A Multicenter, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study to Evaluate the Safety and Maintenance of Efficacy of Ecopipam in Children, Adolescents and Adults With Tourette's Disorder
Phase: PHASE3
Conditions: Tourette Disorder
Sponsor: Emalex Biosciences Inc.

 
ECOPIPAM (EBS-101) 
EBS-101-TD-301 
IND Number: 
109746 
EU CT Number:  
 
2023-503494-38-00 
EudraCT Number:  
2022-001961-11 
Protocol Title:  
A Multicenter, Double-Blind, Placebo-Controlled, 
Randomized Withdrawal Study to Evaluate the Safety 
and Maintenance of Efficacy of Ecopipam in Children, 
Adolescents and Adults with Tourette’s Disorder 
Public Title:   
Ecopipam Tablets to Study Tourette’s Disorder in Children, 
Adolescents and Adults 
Indication Studied: 
Children, Adolescent and Adult Subjects with Tourette’s Disorder 
Protocol Version/Date: 9.0, 05 Mar h 2024 
Sponsor Address: 
Emalex Biosciences, Inc. 
330 No th Wabash Avenue, Suite 3500 
Chicago, IL 60611 
The program will be completed according to the guidelines of Good Clinical Practice. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study subjects 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki. 
Confidentiality Statement 
The information in this document contains trade and commercial information that is privileged or 
confidential and may not be disclosed unless such disclosure is required by federal or state law or 
regulations. In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you which is 
indicated as privileged or confidential. 
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 2 of 96 
SUMMARY OF SIGNIFICANT CHANGES 
 
 
SIGNIFICANT PROTOCOL CHANGES 
V8.0 to V9.0 
RATIONALE 
Updated schedule of assessments to emphasize 
neurological exam as part of physical exam at 
the Week 4/Day 29 visit and to allow for 
laboratory assessment if serotonin syndrome 
symptoms are present. 
 
Updated to include the assessment of 
serotonin syndrome per request from FDA.  
Updated schedule of assessments to delete the 
need for blood pressure measurements to be 
performed prior to ECG. 
 
Allow flexibility in the way the assessments 
are performed.  
Hydroxyzine removed from prohibited 
medication list (Section 23 and Section 24). 
 
To corr ct hydroxyzine being listed both as 
prohibited and allowed medication.  
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 4 of 96 
INVESTIGATOR’S AGREEMENT 
 
I have read the protocol EBS-101-TD-301 and agree to conduct the study as outlined.  I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 5 of 96 
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 
 
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 6 of 96 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Emalex Biosciences, Inc. 
Name of Investigational Product: 
Ecopipam Tablets 
Protocol Number: EBS-101-TD-301 
Title of Study:  
A Multicenter, Double-Blind, Placebo-Controlled, Randomized Withdrawal Study to Evaluate the 
Safety and Maintenance of Efficacy of Ecopipam in Children, Adolescents and Adults with 
Tourette’s Disorder 
Study centers: Approximately 90 sites  
Studied period (years):  
Estimated date first subject enrolled: 1Q 2023 
Estimated date last subject completed: 3Q 2024 
Phase of development:  
3 
Objectives:  
Primary: 
The primary objective of this study is to evaluate the maintenance of efficacy of ecopipam tablets in 
children   and < 12 years of age) and adolesc nts   DQG   \HDUV RI DJH with Tourette’s 
Disorder (TD). 
Secondary: 
The secondary objectives of this study are to evaluate the safety and tolerability of ecopipam dosed at 
1.8 mg/kg/day (2 mg/kg/day ecopipam HCl) in children   WR  \HDUV RI age), adolescents  
and < 18 years of age), and adults   \HDUV RI age) with TD, to evaluate the maintenance of 
efficacy of ecopipam in adults ( 18 years of age), and to characterize the pharmacokinetics (PK) of 
ecopipam in all subjects. 
Exploratory: 
To evaluate the population PK/pharmacodynamic (PD) relationships with ecopipam during the open-
label Stabilization period of the study. 
Methodology:  
This is a multicenter study which includes an open-label period followed by double-blind, placebo-
controlled, randomized withdrawal period in children   and < 12 years of age), adolescents  12 
and < 18 years of age), DQG DGXOW VXEMHFWV  18 years of age) with TD.  
After providing informed consent (adult subjects or children/adolescent caregivers) and assent 
(children/adolescents) and following an up to 28-day Screening period and completion of Eligibility 
Review by the study team, subjects will proceed to the Baseline visit (Day 1).  At the Baseline visit, 
eligible subjects will be entered into an open-label Stabilization period and start a 4-week Titration 
phase to achieve a target steady-state dose of 1.8 mg/kg/day ecopipam (2 mg/kg/day ecopipam HCl) 
followed by an 8-week open-label Maintenance phase.  
During the open-label Stabilization period, subjects will return to the clinic at Baseline (Day 1) and 
Weeks 4, 8 and 12 after Baseline.  Subjects will have a telephone visit at Week 2 to assess adverse 
events (AEs) and other safety parameters.  Efficacy assessments will be conducted at Weeks 4, 8 and 
12.  PK assessments will be conducted at Weeks 4 and 8.  A PK assessment may be conducted at 
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 7 of 96 
Week 12 if the Week 8 PK assessment is missed.  Safety assessments will be conducted at all visits 
including the telephone visit at Week 2.  
5HVSRQGHUV WR HFRSLSDP GHILQHG DV WKRVH ZLWK   LPSURYHPHQW from Baseline on the YGTSS-
TTS (Yale Global Tic Severity Scale-; Total Tic Score) at both Weeks 8 & 12 during the open-label 
Stabilization period, will be randomized to ecopipam 1.8 mg/kg/day (2 mg/kg/day ecopipam HCl) or 
placebo in a 1:1 fashion and enter a double-blind Randomized-Withdrawal (R/WD) period at Week 
12.  Subjects randomized to placebo will be tapered off ecopipam in a blinded fashion in decrements 
of 22.4-mg/day (25-mg/day ecopipam HCl).   
During the R/WD period, subjects will return to the clinic every week for the first 4 weeks and every 
2 weeks thereafter (Weeks 13, 14, 15, 16, 18, 20, 22 and 24) and efficacy and safety assessments will 
be conducted at each of these visits.  Any subject meeting Relapse criteria, defined as the loss of 
 RI WKH LPSURYHPHQW H[SHULHQFHG RQ WKH YGTSS-TTS from Baseline (Day 1) to the last visit of 
the open-label Stabilization period (Week 12), or initiation of additional medications to treat 
symptoms of TD, or requirement of hospitalization for worsening symptoms of TD will be withdrawn 
from blinded study medication (ecopipam or placebo). 
Non-responders to ecopipam during the open-label Stabilization p riod at either Week 8 or Week 12, 
Responders to ecopipam who complete the R/WD period, any subject who meets Relapse criteria 
during the R/WD period, and any subject who discontinues the study prematurely due to any reason 
will be tapered off ecopipam in decrements of 22.4-mg/day and will complete the Week 24/ 
Relapse/ET visit.  Subjects assigned to placebo will receive placebo taper down medication to 
preserve the blind.   
Follow Up visits will be conducted in the clinic 7 and 14 days after the last dose of study medication.  
Subjects who do not roll into the open-label ext nsion study EBS-101-TD-391 will also be contacted 
by telephone 30 days after the last dose of s udy medication to determine any adverse events.   
Subjects who experience relapse may be treated for their TD with medications recommended by the 
PI or referred back to their primary physician for treatment after completing Day 7 and 14 follow-up 
visits.   
Responders to ecopipam who complete the R/WD period and who complete the Week 24/Relapse/ET 
visit and the Day 7 and 14 follow-up visits are eligible to enter the long-term open-label study EBS-
101-TD-391.  Subjects who meet he criteria for Relapse and complete the Week 24/Relapse/ET visit 
and the Day 7 and 14 follow-up visits  will have the opportunity to enter the long-term open-label 
study.   
In anticipation of reaching the target number of Relapse events, randomization into the double-blind 
R/WD period may be closed, at which time subjects in the open-label Stabilization period may 
continue in the study until the Week 12 visit.  Upon completion of the Week 12 visit, subjects will 
have the opportunity to enter the long-term open-label study, EBS-101-TD-391.   
The Sponsor may elect to re-open randomization as required.   
Once the target number of Relapse events is met, all subjects may enter the long-term open-label 
study EBS-101-TD-391 once the Week 24/Relapse/ET visit and the Day 7 and 14 follow-up visits 
have been completed.   
The study will be considered completed once all subjects have completed the 30-Day telephone 
Follow Up call or enter the open-label study EBS-101-TD-391.   
 
