: TMF 
Page 7 of 44 
1. 
Glossary of Abbreviations 
Abbreviation 
Description 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIMS 
 
Abnormal Involuntary Movement Scale 
ATC 
Anatomic Therapeutic Classification 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body Mass Index 
C&A-GTS-QOL 
Child and Adolescent Gilles De La Tourette Syndrome-Quality of Life 
Scale 
CDRS-R 
-Revised 
CGI 
Clinical Global Impression 
CGI-TS-I 
 
CGI-TS-S 
 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
HbA1c 
Hemoglobin A1c 
HCl 
Hydrochloride 
ITT 
Intention-to-Treat set 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-treat 
PARS 
Pediatric Anxiety Rating Scale 
PO 
Oral (per os) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SS 
Safety Set 
TEAE 
Treatment Emergent Adverse Event 
TS 
 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
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Page 8 of 44 
Abbreviation 
Description 
YGTSS-TTS 
Yale Global Tic Severity Scale-Total Tic Score 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
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2. 
Purpose  
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables, and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
2.1. 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality control 
of all tables, figures, and listings. 
2.2. 
Timings of Analyses 
The primary analysis of safety and efficacy is planned after all subjects complete the final study visit or 
terminate early from the study. 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
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SAP Version: V2.0 11-Jul-2023 
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3. 
Study Objectives 
3.1. 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of ecopipam tablets 
 of the EBS-101-CL-001 study) with 
Syndrome (TS) that were previously enrolled in the EBS-101-CL-001 study (Phase 2b) and completed the 
Phase 2b study.  
3.2. 
Secondary Objective(s) 
The secondary objective of this study is to evaluate the durability of effect of ecopipam in pediatric 
years at Baseline of the EBS-101-CL-001 study) with TS. 
3.3. 
Brief Description 
This is an international, multicenter, open-label, long-term extension study evaluating the safety of 
ecopipam tablets for the treatment of children and adolescent subjects with TS. Subjects who completed 
the Phase 2b, randomized double-blind efficacy and safety study (EBS-101-CL-001) and who continue to 
meet the inclusion/ exclusion criteria for this study will be eligible to participate in this study. All subjects 
will be titrated to a target dose of 2 mg/kg/day as subjects participating from previous studies will be 
tapered down from study medication to maintain the blind. Subjects will complete study visits every month 
for 1 year. Follow Up visits will be conducted 7 and 14 days after the last dose of study medication and a 
Follow Up phone call will be conducted 30 days after the last dose of study medication. Study Visits 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.  
Safety will be monitored throughout the study at all visits by repeated monitoring of adverse events (AEs), 
vital signs, the Columbia-Suicide Severity Rating Scale (C-SSRS), the Abnormal Involuntary Movement 
Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), the Pediatric Anxiety Rating Scale (PARS) and 
Children's Depression Rating Scale-Revised (CDRS-R). In addition to these assessments, at Baseline, 
Months 1, 3, 6, 9 and 12 safety will also be monitored by clinical and laboratory evaluations, and 
electrocardiogram (ECG) monitoring. In addition to the scales aforementioned, the Yale Global Tic 
Severity Scale (YGTSS), Clinician Global Impression of Tourette Syndrome of Severity (CGI-TS-S), the 
Clinician Global Impression Tourette Syndrome of Improvement (CGI-TS-I) and the Gilles de la Tourette 
Syndrome Quality of Life Scale for Children and Adolescents (C&A-GTS-QOL) will also be assessed at 
Baseline, Months 1, 3, 6, 9 and 12. At the Follow Up visits, AE monitoring, the C-SSRS, clinical and 
laboratory evaluations and vital signs will be assessed. A Follow Up phone call will be conducted 30 days 
after the last dose of study medication to assess AEs. Subjects will be monitored for signs of abuse, and 
withdrawal or dependence. 
3.4. 
Subject Selection 
3.4.1. 
Inclusion Criteria 
Subjects eligible for inclusion in this study must fulfill all of the criteria listed in section 8.1 of the protocol. 
3.4.2. 
Exclusion Criteria 
Subjects will not be eligible if they meet any of the criteria listed in section 8.2 of the protocol. 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
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SAP Version: V2.0 11-Jul-2023 
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Page 11 of 44 
3.5. 
Determination of Sample Size 
This is a one-year safety and tolerability study as a follow up to the double-blind study (EBS-101-CL-001) 
and number of subjects enrolled in this is dependent on the number of subjects completing that study.  
3.6. 
Treatment Assignment 
Since this is an open-label study, all subjects that have cleared the inclusion/exclusion criteria will be 
administered ecopipam HCl at a target dose of 2 mg/kg/day. 
3.7. 
Administration of Study Medication 
Ecopipam Hydrochloride (HCl) will be supplied as 12.5-, 37.5-, 50-, 75-, and 100-mg tablets. The target 
dose is 2 mg/kg via oral (per os) (PO) administration.  
During the 4-week titration period, the following ecopipam HCl doses will be administered for each of the 
weight bands: 
 
- 23 kg will titrate from 12.5 mg daily to 37.5 mg daily: 12.5 mg during 
Week 1, 25 mg (two 12.5-mg tablets) 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 (two 12.5-mg tablets) 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 (two 12.5-mg tablets) 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 (two 12.5-mg 
tablets) 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 (two 12.5-mg 
tablets) during Week 1, 50 mg during Week 2, 100 mg during Week 3, and 150 mg (two 75-mg 
tablets) during Week 4.  
 
Those who weigh >83 kg will titrate from 25 mg daily to 200 mg daily: 25 mg (two 12.5-mg 
tablets) during Week 1, 50 mg during Week 2, 100 mg during Week 3, and 200 mg (two 100-mg 
tablets) during Week 4.  
During the treatment phase, the following ecopipam HCl doses will be administered for each of the weight 
bands:  
 
-
 
 
Those who weigh >23-
 
 
Those who weigh >34-
 
 
Those who weigh >44-
ly.  
 
Those who weigh >68-
 
 
Those who weigh >83 kg will receive 200 mg daily.  
All doses will be administered PO once daily in the evening.  
At the end of the open-label treatment phase, subjects will titrate off therapy and receive ecopipam HCl 
doses that will be reduced by 25 mg/day until off of drug; signs of symptoms of withdrawal will be 
monitored.  
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
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Subjects with weight changes during the course of the study resulting in change in weight band may 
titrate to the dosing of the new weight band at the discretion of the Investigator and with the approval of 
the Medical Monitor. If approved, the dose of study medication should be increased according to the 
titration scheme noted for the new weight band. 
3.8. 
Study Procedures and Flowchart 
Subjects will complete study visits every month for 1 year. Follow Up visits will be conducted 7 and 14 
days after the last dose of study medication and a Follow Up phone call will be conducted 30 days after 
the last dose of study medication. 
See Appendix section 16.1 for the Schedule of Assessments. 
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Statistical Analysis Plan for Interventional Studies
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4. 
Endpoints 
4.1. 
Efficacy Endpoints 
 
Changes in the Yale Global Tic Severity Scale  Total Tic Score (YGTSS-TTS) from baseline to 
Months 1, 3, 6, 9, 12. 
 
Changes in the Yale Global Tic Severity Scale  Impairment (YGTSS-I) and Global (YGTSS-TTS 
+ YGTSS-I = YGTSS-GS) from baseline to Months 1, 3, 6, 9, 12. 
 
Changes in Clinical Global Impression of Tourette Syndrome of Severity (CGI-TS-S) from 
Baseline to Months 1, 3, 6, 9, 12. 
 
Clinician Global Impression Tourette Syndrome of Improvement (CGI-TS-I) at Months 1, 3, 6, 9, 
12. 
 
Changes in Gilles de la Tourette Syndrome Quality of Life Scale for Children and Adolescents 
(C&A-GTS-QOL) from Baseline to Months 1, 3, 6, 9, 12. 
4.2. 
Safety Endpoints 
 
Assessment of AEs or serious adverse event (SAEs) and their relationship to study drug 
(Unrelated, Possible Related, or Probably Related). 
 
Changes from baseline in clinical laboratory analysis (Hematology, Chemistry, Urinalysis and 
Hemoglobin A1c (HbA1c) assessments). 
 
Changes from baseline in vital signs. 
 
Changes from baseline in ECG. 
 
Changes from baseline in physical examination findings. 
4.3. 
Other Safety Endpoints 
 
Changes from baseline in Columbia Suicide Severity Rating Scale (C-SSRS) results. 
 
Changes from baseline in Abnormal Involuntary Movement Scale (AIMS) results. 
 
Changes from baseline in Barnes Akathisia Rating Scale (BARS) results. 
 
Changes from baseline in Children's Depression Rating Scale-Revised (CDRS-R) results. 
 
Changes from baseline in Pediatric Anxiety Rating Scale (PARS) results. 
 
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Statistical Analysis Plan for Interventional Studies
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5. 
Analysis Sets 
5.1. 
Enrolled Set 
The Enrolled Set will include all subjects who complete the Phase 2b, randomized double-blind efficacy 
and safety study (EBS-101-CL-001) and who continued to meet the inclusion and exclusion criteria and 
enrolled in this study. The Enrolled Set will be used for subject listings and summaries of subject 
disposition. 
5.2. 
Safety Set  
The Safety Set (SS) will include all subjects who received at least one dose of study drug from the open 
labelled study. The Safety Population will be used for the analysis of the safety endpoints. 
5.3. 
Modified Intent-to-Treat Set 
The Modified Intention-to-Treat (mITT) set will consist of all subjects who receive at least one dose of study 
drug and have at least one post Baseline scoring of YGTSS. All efficacy analyses will be conducted using 
the mITT population.  
5.4. 
Intention-to-Treat Set 
The Intention-to-Treat (ITT) set will include all enrolled subjects. All efficacy analysis will also be conducted 
using the ITT population. 
 
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Statistical Analysis Plan for Interventional Studies
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6. 
General Aspects for Statistical Analysis 
6.1. 
General Methods 
All analyses and outputs will be produced using SAS® version 9.4 or later. Continuous variables will be 
summarized using the number of observations (n), mean, standard deviation (SD), median, minimum, and 
maximum. Categorical variables will be summarized using frequency counts (n), and percentages. 
All relevant subject data will be included in listings. All subjects entered the database will be included in 
subject data listings. All by visit summaries will use the nominal visit. Unscheduled visits will not be 
summarized but will be included in the listings.  
6.2. 
Key Definitions 
Treatment emergent adverse events (TEAEs) are defined as any adverse events that start or increase in 
intensity on or after the first dose of open-label treatment on Day 1.  
Duration of exposure is defined as (Date of Last Dose  Date of First Dose) +1. If date of last dose is 
unknown, then the date of last clinical visit will be used to impute the date of last dose.  
Baseline is defined as the last measurement taken before the first dose of open-label treatment on Day 1.  
Change from baseline will be calculated for the post-baseline assessment as post-baseline value  
baseline value. 
6.3. 
Missing Data 
Partial dates of medications will be imputed solely for the purpose of defining prior/concomitant status for 
medications.  Dates will be defined using the hierarchy of derivations below. 
 
For missing start day where month and year are present, the start day will be set to the 1st of the 
month, unless the month and year are the same as the first dose month and year and the 1st of 
the month is before the first dose date, in which case, the start date will be set to the first dose date.  
 
For missing start day and month where year is present, the start day and month will be set to 
January 1st, unless the year is the same as the first dose year and January 1st is before the first 
dose date, in which case, the start date will be set to the first dose date.  
 
For missing end day where month and year are present, the end day will be set to the last day of 
the month, unless the month and year are the same as the trial termination month and year, in 
which case, the end date will be set to the trial termination date.  
 
For missing end day and month, where year is present, the end date will be set to the trial 
termination date if the years are the same. If the trial termination year is greater than the end year, 
the end day and month will be set to December 31st. 
Partial onset dates for adverse events will be imputed in the same manner described above for partial start 
dates for the purpose of defining treatment emergent status. 
6.4. 
Visit Windows 
The following visit windows will be used in the summarization or analysis of safety laboratory, vital signs, 
ECG, and physical exam data. If more than 1 data point falls within the window, then the data point 
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Statistical Analysis Plan for Interventional Studies
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closest to the target day will be used. If there are 2 data points equidistant to the target day, one high and 
one low, then the high data point will be used. Visit windowing will not be applicable to follow-up visits. 
If Baseline is Day 1, then: 
Month 1  (target day = 29)  2 - 42 
Month 2  (target day = 57)  43 - 70 
Month 3  (target day = 85)  71 - 98 
Month 4  (target day = 113)  99 - 126 
Month 5  (target day = 141)  127 - 154 
Month 6  (target day = 169)  155 - 182 
Month 7  (target day = 197)  183 - 210 
Month 8  (target day = 225)  211 - 238 
Month 9  (target day = 253)  239 - 266 
Month 10  (target day = 281)  267 - 294 
Month 11  (target day = 309)  295 - 322 
 Month 12  (target day = 337)  323 and above (and not a follow-up visit) 
For all efficacy and safety scales a modified last observation carried forward (LOCF) approach will be 
used to reassign Early Termination visits. Early Termination visits will be assigned to the next scheduled 
termination. 
6.5. 
Pooling of Centers 
Analyses will not include study site as a factor in the model. Region (North America and Europe) will be 
included, so sites will not be pooled based on the number of subjects, but by region.   
6.6. 
Subgroups 
Subgroups to be analyzed for select endpoints include age group (children 6-12 and adolescents 13-18) 
and region (North America and Europe). 
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7. 
Demographic, Other Baseline Characteristics and Medication 
7.1. 
Subject Disposition and Withdrawals 
Subject disposition will be presented for all subjects, which include the following: 
 