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Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 8 of 96 
Number of subjects (planned): The minimum number of subjects enrolled will be based on the 
number of Relapses in the combined children and adolescent groups DJH   WR   \HDUV RI DJH.  
Subject enrollment will stop around the time that 49 Relapse events are anticipated to occur among 
these subjects.  The number of Relapses among adults will not determine number of subjects enrolled 
in the study.  
Assuming the proportions of child and adolescent subjects who Relapse in the R/WD period are 
LQ WKH SODFHER JURXS DQG  LQ WKH HFRSLSDP JURXS DSSUR[LPDWHO\ 98 subjects (~49 subjects per 
treatment group) may need to be Randomized to achieve this number of Relapse events.   
$VVXPLQJ D 5HVSRQVH UDWH RI , approximately 196 subjects age   WR   \HDUV RI DJH would 
need to enter the open-label Stabilization period to randomize 98 subjects aged   WR   \HDUV. 
Adult subjects with TD who meet all inclusion criteria and none of the exclusion criteria are eligible 
to enroll in the study, and approximately 40 adult subjects are estimated to enroll.    
Diagnosis and main criteria for inclusion:  
Inclusion Criteria: 
1. If <18 years of age, subject’s parent or legal guardian must sign a written informed consent 
and subject must sign a written informed assent according to the requirements of the site’s 
,5%(& ,I  \HDUV RI DJH Vubject must sign a written informed consent according to the 
requirements of the site’s IRB/EC. 
2. 6XEMHFWV PXVW EH  6 years of age at time of screening. 
3. Subjects must weigh at OHDVW 18 kg (39.6 lbs ). 
4. Subjects must have TD based on the Diagnostic and Statistical Manual for Mental Disorders 
– 5th Edition-Text Revision (DSM-5-TR) diagnostic criteria for TD.  
5. Subjects must exhibit both motor and vocal tics that cause impairment with normal routines. 
6. Subjects must have a minimum s ore of 20 on the YGTSS-TTS at Screening and at Baseline 
visits with tic symptoms causing impairment in the subject’s normal routines, including 
academic achievement, and/or occupational functioning, and/or social activities, and/or 
relationships or wh se symptoms distress the subject to the extent that treatment is 
appropriate. 
7. Female participants of childbearing potential must agree to use a highly effective method of 
FRQWUDFHSWLRQ LH SUHJQDQF\ UDWH RI OHVV WKDQ  SHU \HDU GXULQJ WKH VWXG\ DQG IRU  GD\V
after the discontinuation of the IMP.  Adequate contraceptive methods include combined 
hormonal contraception associated with inhibition of ovulation (oral, intravaginal, 
transdermal), progestogen-only hormonal contraception with inhibition of ovulation (oral, 
injectable, implantable), intrauterine devices (IUDs), intrauterine hormone-releasing system 
(IUS), true sexual abstinence (when this is in line with the preferred and usual lifestyle of the 
participant), bilateral tubal occlusion, vasectomized male partner or a female participant who 
is not of childbearing potential. 
Female participants and female partners of male study participants using a hormonal 
contraceptive must also use a barrier method (i.e., condom or occlusive cap [diaphragm or 
cervical/vault caps]) and should have been stable on their hormonal contraceptive treatment 
for at least 4 weeks prior to Screening.   
8. 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.  
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Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 9 of 96 
9. For sites in the EU only, the subject must have received an adequate trial of non-
pharmacological therapy without adequate response prior to study enrollment. 
Exclusion Criteria: 
1. Subjects with previous exposure to ecopipam (e.g., participated in study PSY301, PSY302 or 
EBS-101-CL-001).  
2. Subjects with any unstable mood disorder (DSM-5-TR criteria) at Screening or Baseline. 
3. Subjects who have unstable medical illness or clinically significant abnormalities on 
laboratory tests, or ECG at Screening as determined by the Principal Investigator.  
4. Subjects with a significant risk of attempting suicide based on history (suicide attempt in past 
1 year or who have had 2 or more lifetime suicide attempts) or who had an answer of ‘‘yes’’ 
on any question other than 1–3 (currently or within the past 30 days) on the 
baseline/screening version of the Columbia Suicide Severity Rating Scale (C-SSRS). 
5. Subjects with a clinical presentation at Screening or Baseline 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). 
6. Female subjects who are currently pregnant or lactating or planning to become pregnant 
during the study.  
7. Subjects who have moderate to severe renal impairment.    
8. Subjects who have hepatic impairment at Screening.  
9. Subjects with current or recent (past 3 months) history of DSM-5-TR substance use disorder 
(except for nicotine).  
10. Subjects with positive urine drug screen for cocaine, amphetamine, benzodiazepines, 
barbiturates, phencyclidine (PCP), or opiates at Screening, except those receiving stable, 
prescribed treatment for attention deficit/hyperactivity disorder (ADHD). 
11. Subjects with a  GLIIHUHQFH LQ WKH DEVROXWH FKDQJH LQ YGTSS-TTS between the 
Screening visit and the Baseline visit. 
12. Subjects with a lifetime history of bipolar disorder type I or II, dementia, schizophrenia, or 
any other psychotic disorder  
13. Subjects with an on et of a maj r depressive episode in the past 6 months.  
14. Subjects with a PHQ-9 score 10 at Screening or Baseline. 
15. Subjects with a history of seizures (excluding febrile seizures that occurred >2 years prior to 
Screening). 
16. Subjects with a history of neuroleptic malignant syndrome. 
17. Subjects with a myocardial infarction within 6 months prior to Screening.  
18. Subjects who have had previous treatment with:  
o investigational medication within 4 weeks prior to Screening  
o oral neuroleptics within 4 weeks prior to Screening 
o depot neuroleptics within 3 months prior to Screening (e.g., risperidone 
microspheres) or 6 months prior to screening (e.g., paliperidone palmitate) 
19. Subjects receiving any other medication to treat motor or vocal tics for at least 14 days prior 
to Baseline.  
20. Subjects receiving unstable doses or excluded medications to treat depression, anxiety or 
ADHD during the 4 weeks prior to Screening. 
21. Subjects who have a need for medications which would have unfavorable interactions with 
ecopipam, e.g., CYP2D6, CYP3A4, CYP2C19, P-gp, substrates with a narrow therapeutic 
window (e.g., digoxin), inhibitors of CYP2D6 (e.g., fluoxetine), broad-spectrum UGT 
enzyme inhibitors (e.g., valproic acid), dopamine antagonists (e.g., neuroleptics) or agonists 
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 10 of 96 
(including bupropion), tetrabenazine, VMAT-2 inhibiters (e.g. tetrabenazine), tricyclics and 
tetracyclics, monoamine oxidase inhibitors, or St. John’s Wort.  See Section 23.  
22. Subjects who have initiated new psychological therapies or deep brain stimulation within 10 
weeks prior to Baseline visit. 
23. Initiation or changes in psychological therapies during the study (i.e., Habit Reversal 
Training or Comprehensive Behavioral Intervention for Tics) as well as deep brain 
stimulation. 
24. Subjects unable to swallow tablets.  
25. Subjects with a known hypersensitivity to any excipients of ecopipam tablets, including 
subjects with confirmed lactose intolerance. 
26. Subjects who are employed by the sponsor, vendors working on the study, study site 
personnel or their family members. 
27. Siblings or family members of any current subject participating in the study.   
28. Subjects deprived of liberty by administrative or judicial decision, patients under court 
protection, guardianship, curatorship or family guardianship.   
29. 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 11.2-, 22.4-, 33.6-, 44.8-, 67.2- and 89.6-mg tablets containing 12.5-, 25-, 37.5-, 50-, 75- 
and 100-mg ecopipam HCl respectively; 1.8 mg/kg/day ecopipam (2 mg/kg/day ecopipam HCl) 
target dose; oral administration. 
Dosing will be stratified by the following weight bands to better achieve the 1.8 mg/kg/day ecopipam 
 PJNJGD\ HFRSLSDP +&O WDUJHW GRVH  -  NJ ! -  NJ ! -  NJ ! -  kg, 
>68 -  NJ !  NJ 'RVLQJ ZLOO EH EDVHG RQ WKH VXEMHFW¶V ZHLJKW DW WKH %DVHOLQH DQG ZLOO QRW EH
adjusted if the subject’s weight changes at subsequent visits.  
During the 4-week titration phase of the Stabilization period, the following ecopipam HCl doses or 
matching placebo will be administered for each of the weight bands:  
Weight 
(kg) 
Week 1 
Week 2 
Week 3 
Week 4 
 
ecopipa
m 
mg/day 
ecopipa
m HCl 
mg/day 
ecopipa
m 
mg/day 
ecopipa
m HCl 
mg/day 
ecopipa
m 
mg/day 
ecopipa
m HCl 
mg/day 
ecopipa
m 
mg/day 
ecopipa
m HCl 
mg/day 
 - 
 
11.2 
12.5 
22.4 
25 
33.6 
37.5 
33.6 
37.5 
>23 - 
 
11.2 
12.5 
22.4 
25 
33.6 
37.5 
44.8 
50 
>34 - 
 
11.2 
12.5 
22.4 
25 
44.8 
50 
67.2 
75 
>44 - 
 
22.4 
25 
44.8 
50 
67.2 
75 
89.6 
100 
>68 - 
 
22.4 
25 
44.8 
50 
89.6 
100 
134.4 
150 
>83 
22.4 
25 
44.8 
50 
89.6 
100 
179.2 
200 
 
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Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 11 of 96 
During the 8-week maintenance phase of the Stabilization period and for those randomized to 
ecopipam in the R/WD period, the following ecopipam doses (or matching placebo for those 
randomized to placebo during the R/WD period) will be administered for each of the weight bands:  
x 
7KRVH ZKR ZHLJK  -  NJ ZLOO UHFHLYH  PJ  PJ HFRSLSDP +&O GDLO\ 
x 
Those who weigh >23 -  ZLOO UHFHLYH  PJ  PJ HFRSLSDP +&O GDLO\ 
x 
Those who weigh >34 -  ZLOO UHFHLYH  PJ  PJ HFRSLSDP +&O daily. 
x 
Those who weigh >44 -  NJ ZLOO UHFHLYH  PJ  PJ HFRSLSDP +&O GDLO\ 
x 
Those who weigh >68 -  NJ ZLOO UHFHLYH  PJ  PJ HFRSLSDP +&O GDLO\ 
x 
Those who weigh >83 kg will receive 179.2 mg (200 mg ecopipam HCl) daily.  
All doses will be administered once daily in the evening without regard to meals. 
Non-responders to ecopipam during the open-label Stabilization period, subjects randomized to 
placebo during the R/WD period, responders to ecopipam who complete the R/WD period, any 
subject who meets Relapse criteria during the R/WD period, and any subject who discontinues the 
study prematurely due to any reason will be tapered off ecopipam in decrements of 22.4 mg/day 
(25 mg ecopipam HCl) until off drug; signs or symptoms of wi hdrawal, abuse and dependence will 
be monitored.  Subjects assigned to placebo will receive placebo taper down medication to preserve 
the blind. 
Duration of treatment:  
Eligible subjects will receive open-label ecopipam tablets for up to 12 weeks.  Subjects who qualify 
as Responders will be randomized at Week 12 to receive either ecopipam tablets or matching placebo 
for up to 12 weeks for a total of up to 24 weeks of treatment.    
Reference therapy, dosage, and mode of administration:  
Placebo-controlled, matching placebo tabl ts given by mouth (PO) in the evening. 
Criteria for evaluation: 
Efficacy:   
Primary Efficacy Endpoint: 
x 
Time from Randomization (Week 12) to Relapse in subjects  6 and < 18 years for ecopipam 
compared to placebo during the double-blind, R/WD period. 
Secondary Efficacy Endpoint: 
x 
Time from Randomization (Week 12) to Relapse in all subjects irrespective of age for 
ecopipam compared to placebo during the double-blind R/WD period. 
Exploratory Efficacy Endpoints: 
x 
Time from Randomization (Week 12) to a worsening by at least one category of the 
CGI-TS-S in subjects 6 and < 18 years for ecopipam compared to placebo during the 
double-blind R/WD period.  If there is a strong correlation of this endpoint with Relapse 
criteria based on the YGTSS-TTS, it may be considered as a secondary endpoint with 
agreement from Health Authorities.    
x 
Time from Randomization (Week 12) to a worsening by at least one category of the 
CGI-TS-S in all subjects for ecopipam compared to placebo irrespective of age.  If there is a 
strong correlation of this endpoint with Relapse criteria based on the YGTSS-TTS, it may be 
considered as a secondary endpoint with agreement from Health Authorities.   
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Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 12 of 96 
x 
Mean change from Randomization (Week 12) to Week 24 in the YGTSS-TTS for ecopipam 
compared to placebo. 
x 
Mean change from Randomization (Week 12) to Week 24 in the Clinical Global Impression 
of Tourette Syndrome Severity (CGI-TS-S) for ecopipam compared to placebo. 
x 
Mean change from Randomization (Week 12) to Week 24 in the YGTSS-Global Severity 
(GS) score for ecopipam compared to placebo. 
x 
Mean change from Randomization (Week 12) to Week 24 in the Caregiver Global 
Impression of Change (CaGI-C) for ecopipam compared to placebo. 
x 
Time from Randomization (Week 12) WR D ORVV RI   RI WKH LPSURYHPHQW IURP %DVHOLQH 
(Day 1) experienced on the Yale Global Tic Severity Scale- Total Tic Score (YGTSS-TTS) at 
the last visit (Week 12) in the open-label Stabilization period.  
x 
Mean change from Randomization (Week 12) to Week 24 in the Clinical Global Impression 
of Tourette Syndrome Improvement (CGI-TS-I) for ecopipam compared to placebo. 
x 
Mean change from Randomization (Week 12) to Week 24 in the Premonitory Urge for Tics 
Scale (PUTS) for ecopipam compared to placebo. 
x 
Mean change from Baseline (Day 1) to Week 24 in Gill s de la Tourette Syndrome–Quality 
of Life Scale for Children and Adolescents (C&A-GTS-QOL) score for ecopipam compared 
to placebo.  
x 
Mean change from Baseline (Day 1) to Week 24 in Gilles de la Tourette Syndrome–Quality 
of Life Scale (GTS-QOL) score in adults f r ecopipam compared to placebo.  
x 
Mean change from Baseline (Day 1) to Week 12 in the YGTSS-TTS.   
x 
Percentage of subjects with a decrease in their YGTSS-776 E\  RU JUHDWHU DW DQ\ WLPH
point from Baseline (Day 1) to Week 12.  
x 
Mean change from Baseline (D y 1) to Week 24 in the YGTSS-TTS for ecopipam compared 
to placebo. 
x 
Mean change from Baselin  (Day 1) to Week 24 in the YGTSS-GS score for ecopipam 
compared to placebo  
x 
Mean change from Baseline (Day 1) to Week 24 in the Clinical Global Impression of 
Tourette Syndrome Severity (CGI-TS-S) for ecopipam compared to placebo. 
x 
Caregiver Global Impression of Change (CaGI-C) through Week 24 for ecopipam compared 
to placebo.   
x 
Mean change from Randomization (Week 12) to Week 24 in the Gilles de la Tourette 
Syndrome–Quality of Life Scale for Children and Adolescents (C&A-GTS-QOL) for 
ecopipam compared to placebo.   
x 
Mean change from Baseline (Day 1) to Week 24 in the Clinical Global Impression of 
Tourette Syndrome Improvement (CGI-TS-I) for ecopipam compared to placebo. 
x 
Time from Randomization (Week 12) to treatment discontinuation during the double-blind 
R/WD period for ecopipam compared to placebo.  
x 
7LPH IURP 5DQGRPL]DWLRQ :HHN  WR ORVV RI   RI WKH LPSURYHPHQW H[SHULHQFHG RQ
the Yale Global Tic Severity Scale- Total Tic Score (YGTSS-TTS) from Baseline (Day 1) to 
the last visit (Week 12) in the open-label Stabilization period for ecopipam compared to 
placebo. 
x 
To evaluate the population PK/pharmacodynamic (PD) relationships with ecopipam during 
the open-label Stabilization period of the study. 
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Additional analyses will include efficacy endpoints listed above at all earlier timepoints, and the 
YGTSS subscales individually (Motor, Vocal, and Impairment).  The correlation between subjects 
meeting Relapse criteria based on YGTSS-TTS and those who also had at least a 1-point reduction on 
CGI-TS-S will also be investigated.  If there is a strong correlation between subjects 6 and <18 years 
who meet Relapse criteria based on the YGTSS-TTS and have a worsening by at least one category 
of the CGI-TS-S, Relapse will not be a competing risk, and therefore the time to worsening of the 
CGI-TS-S IRU VXEMHFWV  DQG  \HDUV will be considered a secondary endpoint.  Similarly, if there 
is a strong correlation between all subjects irrespective of age who meet Relapse criteria based on the 
YGTSS-TTS and have a worsening by at least one category of the CGI-TS-S, Relapse will not be a 
competing risk, and therefore the time to worsening of the CGI-TS-S for all subjects irrespective of 
age will be considered a secondary endpoint. 
Subgroup analyses will also be conducted on all efficacy endpoints listed above for the following 
populations: 
x 
&KLOGUHQ   DQG   \HDUV RI DJH $GROHVFHQWV   DQG   \HDUV RI DJH DQG $GXOWV
 18 years of age). 
x 
Subjects per region 
x 
Males and Females 
x 
Ethnicity 
$GGLWLRQDOO\ 7LPH IURP 5DQGRPL]DWLRQ WR D ORVV RI   LPSURYHPHQW RQ WKH <*766-TTS will 
also be analyzed using the following subgroups: 
x 
Early Responders (at Week 4) and Later Responders (at Week 8) 
Rank order of hierarchy of the secondary and exploratory endpoints will be outlined in the statistical 
analysis plan.  
 
Safety:   
Safety will be assessed by monitor ng and recording all adverse events (AEs) and Serious Adverse 
Events (SAEs) at all Visits, regular monitoring of hematology, blood chemistry, urinalysis and 
prolactin (Screening, Basel n  Weeks 12 and 18, Completion [Week 24] or Relapse/Early 
Termination, and 7- and 14-day Follow Up visits).  HbA1c will be measured at Baseline, Week 12 
and Completion Week 24 visits.  Regular measurement of vital signs and the performance of a 
physical examination will occur at every visit.  An ECG will be done at Screening, Baseline and 
Weeks 4, 12, 18, and 24 and at the 7-and 14-day Follow Up visits.  An additional assessment will 
include the Columbia-Suicide Severity Rating Scale (C-SSRS) (all Visits except 30-day Follow up 
visit).  Additional safety outcomes (occurring at specified visits at Baseline and Weeks 4, 8, 12, 13, 
14, 15, 16, 18, 20, 22, and 24) will include the Children’s Depression Rating Scale-Revised (CDRS-
R) for children and adolescents, the Pediatric Anxiety Rating Scale (PARS), for children and 
adolescents, the Swanson, Nolan and Pelham (SNAP-IV-26) questionnaire for children and 
adolescents, the Children’s Yale-Brown Obsessive-Compulsive Scale-II (CY-BOCS-II), the Conners 
Adult ADHD Rating Scale – Self Report:Short Version (CAARS-S:S) for adults, the Hamilton 
Rating Scale for Anxiety (HAM-A) for adults, the Patient Health Questionnaire-9 (PHQ-9) for adults, 
the Yale-Brown Obsessive-Compulsive Scale-II (Y-BOCS-II) for adults, and the Extrapyramidal 
Symptom Rating Scale (ESRS) for children, adolescents, and adults. 
 