Number of subjects enrolled 
 
Number (%) of subjects in the Safety Set 
 
 
Number (%) of subjects in the Modified Intent-to-Treat Set 
 
Number (%) of subjects who completed the study 
 
Number (%) of subjects who discontinued study prematurely and their reason 
A separate by-subject listing of subject disposition and withdrawal will also be provided. 
7.2. 
Demographic and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized for the Modified Intent-to-Treat and 
ITT Set. Summary statistics and by-subject listings will be provided. 
Demographics and baseline characteristics will include age, sex, ethnicity, race, weight, height, body 
mass index (BMI). 
Age at Study day 1 = (Study day 1 visit date - date of birth + 1) / 365.25 and truncated to complete years. 
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = Weight(kg)/[Height(m)2] 
Demographics and baseline characteristics will also be summarized by treatment group (ecopipam, 
placebo and overall) from CL (EBS-101-CL-001) study. 
7.3. 
Medical History 
A summary table of the number and percentage of subjects by medical history, system organ class (SOC) 
and preferred term will be produced from the Safety Set. Medical history will be sorted alphabetically by 
SOC and in descending order of subjects per preferred term within each SOC.  
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
22.0 or higher.  
A separate by-subject listing of medical history will also be provided. 
Medical History will also be summarized by treatment group (ecopipam, placebo and overall) from CL 
(EBS-101-CL-001) study. 
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7.4. 
Medication 
All prior and concomitant medications will be summarized based on classification using the Anatomical 
Therapeutic Chemical (ATC) classification and preferred drug name from the World Health Organization 
Drug Dictionary, version Mar 2019, or later.  
A separate by-subject listing of medications will also be provided. 
7.4.1. 
Prior Medication 
Prior medications are defined as medications entered in the eCRF that either start, or end before the first 
dose of study medication. Prior medications will be summarized by ATC level 2 and preferred drug name 
for the Safety Set. 
Prior medications which continue after first dose of study medication will also be classified as a 
concomitant medication. 
7.4.2. 
Concomitant Medication 
Concomitant medications are defined as medication on the eCRF that are taken on or after or are 
ongoing at the start date of dosing. Concomitant medications will be summarized by ATC level 2 and 
preferred drug name for the Safety Set. 
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8. 
Efficacy 
The mITT as well as ITT set will be used for the analysis of the efficacy endpoints. 
The YGTSS, CGI-TS-S, and C&A-GTS-QOL will be assessed at Baseline, Months 1, 3, 6, 9 and 12. The 
CGI-TS-I will be assessed at Months 1, 3, 6, 9 and 12. 
8.1. 
Yale Global Tic Severity Scale (YGTSS)  
The YGTSS is a clinician-completed rating scale used to quantify overall tic severity as well as specific 
subdomains of tic number, frequency, intensity, complexity and interference. 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 total tic score (TTS) ranging from 0 to 50. The YGTSS also provides for an overall 
. Global YGTSS (YGTSS-GS) is the total of YGTSS-TTS 
and impairment score (YGTSS-I). Efficacy will be analyzed for the YGTSS-TTS, YGTSS-I and YGTSS-
GS. 
The observed YGTSS-TTS along with motor and phonic subdomains, YGTSS-I and YGTSS-GS values 
and their changes from baseline will be summarized by visit. The paired t-test will be used for analyzing 
the change from baseline within treatment. 
The percent of subjects with a 25% or greater improvement on the YGTSS-TTS score at any time 
between the Baseline visit and post-baseline visit will be considered as a Response.  Any subject who 
has at least 1 Response (>=25% improvement) will be considered as a Responder; otherwise, the subject 
will be considered a Non-Responder. Responder and Non-Responder will be summarized at each post-
baseline visit and overall. 
YGTSS-TTS will also be summarized by treatment group (ecopipam, placebo and overall) from CL (EBS-
101-CL-001) study. 
All YGTSS data will be presented in a listing. 
8.2. 
 &Severity (CGI-TS-I &S) 
The CGI consists of 2 reliable and valid 7-item Likert scales used to assess severity and change in 
clinical symptoms. 
-
TS-I. The CGI severity scale (CGI-TS-S) will be used at each study site visit and ranges from 1 = 
Normal, not ill 
E
 
The CGI-TS-S will be assessed at Baseline, Months 1, 3, 6, 9 and 12. The observed CGI-TS-S values 
and their changes from baseline will be summarized by visit. The paired t-test will be used for analyzing 
the change from baseline within treatment. 
The CGI-TS-I will be assessed at Months 1, 3, 6, 9, and 12. The observed CGI-TS-I values will be 
summarized by visit. 
All CGI-TS-I and CGI-TS-S data will be presented in a listing. 
8.3. 
Gilles de la Tourette Syndrome Quality of Life Scale for Children and Adolescents (C&A-
GTS-QOL) 
C&A-GTS-QOL is a patient-reported health related quality of life measure developed for children and 
adolescents. Versions of the scale appropriate for subjects 6-12 years of age and 13-18 years of age will 
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be provided. Subjects who turn 13 during the course of the study should continue to be assessed using 
the version of the scale initially administered. 
The C&A-GTS-QOL is a 27-item questionnaire specific to TS patients that asks the patient to assess the 
extent to which their quality of life is impacted by their symptoms. The C&A-GTS-QOL contains 6 
subscales (cognitive, coprophenomena, psychological, physical, obsessive-compulsive, and activities of 
daily living (ADL)) and uses a 5 point Likert scale ranging from no problem to extreme problem. Patients 
will also be asked how satisfied they feel overall with their life at that moment by using a Visual Analogue 
Scale (VAS) between 0 and 100 (Su et al 2017). Following are the questions assessed in each C&A GTS 
QOL subscale: 
 
Cognitive (questions 11, 12, 13, 14, 18, 20, 21, 23) (range: 0- 32) 
 
Psychological (questions 15, 16, 17, 19, 25, 27) (range: 0  24) 
 
Obsessive-compulsive (questions 7, 8, 9, 10) (range: 0  16) 
 
Physical (questions 1, 3, 4) (range: 0  12) 
 
Coprophenomena (questions 5, 6, 22) (range: 0 -12) 
 
ADL (questions 2, 24, 26) (range: 0-12) 
Scores for the six subscales are generated by summing items and, for ease of interpretation, 
transformation to a range of 0 to 100 (100x [(observed score - min possible score)/ (max possible score - 
min possible score)]). The total score, resulting from the sum of the subscale scores, is also normalized to 
a 0 100 range. For C&A GTS-QOL, if a response to 1 question is missing within the subscale, the 
missing response will be replaced with the average of the remaining responses within the subscale; if 
responses to 2 or more questions within a subscale are missing, the missing responses will not be 
replaced and the subscale score will be set to missing; if at least 1 subscale is missing then the total 
score will be set to missing. For all analysis and summary, transformed scores will be used. 
Summary statistics for the overall VAS score, QOL subscale scores for Cognitive, Psychological, 
Obsessive-compulsive, Physical, Coprophenomena, and ADL and QOL total score will be presented 
along with a full data listing by visit. The paired t-test will be used for analyzing the change from baseline 
within treatment. Mean C&A-GTS-QOL Change from Baseline Total Score and VAS Change from 
Baseline Score Over Time will be illustrated in a figure. 
 
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9. 
Safety 
The population used for safety analyses will be the Safety Set (SS). Study Visits 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. Safety will be monitored throughout the study at all visits by repeated monitoring of 
adverse events (AEs), vital signs, the Columbia-Suicide Severity Rating Scale (C-SSRS), the Abnormal 
Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), the Pediatric Anxiety 
Rating Scale (PARS) and Children's Depression Rating Scale-Revised (CDRS-R). In addition to these 
assessments, at Baseline, Months 1, 3, 6, 9 and 12 safety will also be monitored by clinical and 
laboratory evaluations and electrocardiogram (ECG) monitoring. At the Follow Up visit, AE monitoring, the 
C-SSRS, clinical and laboratory evaluations and vital signs will be assessed. Laboratory evaluations will 
include hematology, chemistry, urine values and HbA1c. A Follow Up phone call will be conducted 30 
days after the last dose of study medication to assess AEs. Subjects will be monitored for signs of abuse, 
and withdrawal or dependence. Additional assessments (all visits except the follow up visit) will include 
the AIMS, the BARS, the CDRS-R and the PARS. C-SSRS will also be assessed (all visits including the 
Follow Up visit).  
All safety data will be summarized in Safety Set. 
9.1. 
Extent of Exposure 
Duration of exposure will be summarized using descriptive statistics. The duration of exposure will be 
categorized in months (<1, 1-<2, 2-<3, 3-<4, 4-<5, 5-<6, 6-<7 ,7-<8, 8-<9, 9-<10, 10-<11, 11-<12, 12 
months) as well as in days (1-27, 28-55, 56-83, 84-111, 112-139, 140-167, 168-195, 196-223, 224-251, 
252-279, 280-307, 308-335, 
. Duration of exposure (months) will be calculated as ((Date of Last 
Dose  Date of First Dose) +1)/30.25. If date of last dose is unknown, then the date of last clinical visit will 
be used. 
A listing including study drug administration information from the eCRF will be presented. 
9.2. 
Treatment Compliance  
Subjects are expected to take study medication once per day.  
Treatment compliance, as a percentage, will be calculated as compliance (%) = (Sum of Study drug 
taken= Yes) / (number of days in study) x 100. The number of actual doses taken will be recorded on the 
eCRF. 
statistics (number of subjects, mean, SD, median, minimum, and maximum) for number of actual tablets 
taken, number of expected tablets taken, and treatment compliance will be summarized. 
9.3. 
Adverse Events (AEs) 
An AE is any untoward medical condition that occurs in a subject while participating in this clinical study. 
The AEs will be coded to system organ class (SOC) and preferred term (PT) using the MedDRA 
dictionary, version 25.0. The National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE), version 4.03 will be used to assess the severity of AEs.  
All AEs that occur after the first study drug administration 
drug administration will be considered treatment-emergent adverse events (TEAEs). 
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Summaries will focus on the TEAEs (simply referred to as adverse events in summary tables). A subject 
with 2 or more TEAEs within the same level of summarization (i.e., SOC or PT) will be counted only once 
in that level using the most severe event or most related event. 
Summaries presenting the frequency of AEs by SOC and PT will be sorted by descending frequency of 
SOC and then, within a SOC, by descending frequency of PT. 
The following summary tables will be provided: 
1) An overall summary with the number and percentage of patients reporting AEs, serious AEs, 
grade 3 or higher AEs, treatment-related AEs, AEs leading to study treatment discontinuation and 
AEs with outcome of deaths. 
2) AEs and Treatment-Related Adverse Events (TRAEs) by maximum severity 
3) AEs and Serious Adverse Events (SAEs) by maximum relatedness 
4) AEs overall and by SOC and PT 
5) AEs overall and by SOC, PT and highest CTCAE grade 
6) TRAEs overall and by SOC and PT 
7) TRAEs overall and by SOC, PT and highest CTCAE grade 
8) AEs leading to study treatment termination overall and by SOC and PT 
9) AEs leading to study treatment termination overall and by SOC and highest CTCAE grade 
10) CTCAE Grade 3 or higher AEs, overall and by SOC and PT 
11) SAEs overall and by SOC and PT 
A SAE is an AE which falls into one or more of the following categories: 
a. Results in death 
b. Is life-threatening 
c. Requires inpatient hospitalization or prolongation of existing hospitalization   
d. Results in persistent or significant disability or incapacity  
e. Is a congenital anomaly/birth defect  
f. 
Is any other important medical event  
12) SAEs overall and by SOC and PT and by age group (children 6-12 and adolescents 13-18) 
13) Adverse Event of Special Interests (AESIs) overall and by SOC and PT 
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Adverse Events of Special Interest (AESI) for ecopipam include Convulsions, Depression and 
Suicide/Self Injury, Drug Abuse, Dependence and Withdrawal, Dyslipedaemia, Hepatic Disorders, 
Hyperglycaemia/New Onset Diabetes Mellitus, NMS, and Psychosis and Psychotic Disorders. 
AESI for Parkinsonism include Ataxia, Confusional state, Coordination abnormal, Somnolence, 
Disturbance in attention, Dyskinesia, Hyperkinesia, Gait disturbance, Memory impairment, 
Tremor, Vertigo, Agitation, Anxiety, Disturbance in attention, Dystonia, Bradykinesia, 
Musculoskeletal stiffness, Dysstasia, Gait disturbance, Posture abnormal, Balance disorder, 
Movement disorder, Movement disorder, Dyskinesia, Muscle rigidity, Coordination abnormal, 
Muscle contracture, Bradykinesia, Gait disturbance, Terminal insomnia, Nightmare, Poor quality 
sleep, Sleep disorder, Fatigue, Dizziness, Balance disorder, Restlessness, Amnesia, Confusional 
state, Dementia, Mental impairment, Speech disorder, Dysphonia, Vocal cord dysfunction, 
Parosmia, Anosmia, Urinary incontinence, Anxiety, Apathy, Joint stiffness, Reduced facial 
expression, Confusional state, Flat affect, Constipation, Depression, Dysphagia, Drooling, Fall, 
Fear of falling, Loss of visual contrast sensitivity, Muscle tightness, Dysgraphia, Dyskinesia, and 
Weight decreased. 
AESI summary tables are listed below: 
 
AESI for ecopipam overall and by system organ class and preferred term 
 
AESI for Parkinsonism overall and by system organ class and preferred term.  
In this summary, a patient is counted once at the system organ class and once at each preferred 
term within the system organ class. 
14) Most common AEs (>= 5%) first onset experienced during treatment period will be summarized 
by month and preferred term. 
15) Most common AEs (>= 5%) new incidence or ongoing, experienced during treatment period will 
be summarized by month and preferred term. 
9.4. 
Laboratory Evaluations 
Blood samples for hematology and biochemistry are to be collected at Baseline, Months 1, 3, 6, 9 and 12 
and One and Two Weeks Post Last Dose. Urine samples for urinalysis will be collected at Baseline, 
Months 1, 3, 6, 9 and 12. HbA1c will be measured at Months 1, 3, 6, 9 and 12. All results will be provided 
using International System of Units (SI). 
Descriptive statistics for hematology, biochemistry, urinalysis and HbA1c will be provided for each test 
parameter and for change from baseline by visit. Shift tables (i.e., low-normal-high at Baseline versus low-
normal-high at each post-baseline visit in a 3-by-3 contingency table) will be provided for hematology, 
biochemistry, urinalysis and HbA1c to assess changes from Baseline in laboratory values by visit. Shift 
(0.5% change ranging from <4.0% to >7.5%) from baseline will be summarized for HbA1c by visit. Also 
shift (<170, 170-199, >=200) from baseline for total cholesterol will be summarized by visit. 
Separate listings will be provided for all laboratory evaluations (hematology, biochemistry, urinalysis and 
HbA1c). 
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9.5. 
Vital Signs  
Vital sign measurements including sitting systolic blood pressure, sitting diastolic blood pressure, sitting 
pulse rate, supine orthostatic systolic blood pressure, supine orthostatic diastolic blood pressure, supine  
pulse rate, standing orthostatic systolic blood pressure, standing orthostatic diastolic blood pressure, and 
standing pulse rate at each scheduled time and changes from baseline in vital sign measurements will be 
summarized with descriptive statistics at each scheduled time point.  
Body height will be measured at Baseline and will be summarized.  Weight will be measured at each 
schedule visit and, along with changes from baseline, will be summarized with descriptive statistics at 
each scheduled time point. Weight will be displayed in kilograms; height will be displayed in centimeters.   
Body mass index (BMI) will be derived from the weight at each visit and from height (at screening), along 
with changes from baseline, will be summarized with descriptive statistics at each schedule timepoint. 
BMI will be displayed in kilograms per meter squared. 
The Centers for Disease Control and Prevention (CDC) growth charts will be used to calculate weight z-
score, height z-score and BMI z-scores. Shift (0.5 change ranging from <-3 to >3) from baseline will be 
summarized for weight z-score, height z-score and bmi-z score by visit. Mean BMI, height and weight z-
scores over time will be illustrated in a figure. 
Heart rate outliers such as >25% decrease change from baseline, <50, >25% decrease change from 
baseline and <50 as well as >25% increase change from baseline,>100, >25% increase change from 
baseline and >100 will be summarized by visit and overall. 
All vital signs data will be presented in a listing. 
9.6. 
ECG 
The following ECG data will be collected at Baseline, Months 1, 3, 6, 9 and 12: 
 