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Page 14 of 96 
PK: 
Blood samples will be collected to measure concentrations of ecopipam and its major (active) 
metabolites at Weeks 4 and 8.  If the Week 8 PK assessment is missed, samples may be drawn at 
Week 12 during the open-label Stabilization period.   
For the Week 4 visit, subjects and parents/caregivers (as applicable) will be instructed to skip the 
study medication on the evening prior to the Week 4 visit and to record the date and time that their 
last dose of study medication was taken.  The study drug administration will occur on the day of the 
Week 4 visit at the site under the supervision of the study investigator.  An intravenous catheter will 
be placed, and the subject will have samples collected at the following time windows:  one sample at 
predose (34 to 44 hours since the last dose), one sample between 0.5 and 1.5 hours after 
administration of study medication, and one sample between 2 and 4 hours after study drug 
administration.  Any samples should be collected at least 30 min apart.  
For the Weeks 8 or 12 visit, subjects and parents/caregivers (as applicable) will be asked to record the 
date and time that their last dose of study drug administration was taken.  A blood sample for PK will 
be collected.  The time of sample collection will be recorded.  Blood samples will be processed as 
outlined in the laboratory manual and analyzed for concentration of ecopipam and its major 
metabolite N -desmethylecopipam (EBS-101-40853). 
Statistical methods: 
Efficacy:  
Sample Size Justification: 
The planned number of Relapse events for the double blind R/WD Phase is 49 in children and 
adolescents.  This number of events will provide 85 SRZHU WR GHWHFW D GLIIHUHQFH EHWZHHQ WUHDWPHQW
groups, assuming a hazard ratio of 0.4 for Relapse and statistical testing at alpha level 0.05 (2-sided).  
Subject enrollment will stop around the time that 49 Relapse events for children and adolescents are 
anticipated to have occurred.  The number of Relapse events among adults will not determine study 
completion. 
Assuming the proportion of subjects who Relapse in the double-blind R/WD SKDVH LV  LQ WKH
SODFHER JURXS DQG  LQ WKH HFRSLSDP JURXS DSSUR[LPDWHO\ 98 subjects (49 subjects per group) 
will be required to achieve this number of Relapse events. 
Total Number of Subjects: 
Approximately 196 subjects (children and adolescents) will be enrolled into the open-label 
Stabilization Period in order to randomize 98 subjects age   WR   \HDUV RI DJH assuming the 
stabilization Response rate in the open-label Stabilization Period LV   In addition, approximately 
40 adult subjects are also anticipated to be enrolled.   
Interim Analysis:  
An interim analysis (IA) will be conducted by an independent data safety monitoring board (DSMB) 
DIWHU DSSUR[LPDWHO\  RI 5HODSVH HYHQWV KDYH DFFUXHG  5HODSVH HYHQWV  Full details will be 
provided in the Statistical Analysis Plan (SAP). 
Analysis Population and Methods: 
The Modified Intention-to-Treat (mITT) population will include all randomized subjects who 
received at least one dose of study drug post randomization.  The mITT population will be used for 
the analysis of the efficacy endpoints. 
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Protocol_9.0_05 Mar 2024 | VV-TMF-38683299 | 1.0
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Protocol EBS-101-TD-301 
Ecopipam 
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Confidential 
Page 15 of 96 
The primary efficacy endpoint for this trial is Time from Randomization (Week 12) to Relapse in 
VXEMHFWV   DQG   \HDUV during the double-EOLQG 5:' SHULRG GHILQHG DV D ORVV RI   RI WKH
improvement experienced on the YGTSS-TTS from Baseline (Day 1) to the last visit (Week 12) in 
the open-label Stabilization period for ecopipam compared to placebo, or initiation of additional 
medications to treat symptoms of TD; or requirement of hospitalization for worsening symptoms of 
TD.  Data from subjects who complete or discontinue from the double-blind R/WD period without 
Relapse will be considered as censored observations.  The log rank test will be the primary test of 
statistical significance.  Kaplan-Meier curves will be used to compare the times to relapse between 
the treatment groups.  7KH KD]DUG UDWLR DQG LWV  FRQILGHQFH LQWHUYDO &, ZLOO EH HVWLPDWHG IURP
the Cox proportional hazard model with treatment as a factor.  The proportional hazards assumption 
will be evaluated graphically and analytically, for example by assessing martingale and Schoenfeld 
residuals and by modeling time-dependent covariates.  The secondary endpoint will be evaluated in a 
similar manner as the primary efficacy endpoint.  Details will be provided in the SAP.  
The Per-Protocol (PP) population will include subjects from the mITT population who have no major 
protocol deviations that may adversely impact assessment of effica y.  Before data are released for 
statistical analysis, a blinded review of all data will be perf rmed to identify protocol deviations that 
may potentially affect the results.  At this time, it will be determined if subjects and/or data should be 
excluded from the PP Population.  The list of subjects or observations to be excluded from the PP 
Population, along with the reason for exclusion, will be finalized prior to database unblinding.  
Protocol deviations that occur due to COVID-19 rel ted issues or other qualifying events will be 
categorized separately as applicable.    
Efficacy endpoints will be tested using a rank order hierarchy to preserve alpha.  Full details will be 
specified in a formal SAP. 
Safety: 
The safety population will include all enrolled subjects who received at least one dose of study drug.  
The safety population will be used for the analysis of the safety endpoints. 
PK:  
Plasma concentration-time data will be summarized in the Clinical Study Report (CSR).  Population 
pharmacokinetic and pharmacodynamic analyses will be conducted and summarized separately, using 
data from this study along with data from other studies.  The methodology for analyses will be 
reported in a separate analysis plan. 
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Protocol EBS-101-TD-301 
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Page 16 of 96 
3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
SUMMARY OF SIGNIFICANT CHANGES .................................................................................2 
SIGNATURE PAGE .......................................................................................................................3 
INVESTIGATOR’S AGREEMENT ...............................................................................................4 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................5 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS ...........................................................................................16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................21 
5. 
INTRODUCTION ........................................... ........................................................24 
5.1. 
Background on Tourette’s Disorder ................ ........ ...............................................24 
5.1.1. 
Disrupted Dopamine Systems in Tourette’s Disorder ................................................25 
5.2. 
Background on Ecopipam .............................
.........................................................25 
5.2.1. 
Nonclinical Data ......................................
...............................................................25 
5.2.1.1. 
Toxicology ................................... ........ .....................................................................25 
5.2.2. 
Clinical Data .......................... ..................................................................................26 
5.3. 
Risk-Benefit Assessment .. ..... .... .............................................................................31 
5.3.1. 
Assessment of Risk ....... .....
..................................................................................31 
5.3.2. 
Assessment of Benefit ....... .......................................................................................32 
5.3.3. 
Methods to Minimize Risks ......................................................................................33 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................34 
6.1. 
Primary Objective .......................................................................................................34 
6.2. 
Secondary Objectives .................................................................................................34 
6.3. 
Exploratory Objective .................................................................................................34 
7. 
INVESTIGATIONAL PLAN .....................................................................................35 
7.1. 
Overall Study Design ..................................................................................................35 
7.2. 
Number of Subjects ....................................................................................................37 
7.3. 
Treatment Assignment ................................................................................................37 
7.4. 
Dose Adjustment Criteria ...........................................................................................37 
7.5. 
Criteria for Subject Study Discontinuation .................................................................37 
7.6. 
Criteria for Study Termination ...................................................................................38 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................43 
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8.1. 
Inclusion Criteria ........................................................................................................43 
8.2. 
Exclusion Criteria .......................................................................................................43 
8.3. 
Subject Withdrawal, Removal, and Replacement Criteria .........................................45 
9. 
TREATMENT OF SUBJECTS ..................................................................................46 
9.1. 
Description of Study Drug ..........................................................................................46 
9.2. 
Concomitant Medications ...........................................................................................46 
9.2.1. 
Allowable Medications for Common Comorbid Conditions ......................................46 
9.3. 
Prohibited Therapies ...................................................................................................47 
9.4. 
Treatment Compliance ................................................................................................48 
9.5. 
Randomization and Blinding .......................... .........................................................48 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................49 
10.1. 
Study Drug .................................................. .. ..... ....................................................49 
10.2. 
Study Drug Packaging and Labeling ..... ....
........................................................49 
10.3. 
Study Drug Storage ...............................
...............................................................49 
10.4. 
Study Drug Preparation ............... ........ .....................................................................49 
10.5. 
Administration ......................... ........ .........................................................................50 
10.6. 
Dosing Rationale .............. ..
.... ............................................................................51 
10.7. 
Study Drug Accountability . .... .................................................................................51 
10.8. 
Study Drug Handling and Disposal ............................................................................52 
11. 
ASSESSMENT OF EFFICACY ................................................................................53 
11.1. 
Primary Efficacy Assessment .....................................................................................53 
11.1.1. 
Yale Global Tic Severity Scale (YGTSS) ..................................................................53 
11.2. 
Secondary Efficacy Assessment .................................................................................53 
11.3. 
Exploratory Efficacy Assessments .............................................................................54 
11.3.1. 
Clinical Global Impression Tourette Syndrome (CGI-TS)20,12 ..................................56 
11.3.2. 
Caregiver Global Impression of Change (CaGI-C)12 .................................................56 
11.3.3. 
Premonitory Urge for Tics Scale (PUTS)22 ................................................................56 
11.3.4. 
Gilles de la Tourette Syndrome – Quality of Life scale for Children aged 
6-12 years and Adolescents aged 13-18 years (C&A GTS-QOL)16 ...........................57 
11.3.5. 
Gilles de la Tourette Syndrome – Quality of Life Scale (GTS-QOL)23 .....................57 
11.4. 
Pharmacokinetics Assessments ..................................................................................57 
12. 
ASSESSMENTS OF SAFETY ..................................................................................58 
12.1. 
Safety Parameters .......................................................................................................58 
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12.1.1. 
Columbia Suicide Severity Rating Scale (C-SSRS)10 ................................................58 
12.1.2. 
Children’s Depression Rating Scale-Revised (CDRS-R) ...........................................58 
12.1.3. 
Patient Health Questionnaire-9 (PHQ-9)25 .................................................................59 
12.1.4. 
Pediatric Anxiety Rating Scale (PARS)17 ...................................................................59 
12.1.5. 
Hamilton Rating Scale for Anxiety (HAM-A)26 ........................................................59 
12.1.6. 
Extrapyramidal Symptom Rating Scale (ESRS)27 ......................................................59 
12.1.7. 
Children’s Yale-Brown Obsessive-Compulsive Scale-II (CY-BOCS-II)28,29 ............60 
12.1.8. 
Yale-Brown Obsessive-Compulsive Scale-II (Y-BOCS-II)30 ....................................60 
12.1.9. 
Swanson, Nolan and Pelham (SNAP-IV-26)13 ...........................................................60 
12.1.10. 
Conners Adult ADHD Rating Scale – Self Report, Short Version (CAARS-
S:S) ................................................................... ... ...................................................60 
12.1.11. 
Vital Signs ......................................................... ... .................................................61 
12.1.12. 
Electrocardiogram (ECG) .......................... ....... .......................................................61 
12.1.13. 
Central Laboratory Tests: .................. ..... ................................................................61 
12.2. 
Adverse and Serious Adverse Events ......................................................................62 
12.2.1. 
Definition of Adverse Events .. ..
.... .....................................................................62 
12.2.1.1. 
Adverse Event (AE) ............. ..... .............................................................................62 
12.2.1.2. 
Serious Adverse Event (SAE) ... ................................................................................63 
12.2.1.3. 
Other Adverse Event (OAE) ..... ...............................................................................63 
12.3. 
Relationship to Study Drug ........................................................................................63 
12.4. 
Recording Adverse Events .........................................................................................64 
12.5. 
Reporting Serious Adverse Events .............................................................................64 
13. 
STATISTICS ..............................................................................................................66 
13.1. 
Analysis Population ....................................................................................................66 
13.2. 
Data Safety Monitoring Board ....................................................................................66 
13.3. 
Interim Analysis ..........................................................................................................67 
13.4. 
Planned Analysis ........................................................................................................67 
13.4.1. 
Efficacy Analysis ........................................................................................................67 
13.4.2. 
Safety Analysis ...........................................................................................................69 
13.4.3. 
Pharmacokinetics Analysis .........................................................................................69 
13.5. 
Sample Size Justifications ..........................................................................................70 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................71 
14.1. 
Study Monitoring ........................................................................................................71 
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14.2. 
Audits and Inspections ................................................................................................71 
14.3. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................72 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................73 
16. 
ETHICS ......................................................................................................................74 
16.1. 
Ethics Review .............................................................................................................74 
16.2. 
Ethical Conduct of the Study ......................................................................................74 
16.3. 
Written Informed Consent ..........................................................................................74 
16.4. 
Subject Diversity ........................................................................................................74 
16.5. 
Subject Confidentiality and Data Security .................................................................75 
16.6. 
Ethnicity Data Collection ............................... .........................................................76 
17. 
DATA HANDLING AND RECORDKEEPING .... ................................................77 
17.1. 
Inspection of Records ................................. .. ..... ....................................................77 
17.2. 
Retention of Records ............................. ....
........................................................77 
18. 
PUBLICATION POLICY ....................
...............................................................78 
19. 
LIST OF REFERENCES ............. ........ .....................................................................79 
20. 
WMA DECLARATION OF HELSINKI – ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS.................................82 
21. 
CONTRACEPTION GUIDELINES ..........................................................................88 
22. 
ALLOWABLE MEDICATIONS LIST FOR COMORBID CONDITIONS .............89 
23. 
PROHIBITED MEDICATIONS LIST.......................................................................90 
24. 
DISALLOWED CONCOMITANT MEDICATION TIME-FRAMES .....................95 
 