PR interval (msec) 
 
QRS interval (msec) 
 
QT interval 
 
QTc interval (msec) 
 
Overall ECG result (Normal; Abnormal, Not Clinically Significant; Abnormal, Clinically 
Significant). 
An E
 
The actual ECG results along with change from baseline will be summarized at each visit. Shift (<=450, 
>450 to <= 480, > 480 to <= 500, >500) from baseline in QTc interval will be summarized by visit. ECG 
outliers for QTc interval (change from baseline>30 to <=60, >60), PR interval (>25% increase change 
from baseline,>200, >25% increase change from baseline and PR>200) and QRS interval (>25% 
increase change from baseline,>200, >25% increase change from baseline and QRS>200) will be 
summarized by visit and overall. All ECG data will be presented in a listing. 
9.7. 
Physical Examination 
A Physical examination will be performed at Baseline, Month 1, 3, 6, 9 and 12 and One and Two Weeks 
Post Last Dose Follow Up visits. This will include physical examination of the following body areas and 
systems: Head, Eyes, Ears, Nose, Mouth, Throat, Neck (including Thyroid); Thorax; Abdomen; 
Urogenital; Extremities; Neurological; Skin and Mucosae; and Other. 
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A 
 
The Physical examination results will be summarized at each visit. All physical examination data will be 
presented in a listing. 
9.8. 
Other Safety 
9.8.1. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
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. 
The number and percentage of subjects with suicidal behavior and ideation will be summarized at all 
visits during the treatment, end of study/early termination and follow up visits. 
All questionnaire data will be displayed in a listing. 
9.8.2. 
Abnormal Involuntary Movement Scale (AIMS) 
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. It consists of rating the presence and 
severity of movement disorders involving the face, mouth, extremities, and trunk as well as three items of 
global judgment from a scale of 0 (none) to 4 (severe). 
The AIMS total score will be calculated by summing the severity of the 10 items that are rated on a scale 
of 0 to 4. The total score will be summarized at Baseline, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. 
All questionnaire data will be displayed in a listing. 
9.8.3. 
Barnes Akathisia Rating Scale (BARS) 
BARS is used to assess the severity of drug-induced akathisia. Objective Akathisia, Subjective 
Awareness of Restlessness and Subjective Distress Related to Restlessness in the scale measure the 
, ranging from zero (normal) to 3 (most severe) and are summed yielding a 
total score ranging from 0 to 9. The BARS also includes a global clinical assessment of akathisia, ranging 
from zero (absent) to 5 (severe).  
The objective, subjective, total of objective and subjective scores and global scores will be summarized at 
Baseline and every month during treatment for one year. All questionnaire data will be displayed in a 
listing. 
9.8.4. 
Children's Depression Rating Scale-Revised (CDRS-R) 
CDRS-R is a clinically validated rating scale designed to assess psychiatric signs and symptoms of 
depressions in children and adolescents. Fourteen signs and symptoms are rated from 1 (normal) to 7 
(most severe), and 3 signs and symptoms are rated from 1 (normal) to 5 (most severe). The raw 
summary score is the sum of all 17 items, ranging from 17 to 113.   
The raw summary score will be summarized at Baseline and every month during treatment for one year. 
All questionnaire data will be displayed in a listing. 
9.8.5. 
Pediatric Anxiety Rating Scale (PARS)  
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. PARS is a 7-item scale 
that is used to determine severity of symptoms and the PARS total score. Each severity item is coded 
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from zero (none) to 5 (most extreme). Not applicable is coded to 8 and does not know is coded to 9. The 
 
The total score will be summarized at Baseline and every month during treatment for one year. All 
questionnaire data will be displayed in a listing. 
9.9. 
COVID-19 Analyses 
Due to COVID-19 pandemic, additional analyses will be conducted: 
 
Listings of COVID-19 related study disruptions by subject and by site, including descriptions of 
the disruption. 
 
Protocol deviations due to COVID-19 will be summarized by type in a table.  
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10. 
Changes from Analysis Planned in Protocol 
As per protocol, the Modified Intention-to-Treat (mITT) set was defined as all subjects who receive at 
least one dose of study drug which is same as the safety population set. Hence the mITT set definition 
drug and have at least one post 
.   
Following updates and additional analysis were included in the SAP after the data base lock. 
 
An additional analysis set, Intention-to-Treat (ITT) Set, was defined as all enrolled subjects.  All 
efficacy analysis will also be conducted using the ITT population. 
 
Visit windowing will be used in the summarization or analysis of safety laboratory, vital signs, 
ECG, and physical exam data. 
 
For all efficacy and safety scales a modified last observation carried forward (LOCF) approach 
will be used to reassign Early Termination visits. Early Termination visits will be assigned to the 
scheduled visit before early termination. 
 
Demographics and baseline characteristics will also be summarized by treatment group 
(ecopipam, placebo, overall) from CL (EBS-101-CL-001) study in the mITT Set (Table 14.1.3.1a), 
and be also summarized for the ITT Set (Table 14.1.3.1b). 
 
Medical history will also be summarized by treatment group (ecopipam, placebo, overall) from CL 
(EBS-101-CL-001) study in the Safety Set (Table 14.1.3.2a). 
 
Extent of exposure summary by days will be provided as well (Table 14.1.5a). 
 
YGTSS-TTS will also be summarized by treatment group (ecopipam, placebo and overall) from 
CL (EBS-101-CL-001) study (Tables 14.2.1.1.1a). 
 
Efficacy summaries for the ITT Set will be generated (Tables 14.2.1.1.1b, 14.2.1.1.2b, 
14.2.1.1.3b, 14.2.1.1.4b, 14.2.1.2b, 14.2.1.3b, and 14.2.1.4b). 
 
A summary of the percent of subjects with a 25% or greater improvement on the YGTSS-TTS in 
mITT set will be provided (Table 14.2.1.1.5). 
 
will be provided in 
Table 14.3.1.9.1 and by month (new incidence or ongoing) in Table 14.3.1.9.2. 
 
Shifts from baseline summaries in BMI z-score, height z-score, and weight z-score will be 
generated and provided in Table 14.3.4.6a, Table 14.3.4.6b, and Table 14.3.4.6c, respectively. 
Mean BMI, height, and weight z-scores over time will be illustrated in Figure 14.3.4.6a, 
Figure 14.3.4.6b, and Figure 14.3.4.6c, respectively. 
 
A summary of shifts from baseline in 12-lead ECG QTc will be provided in Table 14.3.4.7a. A 
summary of outliers in 12-lead ECG will be provided in Table 14.3.4.7b. 
 
A summary of heart rate outliers will be provided in Table 14.3.4.7c. 
 
Shifts from baseline in HbA1c and total cholesterol will be provided in Table 14.3.4.8 and Table 
14.3.4.9, respectively. 
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Generation of listings for ITT Set: Listing 16.2.4.1b (demographics and baseline characteristics), 
Listing 16.2.6.1b (YGTSS), Listing 16.2.6.2b (CGI-TS), and Listing 16.2.6.3b (C&A-GTS-QOL). 
 
Generation of listings for Safety Set: Listing 16.2.9.1 (Height, Weight, and BMI z-scores). 
 
Generation of figures: mean changes from baseline for C&A-GTS-QOL total score (Figure 
14.2.1.4.1a), mean changes from baseline for C&A-GTS-QOL VAS (Figure 14.2.1.4.1b), mean 
BMI, Height, Weight z-scores over time (Figures 14.3.4.6a, 14.3.4.6b and 14.3.4.6c). 
 