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Version 9.0, 05 March 2024 
 
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Page 20 of 96 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................5 
Table 2: 
Protocol EBS-101-CL-001 Efficacy Results (mITT Data set, MMRM 
analysis with imputation) ............................................................................................29 
Table 3: 
Schedule of Assessments ............................................................................................39 
Table 4: 
Investigational Product ...............................................................................................46 
Table 5: 
Proposed Dosing Regimen .........................................................................................50 
 
LIST OF FIGURES 
Figure 1: 
YGTSS-TTS: Baseline to End of Therapy for the mITT Population in Study 
EBS-101-CL-001 .............................................. .... ...................................................28 
 
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Protocol_9.0_05 Mar 2024 | VV-TMF-38683299 | 1.0
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Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 21 of 96 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol: 
 
Abbreviations 
Terms  
ADD 
Attention Deficit Disorder 
ADHD 
attention deficit/hyperactivity disorder 
ADL 
Activities of Daily Living 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
AMP 
adenosine monophosphate 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Classification 
AUC 
area under the plasma-concentration time course profile  
AUC (0-24 hr) 
area under the plasma-concentration time course profile from  
time 0 (dosing) to 24 hours after dosing 
BUN 
blood urea nitrogen 
C&A-GTS-QOL 
Child and Adole cent Gilles de la Tourette Syndrome-Quality 
of Life Scales 
CAARS-S:S 
Conners Adult ADHD Ratings Scale – Self Report: Short 
Version  
CaGI-C 
Car giver Global Impression of Change 
CFR 
Code of Federal Regulations 
CDI 
Children’s Depression Inventory 
CDRS-R 
Children’s Depression Rating Scale-Revised 
CY-BOCS-II 
Children’s Yale-Brown Obsessive-Compulsive Scale-II 
CGI 
Clinical Global Impression 
CGI-TS-I 
Clinical Global Impression Tourette’s Syndrome of 
Improvement 
CGI-TS-S 
Clinical Global Impression Tourette’s Syndrome of Severity 
Cmax 
maximum observed concentration 
CNS 
Central nervous system 
COVID-19 
SARS-CoV-2 (coronavirus) 
CRA 
Clinical research associate 
CRO 
Clinical research organization 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
coefficient of variation 
DCI 
Diagnostic Confidence Index 
DSM-5-TR 
Diagnostic and Statistical Manual of Mental Disorders – 
5th Edition-Text Revision  
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Protocol_9.0_05 Mar 2024 | VV-TMF-38683299 | 1.0
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DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
ESRS 
Extrapyramidal Symptom Rating Scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GS 
Global score 
GTS-QOL 
 
Gilles de la Tourette Syndrome–Quality of Life Scale 
HAM-A 
Hamilton Rating Scale for Anxiety 
HCl 
Hydrochloride 
123I-ȕ-CIT SPECT 
ȕ-carbomethoxy-ȕ-[4-iodophenyl]tropane) single photon 
emission computed tomography 
HbA1c 
Hemoglobin A1c 
IA 
Interim analysis  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
Ki 
Inhibition constant 
LDH 
lacta e dehydrogenase 
LFT 
Liv r function test(s) 
LND 
Lesch Nyhan Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
OCD 
Obsessive-Compulsive Disorder 
PARS 
Pediatric Anxiety Rating Scale 
PCP 
Phencyclidine 
PET 
Positron emission tomography 
PHQ-9 
Patient Health Questionnaire – 9 
PI 
Principal Investigator  
PO 
Oral (per os) 
PUTS 
Premonitory Urge for Tics Scale 
QD 
Once daily 
SAE 
serious adverse event 
SC 
Subcutaneous 
SCH 
Schering-Plough drug code indicator 
SNAP-IV-26 
Swanson, Nolan, and Pelham-IV-26 questionnaire 
tmax 
time from dosing to the maximum observed concentration 
TD 
Tourette’s Disorder  
THC 
Tetrahydrocannabinol 
TS 
Tourette’s Syndrome 
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TTS 
Total Tic Score 
US 
United States 
WMA 
World Medical Association 
Y-BOCS-II 
Yale – Brown Obsessive-Compulsive Scale-II 
YGTSS 
Yale Global Tic Severity Scale 
YGTSS-GS 
Yale Global Tic Severity Scale- Global Severity  
YGTSS-TTS 
Yale Global Tic Severity Scale- Total Tic Score 
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5. 
INTRODUCTION 
5.1. 
Background on Tourette’s Disorder 
Tourette’s Disorder (TD) 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-TR diagnostic criteria18).  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 4.3 to 1.  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 TD 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 TD and make diagnosis difficult.  Tic severity can 
range from mild to severe according to its frequen y and intensity.   
 
Natural History of Tics 
The tics have a variable course, with severe bouts interspersed with complete absence of 
symptoms.  Onset of tics is seen early in childhood (average approximately 7 years) and peaks in 
the teenage years.  Vocal tics appears several years after the onset of motor tics.  For most 
subjects, the period of worst-ever tic severity is between 7 and 15 years of age, followed by a 
steady decline in tic severity.  As subjects mature, the vast majority of tics will disappear 
permanently, with a small percentage of subjects having tics that persist into adulthood and 
UHTXLUH WUHDWPHQW &RPSOHWH UHPLVVLRQ RI WLFV LV UHSRUWHG LQ DSSUR[LPDWHO\  RI VXEMHFWV
6HYHUH WLFV DUH WKRXJKW WR RFFXU RQO\ LQ DERXW  RI WKH FDVHV3 Approaches to the treatment of 
DSM-5-TR Diagnostic Criteria for Tourette's Disorder  
 
  Note: A tic is a sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or 
vocalization. 
A. Both multiple motor and one or more v cal tics have been present at some time during the 
illness, although not necessarily concurrently.  
B. The tics may wax and wane i  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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Page 25 of 96 
tics include education, behavioral therapy, pharmacological therapy, and treatment of comorbid 
conditions (ADHD, OCD).  $SSUR[LPDWHO\  RI subjects do not need treatment.  Counseling 
and behavioral therapy may be sufficient with mild symptoms.  Medications should be 
considered when tics interfere with peer relationships, social interactions, job or school 
performance or interfere with activities of daily living.  Medications should be started at low 
doses, titrated up slowly to lowest effective dose and tapered slowly during non-stressful periods.  
Medication therapy incudes: dopamine receptor blocking agents, dopamine depleting agents, 
alpha agonists, noradrenergic 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- RI subjects.  
Many subjects eventually discontinue medication therapy due to adverse events, including extra-
pyramidal disorders, somnolence, blood glucose changes, weight gain, and effects on lipids.  A 
selective dopamine-1 (D1) receptor antagonist may mitigate against some of these adverse events 
and has the potential to offer a safer alternative option.  
5.1.1. 
Disrupted Dopamine Systems in Tourette’s Disorder  
The underlying mechanism responsible for TD 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  
x Dopamine-rich areas of the brain (e g., striatum) are believed to control motor tics 
x Clinical neuroimaging studies of TD subjects implicate dopamine-rich brain areas 
x Dopamine antagonists can ameliorate tics  
x Catecholamine depletors (e.g., tetrabenazine) can ameliorate tics 
5.2. 
Background on Ecopipam 
5.2.1. 
Nonclinical Data 
5.2.1.1. 
Toxicology 
The nonclinical development program for ecopipam comprised studies of bioavailability, acute 
and repeated-dose toxicity (including juvenile rats) oral and gavage [PO], intramuscular [IM], 
intravenous [IV], and subcutaneous [SC] routes of administration), cardiovascular; neurological, 
behavioral, and autonomic nervous system, reproductive and endocrinological, and genetic 
toxicity.  Results from the extensive nonclinical studies demonstrate that ecopipam is well 
tolerated.  Ecopipam did not cause any appreciable changes in cardiovascular function, any 
neurological disorders, or loss of efficacy/tolerance.  Ecopipam HCl is not considered 
embryotoxic, fetotoxic, or teratogenic in rats at doses up to 162 mg/kg.  In rabbits, the no-
observable-effect level for both maternal and developmental toxicity is > 150 mg/kg, but 
< 300 mg/kg.  Ecopipam is not considered genotoxic or mutagenic.  However, ecopipam HCl 
was found to have a consistent sedative effect 2 hours after dosing in primates and to cause 
convulsions in mice, rats, and primates after high doses (>10 mg/kg).  Ecopipam did not cause 
any movement disorders in mice, rats, or primates.  
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In a recently completed toxicology study, ecopipam HCl administered at doses of 6, 36, and 
216 mg/kg/day orally to juvenile rats was well tolerated with no compound-related deaths and no 
adverse effects on sexual maturation, Functional Observational Battery testing, acoustic startle 
habituation, ophthalmologic examinations, estrous cycling, mating and fertility, ovarian and 
uterine examinations, clinical pathology, macroscopic pathology, or microscopic pathology.  
Administration resulted in clinical signs and reduction in body weight gains and body weights at 
 36 mg/kg/day and reductions in food consumption at 216 mg/kg/day.  Spleen weights were 
reduced in the 216 mg/kg/day dose group at the end of the dose period; these findings were not 
observed at the end of the recovery period. 
Results of nonclinical pharmacokinetic and metabolism studies showed that ecopipam is rapidly 
absorbed after oral dosing and, in rodents and monkeys, is metabolized to the N-desmethyl 
analog (N-desmethyl-ecopipam or EBS-101-40853).  Both ecopipam and N-desmethyl-ecopipam 
are extensively conjugated.  There are no qualitative differences in metabolic profiles of 
ecopipam between species.  For rodents and nonhuman primates, the estimated oral 
ELRDYDLODELOLW\ RI HFRSLSDP SDUHQW GUXJ ZDV YHU\ OLPLWHG  LQ UDWV DQG  LQ PRQNH\V  
Based on nonclinical hormonal and toxicology studies conducted with ecopipam, there is no 
evidence that ecopipam will have endocrinological effects in humans similar to that of the D2 
antagonists. 
Please refer to the Investigator’s Brochure for m re detailed information about the known 
benefits and risks of ecopipam. 
5.2.2. 
Clinical Data 
Clinical Studies in Subjects with TD 
With respect to TD, the following clinical studies support the use of ecopipam in patients with 
this disease: 
Study PSY301 
This was a Phase 2a, multicenter, non-randomized, open-label study of 44.8 mg ecopipam 
(50 mg ecopipam HCl) daily (Weeks 1–2) and then 89.6 mg (100 mg ecopipam HCl) daily 
(Weeks 3– LQ  DGXOW VXEMHFWV   WR   \HDUV RI DJH ZLWK 7'  The primary efficacy end 
point was the change in the Yale Global Tic Severity Scale, Total Tic Score (YGTSS-TTS) from 
Baseline to Week 8.  
Mean (SD) YGTSS-TTS was 30.6 (8.8) at Baseline and 25.3 (9.2) at 8 weeks (2-tailed paired 
t17 = 4.4; p = 0.0004).  Mean (SD) YGTSS impairment score was 29.7 (10.9) at Baseline and 
22.8 (13.7) at final visit (t17 = 2.2; p = 0.04).  
There was no significant change in premonitory urges or psychiatric symptoms.  Mean change in 
ZHLJKW ZDV í NJ S    The most commonly reported adverse events were sedation 
 IDWLJXH  LQVRPQLD  VRPQROHQFH  DQ[LHW\  KHDGDFKH  DQG
PXVFOH WZLWFKLQJ  
Study PSY302 
Study PSY301 was followed by a Phase 2, placebo-controlled, cross-over study of ecopipam in 
40 children and adolescents with TD which further demonstrated that ecopipam treatment 
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Page 27 of 96 
decreases motor and phonic tics as assessed by the YGTSS-TTS in children and adolescents with 
TD.  This study was a randomized, double-blind, placebo-controlled crossover study to evaluate 
the safety, tolerability, and efficacy of ecopipam in children and adolescents with TD.  Forty 
pediatric patients (7-17 years of age) with TD and a total tic score of 20 on the YGTSS were 
randomized to ecopipam or placebo.  The study consisted of an initial 30-day Treatment period 
(sequence 1), a 2-week Washout period, and a second 30-day Treatment period (sequence 2) 
where patients were crossed to the alternative treatment to which they were randomized.  
The primary endpoint of the study was the change in YGTSS-TTS from Baseline to Day 30 for 
the ecopipam group compared to the placebo group.  Method of analysis was based on the 
intention-to-treat (ITT) population with the last observation carried forward (LOCF).  A simple 
analysis of variance (ANOVA) was prespecified as the primary statistical test.  However, 
because of the numbers of subjects with unequal baseline visits, the assumptions of the ANOVA 
were violated, making it inappropriate to use.  Therefore, the YGTSS-TTS was analyzed using a 
2-way analysis of covariance (ANCOVA).  
Reductions from BL in the YGTSS-TTS were significantly greater on ecopipam than placebo for 
the primary endpoint at Day 30 (-  &, -0.3 to -6.1 P=0.033) and at an earlier timepoint at 
Day 16 (-  &, -0.9 to -6.5 P=0.011).  Significant reductions from BL in the YGTSS-
Global Score (GS) were also observed at Day 30 and Day 16.  There was also a significant 
change in the Clinical Global Impression of Severity (CGI-S) scales from Baseline to Day 30.  
The proportion of children and adolescents with moderate, marked, or severe symptoms 
GHFUHDVHG IURP  DW EDVHOLQH WR  E\ 'D\  RQ HFRSLSDP EXW UHPDLQHG DW  E\
Day 30 on placebo.  
Thirty-ILYH VXEMHFWV  UHSRUWHG DW OHDVW RQH $( GXULQJ WKH VWXG\ ZLWK  AEs reported.  
The most frequently reported AEs   RI VXEMHFWV LQ WKH HFRSLSDP JURXS ZHUH KHDGDFKH
 DEGRPLQDO SDLQ XSSHU LQVRPQLD QDXVHD VRPQROHQFH DQG YRPLWLQJ HDFK   The 
most frequently reported AEs   RI VXEMHFWV LQ WKH SODFHER JURXS ZHUH KHDGDFKH 
QDVRSKDU\QJLWLV  DQG DEGRPLQDO SDLQ XSSHU   Most AEs  ZHUH DVVHVVHG
by the investigator as mild or moderate in severity. 
7ZHQW\ VXEMHFWV  UHSRUWHG D VWXG\ GUXJ-related AE while taking ecopipam and 
10 VXEMHFWV  UHSRUWHG D VWXG\ GUXJ-related AE while taking placebo.  The most frequently 
reported AEs   FRQVLGHUHG UHODWHG WR VWXG\ GUXJ LQ VXEMHFWV WDNLQJ HFRSLSDP ZHUH QDXVHD
 VRPQROHQFH  DEGRPLQDO SDLQ XSSHU GHFUHDVHG DSSHWLWH IDWLJXH KHDGDFKH DQG
VHGDWLRQ DOO . 
There were no deaths in the study.  2QH VXEMHFW  SUHPDWXUHO\ GLVFRQWLQXHG IURP WKH VWXG\
due to an AE of rash.  2QH VXEMHFW  H[SHULHQFHG D VHULRXV $( 6$( RI SV\FKRWLF GLVRUGHU
approximately 55 days after the last dose of ecopipam.  2QH VXEMHFW  UHTXLUHG D GRVH
reduction due to an AE of fatigue. 
7ZR VXEMHFWV  UHSRUWHG VXLFLGDO LGHDWLRQ LQ WKH &-SSRS during the treatment phase.  
Overall, the data suggest that administration of ecopipam did not affect body weight. CDI scores, 
or S-SSRS scores compared with placebo.  No clinically significant abnormalities in clinical 
laboratory evaluations, vital signs, ECG findings, or physical examination findings were 
observed following ecopipam administration. 
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Study EBS-101-CL-001 
Based on the promising results of the Phase 2 clinical studies described above, Emalex initiated a 
Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
evaluating the efficacy and safety of ecopipam in 153 children and adolescents with TD (ages 
> 6 to < 18).  The study was conducted at 68 sites activated across the U.S., Canada, and Europe.  
Patients were randomized to receive either ecopipam tablets at a dose of 1.8 mg/kg/day 
(2 mg/kg/day ecopipam HCl) or placebo tablets.  Study medication was titrated to the target dose 
over four weeks and then maintained for an eight-week treatment period. 
The primary efficacy endpoint was the change from Baseline to Week 12 in the YGTSS-TTS.  
Statistically significant and clinically meaningful results were obtained on this primary endpoint 
at Week12, and significant differences to placebo were found at Weeks 4, 6 and 8 as well.  
Figure 1: 
YGTSS-TTS: Baseline to End of Therapy for the mITT Population in Study 
EBS-101-CL-001 
The key secondary endpoint, the Clinical Global Impression of Tourette Syndrome Severity 
(CGI-TS-S), was also statistically significant at all timepoints from Week 6 to Week 12.  In 
addition, other secondary endpoints were also significant including the YGTSS-Global Severity 
score (YGTSS-GS) and the Caregiver Global Impression of Change (CaGI-C).  Two secondary 
endpoints, Clinical Global Impression of Tourette Syndrome Improvement (CGI-TS-I) and a 
patient rated quality of life instrument, were not statistically significant, although positive trends 
were observed on the CGI-TS-I, with significant results at earlier timepoints. 
A summary of the primary and secondary efficacy data is presented in Table 2 below. 
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Table 2: 
Protocol EBS-101-CL-001 Efficacy Results (mITT Data set, MMRM analysis 
with imputation) 
 
Abbreviation 
Placebo 
(n=74) 
Ecopipam 
(n=75) 
P value 
Outcome Measures:  mITT data set 
Primary Outcome: 
Yale Global Tic Severity Scale-Total 
Tic Score (motor + phonic tic scales) 
Baseline to week 12 
YGTSS-TTS 
-6.42 
-9.87 
0.011 
Key Secondary Outcome: 
Clinical Global Impression of Tourette 
Syndrome – Severity 
Baseline to 12 weeks 
CGI-TS-S 
-0.53 
-0.91 
0.027 
Predefined Hierarchy of Secondary Outcomes: 
Clinical Global Impression of Tourette 
Syndrome of Improvement 
Baseline to week 12 
CGI-TS-I 
3.42 
3.04 
0.079 
Yale Global Tic Severity Scale -Global 
Severity score (motor + phonic + 
overall impairment scales) 
Baseline to week 12 
YGTSS- GS 
-13.56 
-21.41 
0.004 
Caregiver Global Impression of Change 
At week 12 
CaGI-C 
3.55 
2.49 
0.007 
Gilles de la Tourette Syndrome-Quality 
of Life Scale for Children and 
Adolescents 
Baseline to week 12 
C&A-GTS-QOL 
-8.81 
-8.75 
0.978 
6XEMHFWV ZLWK D  LPSURYHPHQW RQ
the YGTSS-TTS 
At any time between baseline and 
12 weeks 
 