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11. 
Reference List 
1. 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. 
2.    SAS Program ( ages 0 to < 20 years ) | Resources | Growth Chart Training | Nutrition | DNPAO 
| CDC 
 
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Statistical Analysis Plan for Interventional Studies
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12. Programming Considerations 
12.1. 
General Considerations 
 
One SAS program can create several outputs. 
 
Each output will be stored in a separate file. 
 
Output files will be delivered in Word format or portable document format pdf. 
 
Numbering of tables, figures, and listings (TFL) will follow ICH E3 guidance (or other logical order for 
studies performed according to GCP) 
12.2. 
Table, Listing, and Figure Format 
12.2.1. General 
 All TFLs will be produced in landscape format, unless otherwise specified.  
 All TFLs will be produced using the Courier New font, size 8.   
 The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
 Headers and footers for figures will be in Courier New font, size 8. 
 Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 TFLs will be in black and white (no color), unless otherwise specified. 
 Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
 Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
erscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
 Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
12.2.2. Headers 
 All output should have the following header at the top left of each page: 
Emalex Biosciences, Inc 
Protocol EBS-101-OL-001          
 All output should have Page n of N at the top or bottom right corner of each page. TFLs are 
internally paginated in relation to the total length (i.e., the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
 The date output was generated should appear along with the program name as a footer on each 
page. 
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12.2.3. Display Titles 
 Each TFL is identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering is 
strongly recommended. A decimal system (x.y and x.y.z) is used to identify TFLs with related 
contents. The title is centered. The analysis set is identified on the line immediately following the 
title. The title and table designation are single spaced. A solid line spanning the margins will 
separate the display titles from the column headers. There will be 1 blank line between the last title 
and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(ITT Analysis Set) 
12.2.4. Column Headers 
 Column headings are displayed immediately below the solid line described above in initial upper-
case characters.  
 In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment group columns and total column (if applicable). P-values may be presented under 
the total column or in separate p-value column (if applicable). Within-treatment comparisons may 
have p-values presented in a row beneath the summary statistics for that treatment. 
 
 
 Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings, if applicable). This is distinct from 
representing the number of subjects in the analysis set. 
12.2.5. Body of the Data Display 
12.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
 Alphanumeric values are left-justified; 
 Numbers containing fractional portions are decimal aligned. 
12.2.5.2. 
Table Conventions 
 Units will be included where available. 
 If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
Severity Rating 
N 
mild 
3 
moderate 
8 
severe 
0 
 
Where percentages are presented in these tables, zero percentages will not be presented and so 
counts of 0 will be presented as 0 and not as 0 (0%). 
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If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups are included. 
 An Unknown or Missing category are added to each parameter for which information is not 
available for 1 or more subjects.  
 Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more significant digit than the original values, and standard deviations are printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
N 
 XX 
Mean (SD) 
 XX.X (XX.XX) 
Median 
 XX.X 
Min, Max 
 XX, XX 
 P-values are 
Every p-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999. 
 Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down 
to 0.0. A common convention is to display as '<0.1', or as appropriate with additional decimal 
places. Unless otherwise noted, for all percentages, the number of subjects in the analysis set for 
the treatment group who have an observation will be the denominator. Percentages after zero 
counts should not be displayed and percentages equating to 100% are presented as 100%, without 
decimal places.  
 Unless otherwise specified, tabular display of data for medical history, prior/concomitant 
medications, and all tabular displays of adverse event data are presented by the body system, 
treatment class, or SOC with the highest occurrence in the overall group in decreasing order, 
assuming all terms are coded. Within the body system, drug class and SOC, medical history (by 
preferred term), drugs (by ATC code), and adverse events (by preferred term) are displayed in 
decreasing order. If incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values which cannot be estimated are reported as 
-  
 The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed in the relevant treatment group (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Describe details of this in 
footnotes or programming notes. 
 For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, describe in a footnote or programming note if the subjects are included 
in the summary statistics for all relevant categories or just 1 category and the criteria for selecting 
the criteria. 
 Where a category with a subheading (such as system organ class) has to be split over more than 
overall summary statistics for the subheading should only be output on the first relevant page. 
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12.2.5.3. 
Listing Conventions 
 Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
 Missing data are 
-
sponding 
- 
whichever is appropriate. 
 Dates are 
are 
represented on subject listings as dashes (--JUL2000). Dates that are missing because they are 
 
 All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
 Units will be included where available. 
12.2.5.4. 
Figure Conventions 
 Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
12.2.6. Footnotes 
 A solid line spanning the margins will separate the body of the data display from the footnotes.  
 All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
 
reference footnote. Each new footnote should start on a new line, where possible. 
 Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines 
of footnotes are planned, then a cover page is strongly recommended to be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each page.  
 The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, and 
myprogram.sas    Table Generation: ddmmmyyyy). 
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13. Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
and figures. An overview of the development of programs is detailed in Syneos Health SOP Developing 
Statistical Programs (3907) 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency and commenting and by review 
of the produced output. 
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14. 
Index of Tables 
The following tables will be produced (table numbers and titles may be different in the final versions): 
Header 
Table Number 
Name 
Analysis Set 
14.1 
 
Demographic Data Summary Tables 
 
 
14.1.1 
Subject Disposition Summary 
Enrolled Set 
 
14.1.2.1 
Protocol Deviations Summary 
Safety Set 
 
14.1.2.2 
Protocol Deviations Due to COVID-19 
Summary 
Safety Set 
 
14.1.3.1 
Demographics and Baseline 
Characteristics Summary  
mITT Set 
 
14.1.3.1a 
Demographics and Baseline 
Characteristics Summary by Treatment 
Group (CL) 
mITT Set 
 
14.1.3.1b 
Demographics and Baseline 
Characteristics Summary 
ITT Set 
 
14.1.3.2 
Medical History Summary 
Safety Set 
 
14.1.3.2a 
Medical History Summary by Treatment 
Group (CL) 
Safety Set 
 
14.1.4.1 
Prior Medications Summary 
Safety Set 
 
14.1.4.2 
Concomitant Medications Summary 
Safety Set 
 
14.1.5 
Extent of Exposure Summary 
Safety Set 
 
14.1.5a 
Extent of Exposure Summary 
Safety Set 
 
14.1.6 
Treatment Compliance Summary 
Safety Set 
14.2 
 
Efficacy Data Summary Tables 
 
 
14.2.1.1.1 
YGTSS-TTS: Summary 
mITT Set 
 
14.2.1.1.1a 
YGTSS-TTS: Summary by Treatment 
Group (CL) 
mITT Set 
 
14.2.1.1.1b 
YGTSS-TTS: Summary  
ITT Set 
 
14.2.1.1.2 
YGTSS-TTS: Subscales Summary  
mITT Set 
 
14.2.1.1.2b 
YGTSS-TTS: Subscales Summary 
ITT Set 
 
14.2.1.1.3 
YGTSS-GS: Summary 
mITT Set 
 
14.2.1.1.3b 
YGTSS-GS: Summary 
ITT Set 
 
14.2.1.1.4 
YGTSS-Impairment: Summary 
mITT Set 
 
14.2.1.1.4b 
YGTSS-Impairment: Summary 
ITT Set 
 
14.2.1.1.5 
YGTSS-TTS: Subjects with a >= 25% 
Improvement 
mITT Set 
 
14.2.1.2 
CGI-TS-S: Summary 
mITT Set 
 
14.2.1.2b 
CGI-TS-S: Summary 
ITT Set 
 
14.2.1.3 
CGI-TS-I: Summary 
mITT Set 
 
14.2.1.3b 
CGI-TS-I: Summary 
ITT Set 
 
14.2.1.4 
C&A-GTS-QOL: Summary 
mITT Set 
 
14.2.1.4b 
C&A-GTS-QOL: Summary 
ITT Set 
14.3 
 
Safety Data Summary Tables 
 
14.3.1 
 
Adverse Events 
 
 
14.3.1.1 
Overall Summary of Adverse Events 
Safety Set 
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Header 
Table Number 
Name 
Analysis Set 
 