 
32 
(4 
53 
 
OR 3.67 
P 
<0.001 
 
The PRVW IUHTXHQW DGYHUVH HYHQWV   DQG KLJKHU WKDQ SODFHER ZHUH KHDGDFKH 
LQVRPQLD  IDWLJXH  QDVRSKDU\QJLWLV  VRPQROHQFH  DQ[LHW\ 
QDXVHD  DQG UHVWOHVVQHVV   For less commonly reported adverse events, the same 
proportion of ecopipam- and placebo-treated patients reported suicidal ideation and depression.  
No deaths were reported in the study, 2 subjects treated with ecopipam and 1 subject treated with 
placebo experienced Serious AEs (SAEs), and 4 ecopipam-treated patients discontinued the 
study due to an adverse event.  No metabolic events were observed and more patients on placebo 
gained weight than those who received ecopipam.  No EPS-related events were observed and no 
difference from placebo was detected for other abnormal movement events.  No clinically 
significant differences between ecopipam and placebo were noted in labs, vital signs, EKGs and 
in commonly used scales to detect anxiety, depression, suicidal ideation and behaviors, akathisia, 
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and tardive dyskinesia.  Ecopipam did not adversely affect comorbid psychiatric conditions of 
ADHD. 
In order to assess abuse potential of ecopipam in study EBS-101-CL-001, sites were instructed to 
assess for symptoms of drug abuse and withdrawal over the course of study medication treatment 
as well as during down-titration.  Standardized Medical Queries (SMQs) based on MedDRA 
classification of preferred terms were conducted for abuse related AEs.  The SMQ terms used 
were A) drug abuse and dependence and B) drug withdrawal.  No symptoms or signs of either 
drug abuse/dependence or withdrawal were reported for subjects in the drug or placebo group.  
This, combined with data available from earlier studies, supports the reasoning that there is a low 
potential for ecopipam to cause drug abuse/dependence or withdrawal. 
Study EBS-101-OL-001  
Subjects who completed EBS-101-CL-001 as well as the 14 day follow up visit and who 
continued to meet the inclusion/exclusion criteria were eligible.  Further, the Investigator had to 
determine that there was a potential benefit from continued participation.  Of the 124 subjects 
who entered the study, 121 received at least one dose of ecopipam.  The dose was adjusted to 
weight using the same weight bands designated for EBS-101-CL-001. 
At study entry, baseline score of the YGTSS-TTS was an average of 29.6, which decreased to  
17.3 at end of study.  The CGI-TS-S score, the key secondary end point of the double-blind 
study, decreased from an average of 4.3 at baseline to 3.3 at six months, and 3.1 at month 12.  
The C&A-GTS-QoL Total Scores improved from a mean of 26.6 at baseline, to 18.7 at 6 
months, and 19.0 at 12 months.  The visual analog scale also improved over the trial.  While 
open label studies can only inform efficacy  these results support the durability of treatment 
effect of ecopipam in TD across multiple measures of disease severity and QoL. 
A total of 80 subjects completed the study and 41 discontinued prematurely with 14 due to 
adverse events.  Two subjects reported SAE: one possibly related to study drug (obsessive 
thoughts) and the other was se ondary to injuries suffered in a tornado and judged as not related 
to study drug.  Ecopipam was not stopped in that case.  
7UHDWPHQW HPHUJHQW DGYHUVH HYHQWV 7($(V ZHUH UHSRUWHG LQ  VXEMHFWV  ZKR UHFHLYHG
ecopipam.  Forty of these events were considered by study investigators to be related to 
HFRSLSDP 7KH PRVW IUHTXHQW 7($(V ZHUH QDVRSKDU\QJLWLV  DQ[LHW\  LQVRPQLD
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 VXLFLGDO EHKDYLRU 1R DGYHUVH PHWDEROLF HYHQWV ZHUH UHSRUWHG DQG ] VFRUHV IRU %0, DOVR
showed no meaningful change. 
$ WRWDO RI  VXEMHFWV  H[SHULHQFHG $(V OHDGLQJ WR WUHDWPHQW WHUPLQDWLRQ  The most 
FRPPRQO\ UHSRUWHG $(V OHDGLQJ WR WUHDWPHQW WHUPLQDWLRQ UHSRUWHG LQ  VXEMHFWV LQFOXGHG
DQ[LHW\ DQG GHSUHVVLRQ  VXEMHFWV HDFK   All other AEs leading to treatment termination 
occurred in 1 subject each. 
With respect to potential AEs attributable to dopamine blockade, 2 subjects reported tremor and 
1 subject each reported akathisia, balance disorder, bruxism, joint lock, and tongue biting.  
   
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Protocol EBS-101-TD-301 
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Overall, neither reported AEs nor scores from systematic assessments for side effects revealed 
safety concerns for subjects treated with ecopipam. 
5.3. 
Risk-Benefit Assessment 
A consideration of the potential of risks that subjects with TD may be exposed to, approaches to 
reducing any such risks, and the possible benefits that they may derive from their participation in 
EBS-101-TD-301 is outlined below.  
5.3.1. 
Assessment of Risk 
A total of 193 children and adolescents (6 to 18) have been exposed to ecopipam, including 181 
pediatric subjects with TD and 12 subjects with LND.   
Ecopipam also been evaluated for safety in 2916 adult patients who participated in clinical trials 
for TD (N = 18) and other indications.  A total of 1049 adult patients were treated with oral 
ecopipam for at least 180 days and 446 adult patients treated with oral ecopipam had at least 
1 year of exposure. 
As 2916 human subjects have been exposed to single and multiple doses of ecopipam and safety 
data including collection of adverse events, physical examinations, laboratory tests, ECGs, etc. 
have been systematically collected, there exists a fair body of information to base the 
understanding of potential risks and approaches to minimizing them in current and future studies.  
The overall safety profile of ecopipam in clinic l studies have shown that the drug is generally 
well tolerated with the adverse events affecting primarily the CNS (e.g., headache, sedation, 
insomnia, psychiatric changes such as anxi ty, depression, and suicidal ideation) and the 
gastrointestinal system (e.g., nausea and vomiting). 
In subjects with TD, ecopipam has been evaluated in five studies, one study in 18 adult subjects, 
one study in 40 children and adolesc nts with an open-label safety extension study, and one 
study in 141 children and adolesc nts with an open-label safety extension study. 
There have been no deaths and 3 patients reported a total of 12 SAEs; one of anxiety (PSY-
302A), one of psychotic disorder (PSY-302A), one of psychotic disorder (PSY-302) which 
occurred 55 days after last study dose, and one subject had 10 SAEs due to injuries suffered 
when his home was hit by a tornado.  Most of the AEs were mild to moderate in severity.  The 
most common AEs were seen in the neurological, psychiatric, and GI systems and included 
sedation, insomnia, headache, somnolence, abdominal pain, anxiety, decreased appetite, nausea, 
vomiting, fatigue, depressed mood and suicidality.  Details of AEs from each study are provided 
in the investigator’s brochure (IB).  There were no meaningful safety differences between 
subjects exposed to ecopipam or placebo from physical examinations, laboratory tests, ECGs, C-
SSRS and systematic assessments using scales to assess co-morbidities in children and 
adolescents.  In addition to above evaluations for safety the impact of ecopipam on movement 
disorders has been studied using scales such as the AIMS, BARS and ESRS and no differences 
have been seen between ecopipam and placebo treated subjects.  
Thus, based on the overall safety profile seen in over 2900 subjects including healthy 
participants, with both children/adolescents and adults being treated, safety data from subjects 
studied in the following conditions (cocaine addiction, Lesch Nyhan Disorder, Pathological 
   