14.3.1.2.1 
Summary of Adverse Events by 
Maximum Severity 
Safety Set 
 
14.3.1.2.2 
Summary of Adverse Events by 
Maximum Relatedness 
Safety Set 
 
14.3.1.3.1 
Summary of Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
 
14.3.1.3.2 
Summary of Adverse Events by System 
Organ Class, Preferred Term and 
Highest CTCAE Grade 
Safety Set 
 
14.3.1.4.1 
Summary of Treatment-Related Adverse 
Events by System Organ Class and 
Preferred Term 
Safety Set 
 
14.3.1.4.2 
Summary of Treatment-Related Adverse 
Events by System Organ Class, 
Preferred Term and Highest CTCAE 
Grade 
Safety Set 
 
14.3.1.5.1 
Summary of Adverse Events Leading to 
Treatment Termination by System 
Organ Class and Preferred Term 
Safety Set 
 
14.3.1.5.2 
Summary of Adverse Events Leading to 
Treatment Termination by System 
Organ Class, Preferred Term and 
Highest CTCAE Grade 
Safety Set 
 
14.3.1.6 
Summary of CTCAE Grade 3 or Higher 
Adverse Events by System Organ Class 
and Preferred Term 
Safety Set 
 
14.3.1.7.1 
Summary of Serious Adverse Events by 
System Organ Class and Preferred 
Term 
Safety Set 
 
14.3.1.7.2 
Summary of Serious Adverse Events by 
System Organ Class and Preferred 
Term by Age Group 
Safety Set 
 
14.3.1.8.1 
Summary of Adverse Events of Special 
Interest (AESI) for Parkinsonism by 
System Organ Class and Preferred 
Term 
Safety Set 
 
14.3.1.8.2 
Summary of Adverse Events of Special 
Interest (AESI) for Ecopipam by System 
Organ Class and Preferred Term 
Safety Set 
 
14.3.1.9.1 
Summary of Most common (>=5%) 
Adverse Event First Onset by Month 
Safety Set 
 
14.3.1.9.2 
Summary of Most common (>=5%) 
Adverse Events by Month (new 
incidence or ongoing) 
Safety Set 
14.3.4.1 
 
Clinical Laboratory Data 
 
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Header 
Table Number 
Name 
Analysis Set 
 
14.3.4.1.1.1 
Clinical Laboratory Results Summary: 
Hematology 
Safety Set 
 
14.3.4.1.1.2 
Shift from Baseline Summary: 
Hematology 
Safety Set 
 
14.3.4.1.2.1 
Clinical Laboratory Results Summary: 
Serum Chemistry 
Safety Set 
 
14.3.4.1.2.2 
Shift from Baseline Summary: 
Chemistry 
Safety Set 
 
14.3.4.1.3.1 
Clinical Laboratory Results Summary: 
Urinalysis 
Safety Set 
 
14.3.4.1.3.2 
Shift from Baseline Summary: Urinalysis 
Safety Set 
 
14.3.4.1.4.1 
Clinical Laboratory Results Summary: 
HbA1c 
Safety Set 
 
14.3.4.1.4.2 
Shift from Baseline Summary: HbA1c 
Safety Set 
14.3.4.2 
 
Vital Signs 
 
 
14.3.4.2.1 
Vital Signs Summary 
Safety Set 
14.3.4.3 
 
Electrocardiogram (ECG) Data 
 
 
14.3.4.3.1 
12-Lead Electrocardiogram Summary 
Safety Set 
 
14.3.4.3.2 
12-Lead Electrocardiogram Overall 
Interpretation Summary 
Safety Set 
14.3.4.4 
 
Abnormal Physical Examination Results 
by Visit 
 
 
14.3.4.4.1 
Physical Examination Summary 
Safety Set 
14.3.4.5 
 
Other Safety Data 
 
 
14.3.4.5.1 
Summary of Columbia Suicide Severity 
Rating Scale (C-SSRS) 
Safety Set 
 
14.3.4.5.2 
Summary of Abnormal Involuntary 
Movement Scale (AIMS) Total Score 
Safety Set 
 
14.3.4.5.3 
Summary of Barnes Akathisia Rating 
Scale (BARS) 
Safety Set 
 
14.3.4.5.4 
Rating Scale  Revised (CDRS-R) Raw 
Summary Score 
Safety Set 
 
14.3.4.5.5 
Summary of Pediatric Anxiety Rating 
Scale (PARS) Total Score 
Safety Set 
 
 
Post-Hoc Analysis 
 
 
14.3.4.6a 
Shift from Baseline Summary: BMI z-
score  
Safety Set 
 
14.3.4.6b 
Shift from Baseline Summary: Height z-
score  
Safety Set 
 
14.3.4.6c 
Shift from Baseline Summary: Weight z-
score  
Safety Set 
 
14.3.4.7a 
Shift from Baseline Summary: 12-Lead 
Electrocardiogram QTC  
Safety Set 
 
14.3.4.7b 
12-Lead Electrocardiogram Outliers 
Safety Set 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
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Header 
Table Number 
Name 
Analysis Set 
 
14.3.4.7c 
Vital Sign: Heart Rate Outliers 
Safety Set 
 
14.3.4.8 
Shift from Baseline Summary: HbA1c  
Safety Set 
 
14.3.4.9 
Shift from Baseline Summary: 
Cholesterol 
Safety Set 
 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
SAP Version: V2.0 11-Jul-2023 
Controlled Document ID: 
 Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 39 of 44 
15. 
Index of Listings 
Data collected in the database will be listed. Numbering of listings may be adjusted to accommodate split 
listings or listings that are omitted due to no records. 
Header 
Listing Number 
Name 
Analysis Set 
(Example) 
16.2 
 
Subject Data Listings 
 
 
16.2.1.1 
Subject Disposition 
Enrolled Set 
 
16.2.1.2 
Baseline Failure 
Enrolled Set 
16.2.2 
 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations 
Safety Set 
 
16.2.2.2 
COVID-19 Study Disruptions 
Enrolled Set 
16.2.3 
 
Subjects Excluded from the Efficacy 
Analysis 
 
 
16.2.3.1 
Analysis Population 
Enrolled Set 
 
16.2.3.2 
Inclusion/Exclusion Criteria 
Enrolled Set 
16.2.4 
 
Demographic Data 
 
 
16.2.4.1 
Demographics and Baseline 
Characteristics 
mITT Set 
 
16.2.4.1b 
Demographics and Baseline 
Characteristics 
ITT Set 
 
16.2.4.2 
Medical History 
Safety Set 
 
16.2.4.3 
Psychiatric History 
Safety Set 
 
16.2.4.4 
Prior and Concomitant Medications 
Safety Set 
 
16.2.5.1 
Study Drug Administration 
Safety Set 
16.2.6 
 
Individual Efficacy Response Data 
 
 
16.2.6.1 
Yale Global Tic Severity Scale (YGTSS) 
mITT Set 
 
16.2.6.1b 
Yale Global Tic Severity Scale (YGTSS) 
ITT Set 
 
16.2.6.2 
Clinical Global Impression of Tourette 
Syndrome (CGI-TS) 
mITT Set 
 
16.2.6.2b 
Clinical Global Impression of Tourette 
Syndrome (CGI-TS) 
ITT Set 
 
16.2.6.3 
Gilles de la Tourette Syndrome Quality 
of Life Scale for Children and 
Adolescents (C&A-GTS-QOL) 
mITT Set 
 
16.2.6.3b 
Gilles de la Tourette Syndrome Quality 
of Life Scale for Children and 
Adolescents (C&A-GTS-QOL) 
ITT Set 
16.2.7 
 
Adverse Event Listings 
 
* 
16.2.7.1 
Adverse Events 
Safety Set 
 
16.2.7.2 
Serious Adverse Events 
Safety Set 
 
16.2.7.3 
Adverse Events Leading to Study 
Termination 
Safety Set 
 
16.2.7.4 
Adverse Events Leading to Death 
Safety Set 
 
16.2.7.5 
Adverse Events of Special Interest for 
Parkinsonism 
Safety Set 
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Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
SAP Version: V2.0 11-Jul-2023 
Controlled Document ID: 
 Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 40 of 44 
Header 
Listing Number 
Name 
Analysis Set 
(Example) 
 
16.2.7.6 
Adverse Events of Special Interest for 
Ecopipam 
Safety Set 
16.2.8 
 
Listing of individual laboratory 
measurements by patient 
 
16.2.8.1 
Clinical Laboratory Data 
 
 
16.2.8.1.1 
Hematology Laboratory Evaluations 
Safety Set 
 
16.2.8.1.2 
Biochemistry Laboratory Evaluations 
Safety Set 
 
16.2.8.1.3 
Urinalysis Laboratory Evaluations 
Safety Set 
 
16.2.8.1.4 
HbA1c Laboratory Evaluations 
Safety Set 
 
 
Other Safety Data 
 
 
16.2.8.2 
Vital Signs 
Safety Set 
 
16.2.8.3 
12-Lead Electrocardiogram 
Safety Set 
 
16.2.8.4 
Physical Examination 
Safety Set 
 
16.2.8.5.1 
Columbia-Suicide Severity Rating Scale 
(C-SSRS)  Suicidal Ideation 
Safety Set 
 
16.2.8.5.2 
Columbia-Suicide Severity Rating Scale 
(C-SSRS)  Intensity of Ideation 
Safety Set 
 
16.2.8.5.3 
Columbia-Suicide Severity Rating Scale 
(C-SSRS)  Suicidal Behavior 
Safety Set 
 
16.2.8.5.4 
Columbia-Suicide Severity Rating Scale 
(C-SSRS)  Actual Attempts 
Safety Set 
 
16.2.8.6 
Abnormal Involuntary Movement Scale 
(AIMS) 
Safety Set 
 
16.2.8.7 
Barnes Akathisia Rating Scale (BARS) 
Safety Set 
 
16.2.8.8 
Revised (CDRS-R) 
Safety Set 
 
16.2.8.9 
Pediatric Anxiety Rating Scale (PARS) 
Safety Set 
 
16.2.9.1 
Height, Weight and BMI Z-Scores 
Safety Set 
 
 
 
 
 
 
 
 
 
 
CCI


Statistical Analysis Plan for Interventional Studies
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001 
This document is confidential. 
SAP Version: V2.0 11-Jul-2023 
Controlled Document ID: 
 Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 41 of 44 
16. 
Index of Figures 
Header 
Figure 
Number 
Name 
Analysis Set 
(Example) 
14.2 
14.2.1.4.1a 
Mean (+/- SD) C&A-GTS-
QOL Change from Baseline 
Total Score Over Time 
mITT Set 
 
14.2.1.4.1b 
Mean (+/- SD) VAS Change 
from Baseline Score Over 
Time  
mITT Set 
14.3 
14.3.4.6a 
Mean (+/- SD) BMI z-Score 
Over Time 
Safety Set 
 
14.3.4.6b 
Mean (+/- SD) Height z-
Score Over Time 
Safety Set 
 
14.3.4.6c 
Mean (+/- SD) Weight z-
Score Over Time 
Safety Set 
 
CCI


 
 
 
 
This document is confidential. 
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Filing requirements: TMF 
Page 42 of 44 
17. 
Appendices 
17.1. 
Schedule of Assessments 
Assessment4 
 
Baseline* 
(Titration) 
 
Treatment 
 
End of 
Study / 
Early 
Terminat
ion 
Follow 
Up Visit 
Follow 
Up 
Phone 
Call 
Study Month 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
One and 
TwoWee
ks Post 
Last Dose  
30 Days 
After 
Last 
Dose  
Study Visit Number 
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
14 & 15   
Visit Window  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
±3days  
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric/
medication History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination  
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Laboratory Tests 
(Hematology and 
Chemistry)2 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Urine Drug Screen 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Urine Pregnancy 
Test 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001
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SAP Version: V2.0 11-Jul-2023 
Controlled Document ID: 
 Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 43 of 44 
Assessment4 
 
Baseline* 
(Titration) 
 
Treatment 
 
End of 
Study / 
Early 
Terminat
ion 
Follow 
Up Visit 
Follow 
Up 
Phone 
Call 
Study Month 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
One and 
TwoWee
ks Post 
Last Dose  
30 Days 
After 
Last 
Dose  
Study Visit Number 
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
14 & 15   
HbA1c 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
YGTSS Score 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
CGI-TS-I 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
CGI-TS-S 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
C&A-GTS-QOL 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Columbia Suicide 
Severity Rating 
Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abnormal 
Involuntary 
Movement Scale 
(AIMS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Barnes Akathisia 
Ratings Scale 
(BARS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Children's 
Depression Rating 
Scale-Revised 
(CDRS-R) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pediatric Anxiety 
Ratings Scale 
(PARS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CCI


Statistical Analysis Plan for Interventional Studies 
Sponsor: Emalex Biosciences, Inc.; Protocol No.: EBS-101-OL-001
This document is confidential. 
SAP Version: V2.0 11-Jul-2023 
Controlled Document ID: 
 Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 44 of 44 
Assessment4 
 
Baseline* 
(Titration) 
 
Treatment 
 
End of 
Study / 
Early 
Terminat
ion 
Follow 
Up Visit 
Follow 
Up 
Phone 
Call 
Study Month 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
One and 
TwoWee
ks Post 
Last Dose  
30 Days 
After 
Last 
Dose  
Study Visit Number 
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
14 & 15   
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense Study Drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
 
 
Collect Unused 
Study Drug/Assess 
Drug Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: BP = blood pressure, CGI = Clinician Global Impression, CGI-TS-I = CGI Tourette Syndrome of Improvement, CGI-TS-S = CGI Tourette 
Syndrome of Severity, ECG = electrocardiogram, HbA1c = Hemoglobin A1c 
* Baseline is to occur within 30 days of the EBS-101-CL-001 14 Day Follow Up Visit (or longer with the permission of the medical monitor). All Baseline 
measurements can be taken from the Day 14 Follow Up Visit of the EBS-101-CL-001 study if performed less than 7 days prior to the Baseline visit. In this 
case, the HbA1c and Urine Drug Screen from the Week 12/Completion Visit of the EBS-101-CL-001 study may be used.  
1 Vital signs will include heart rate, BP, orthostatic BP and heart rate (done supine and then 3 minutes after standing), height and weight. 
2 Subjects should be in a fasting state (8 hours) for laboratory tests. 
3 Study drug dispensation for down titration. 
4 Assessments for Study 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. 
 
CCI


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CCI
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PPD
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