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Protocol_9.0_05 Mar 2024 | VV-TMF-38683299 | 1.0
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Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 32 of 96 
gambling, obesity, schizophrenia, and Tourette’s) ecopipam is safe to continue being studied in 
children, adolescents, and adults with TD.  
5.3.2. 
Assessment of Benefit 
A review of the efficacy evaluations for ecopipam in three studies conducted in subjects with TD 
reveals improvement on the YGTSS-TTS and other measures of illness severity from Baseline to 
Endpoint.  
In a Phase 2a, open-label, non-randomized study (PSY301), the activity and safety of ecopipam 
in 18 adult subjects with TD 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-TTS.  
After ecopipam treatment, the YGTSS-TTS, motor tics score, phonic tics score and overall 
impairment decreased from Baseline to Endpoint, suggesting that the severity of tics was 
decreased.  
In a Phase 2 randomized, double-blind, placebo-controlled, crossover study in children and 
adolescents (ages 7-17 years) with TD 36<  VXEMHFWV ZHUH HQUROOHG DQG  
completed the study.  The primary endpoint was the YGTSS-TTS.   
Ecopipam treatment resulted in a numerical decrease in the YGTSS-TTS relative to the placebo 
treatment, but the decrease was not statistically significant.  The least squares mean (±SE) of the 
difference between ecopipam, and placebo treatm nt were -3.7  &, -0.9 to -6.5 P=0.011on 
Day 16 and -3.2  &, -0.3 to -6.1 P=0.0332 on Day 30.  
In a Phase 2b randomized, double-blind, placebo-controlled, parallel-group study conducted in 
153 children and adolescents (ages 6-18 years) with TD (EBS-101-CL-001), a statistically 
significant (p=0.011, LS mean [SE] difference: - >@  &, -6.1, -0.8) improvement in 
the YGTSS-776 IURP %/ WR :HHN  ZDV REVHUYHG IRU HFRSLSDP FRPSDUHG WR SODFHER 
average reduction from BL to Week 12 for ecopipam treated patients, treatment effect size = 
0.48) and at all earlier timep ints beginning at Week 4. Mean change from BL to Week 12 was 
significant on the key secondary endpoint, CGI-TS-S (p=0.027).  Significant improvement also 
occurred on many secondary endpoints.  Ecopipam had activity on both motor and phonic tics as 
well as measures of overall function in patients with TD, as rated by the clinician and caregiver. 
Based on the available safety data, there are several safety advantages for ecopipam compared to 
D2 antagonists, specifically with respect to lack of EPS-related adverse events, other adverse 
movement events, metabolic events, and lack of weight gain.   
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.  
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
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Confidential 
Page 33 of 96 
5.3.3. 
Methods to Minimize Risks 
The following steps are incorporated in the protocol to minimize risks to subjects:  
x Subjects will be screened by an Eligibility Review study team for determination of 
their appropriateness to participate. 
x All subjects will be evaluated for safety at least every four weeks while receiving 
study medication. 
x All assessment instruments will be administered by raters trained by the rater training 
group for the relevant scale/instrument.  To the extent possible, the same caregiver(s) 
should complete the questionnaires and interviews from the same rater at each 
applicable visit.  
x All subjects will be evaluated using the following scales to assess possible worsening 
of other psychiatric symptoms or other side effects: 
 Columbia Suicide Severity Rating Scale (C SSRS) for all subjects 
 Children’s Depression Rating Scale (CDRS-R) for children and adolescents 
 Patient Health Questionnaire-9 (PHQ-9) for adults 
 Pediatric Anxiety Scale (PARS) for children and adolescents 
 Hamilton Rating Scale for Anxiety (HAM-A) for adults 
 Extrapyramidal Symptom Ra ing Scale (ESRS) for all subjects 
 Children’s Yale-Brown Obsessive-Compulsive Scale-II (CY-BOCS-II) for 
children and adolescents 
 Yale-Brown Obsessive-Compulsive Scale-II (Y-BOCS-II) for adults 
 Swanson, Nolan and Pelham Questionnaire (SNAP-IV-26) for children and 
adolescents 
 Conners Adult ADHD Rating Scale Self Report, Short Version (CAARS-S:S) for 
adults  
In summary, ecopipam is a new chemical entity with a novel mechanism of action that has 
clinical evidence that it may be of therapeutic benefit to subjects with TD.  There is also 
evidence that it is likely to have lower side effect burden (for EPS- and other movement-related 
adverse events, adverse metabolic events and lack of weight gain) than the currently used D2-
receptor 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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Confidential 
Page 34 of 96 
6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the maintenance of efficacy of ecopipam 
tablets in children  6 and < 12 years of age) and adolescents   DQG   \HDUV RI DJH with 
TD. 
6.2. 
Secondary Objectives 
The secondary objectives of this study are to evaluate the safety and tolerance of ecopipam dosed 
at 1.8 mg/kg/day (2 mg/kg/day ecopipam HCl) in children  6 and < 12years of age), 
adolescents   DQG   \HDUV RI DJH and adults   \HDUV RI DJH with TD, to evaluate the 
maintenance of efficacy of ecopipam in adults (ؤ 18 years of age), and to characterize the 
pharmacokinetics (PK) of ecopipam in all subjects. 
6.3. 
Exploratory Objective  
To evaluate the population PK/pharmacodynamic (PD) relationships with ecopipam during the 
open-label Stabilization period of the study and additional exploratory endpoints listed in 
Section 11.3. 
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a multicenter study which includes an open-label period followed by double-blind, 
placebo-controlled, randomized withdrawal period in children   and < 12 years of age), 
adolescents   DQG   \HDUV RI DJH, DQG DGXOW VXEMHFWV  18 years of age) with TD.  
After providing informed consent (adult subjects or caregivers to children/adolescents) and 
assent (children/adolescents) and following an up to 28-day Screening period, and with 
agreement by Eligibility Review by the study team, subjects will proceed to the Baseline visit 
(Day 1).  
Eligibility Review is an evaluation and quality oversight process of subject eligibility.  Sites will 
complete an Eligibility Review packet at Screening which includes key medical information 
(e.g., laboratory results, ECG, medical history, physical examination, concomitant medications), 
scales data (e.g., subject questionnaire responses), and any other information necessary to 
establish subject eligibility per protocol.  A decision to enroll a subject will be made by the 
investigator only after the Eligibility Review is concluded.  The investigator remains responsible 
for ensuring that subjects are eligible for enrollment. 
At the Baseline visit, eligible subjects will be entered into an open-label Stabilization period and 
start a 4-week Titration phase to achieve a target steady-state dose of 1.8 mg/kg/day ecopipam 
(2 mg/kg/day ecopipam HCl) followed by an 8 week open-label maintenance phase.  
During the open-label Stabilization period, subjects will return to the clinic at Baseline (Day 1) 
and Weeks 4, 8 and 12.  Subjects will have a telephone visit at Week 2 to assess adverse events 
(AEs) and other safety parameters.  Efficacy assessments will be conducted at Weeks 4, 8 and 
12.  PK samples will be collected at Weeks 4 and 8.  A PK assessment may be collected at Week 
12 if the Week 8 PK assessment is missed.  Safety assessments will be conducted at all visits.  
5HVSRQGHUV WR HFRSLSDP GHILQHG D WKRVH ZLWK   LPSURYHPHQW IURP %DVHOLQH (Day 1) on 
the YGTSS-TTS at both Weeks 8 & 12 during the open-label Stabilization period, will be 
randomized to ecopipam 1.8 mg/kg/day (ecopipam HCl 2 mg/kg/day) or placebo in a 1:1 fashion 
and enter a double-blind Randomized-Withdrawal (R/WD) period at Week 12.  Subjects 
randomized to placebo will be tapered off ecopipam in a blinded fashion in decrements of 
22.4 mg/day (25 mg/day ecopipam HCl).  
During the R/WD period, subjects will return to the clinic every week for the first 4 weeks and 
every 2 weeks thereafter (Weeks 13, 14, 15, 16, 18, 20, 22 and 24) and efficacy and safety 
assessments will be conducted at each of these visits.   
Any subject meeting Relapse criteria, GHILQHG DV ORVV RI   RI WKH LPSURYHPHQW H[SHULHQFHG
on the YGTSS-TTS from Baseline (Day 1) to the last visit of the open-label Stabilization period 
(Week 12), or initiation of additional medications to treat symptoms of TD,  or requirement of 
hospitalization for worsening symptoms of TD will be withdrawn from blinded study medication 
(ecopipam or placebo).  
Non-responders to ecopipam during the open-label Stabilization period at either Week 8 or 
Week 12, or Responders randomized to ecopipam who complete the R/WD period, or who meet 
   
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Ecopipam
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Relapse criteria during the R/WD period, or who discontinue the study prematurely for any 
reason will be tapered off ecopipam in decrements of 22.4 mg/day (25 mg/day ecopipam HCl) 
and will complete the Week 24/Relapse/ET visit. Subjects assigned to placebo will receive 
placebo taper down medication to preserve the blind.
Follow Up visits will be conducted in the clinic 7 and 14 days after the last dose of study 
medication followed by a telephone call 30 days after the last dose of study medication to 
determine any adverse events, with the exception of subjects who roll into the open-label 
extension study EBS-101-TD-391within 30 days of their last study drug.  
Subjects who experience Relapse may be treated for their TD with medications recommended by 
the PI or referred back to their primary physician for treatment after completing Day 7 and 14 
follow-up visits.  
Responders to ecopipam who complete the R/WD period and who complete the Week 24/
Relapse/ET visit and the Day 7 and 14 follow-up visits are eligible to enter the long-term open-
label study EBS-101-TD-391.  Subjects who meet the criteria for Relapse and complete the 
Week 24/Relapse/ET visit and the Day 7 and 14 follow-up visits will have the opportunity to 
enter the long-term open-label study..  
In anticipation of reaching the target number of Relapse events, randomization into the double-
blind R/WD period may be closed, at which time subjects in the open-label Stabilization period 
may continue in the study until the Week 12 visit   Upon completion of the Week 12 visit, 
subjects will have the opportunity to enter the long-term open-label study, EBS-101-TD-391.  
The Sponsor may elect to re-open randomization as required.  
Once the target number of Relapse events is met, all subjects may enter the long-term open-label 
study EBS-101-TD-391 once the Week 24/Relapse/ET visit and the Day 7 and 14 follow-up
visits has been completed.  
The study will be considered completed once all subjects have completed the 30-Day telephone 
Follow Up call or enters the open-label study EBS-101-TD-391.  
   

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7.2. 
Number of Subjects 
The planned number of Relapse events for the double-blind R/WD period is 49 for children and 
adolescents (age   WR   \HDUV RI DJH).  This number of events will provide 85 SRZHU WR
detect a difference between treatment groups, assuming a hazard ratio of 0.4 for Relapse and 
statistical testing at alpha level 0.05 (2-sided).  Assuming the proportion of subjects who Relapse 
in the double-EOLQG 5:' SHULRG LV  LQ WKH SODFHER JURXS DQG  LQ WKH HFRSLSDP JURXS
approximately 98 children and adolescent subjects (49 subjects per group) will be required to 
achieve this number of events.  Subject enrollment will stop around the time that 49 Relapse 
events for children and adolescents are expected to have occurred.  The number of Relapses 
among adults will not determine study completion. 
To randomize 98 children and adolescent subjects ( WR   \HDUV RI DJH), approximately 196 
child and adolescent subjects will need to be enrolled assuming the Responder rate in the open-
ODEHO 6WDELOL]DWLRQ SHULRG LV  
Adult subjects with TD who meet all inclusion criteria and none of the exclusion criteria are 
eligible to enroll in the study.  Since the symptoms of TD sh w improvement with age and a 
majority of adult patients exhibit minimal symptoms or are asymptomatic, it is anticipated that a 
minority of study participants will be adults.  Hence it is anticipated that approximately 40 adults 
with TD will enter the open-label Stabilization period of this study.   
7.3. 
Treatment Assignment 
Responders to ecopipam in the open-label Stabilization period will be randomized 1:1 to either 
ecopipam or matching placebo for the R/WD period.  Randomization assignment will be 
stratified by weight. 
7.4. 
Dose Adjustment Criteria 
Study drug is packaged for titration up t  the target dose based on the subject’s weight at 
Baseline according to the following weight bands to better achieve the targeted 1.8 mg/kg/day 
ecopipam (2 mg/kg/day ecopipam HCl) WDUJHW GRVH  WR  NJ ! WR  NJ ! WR
 NJ ! WR  NJ ! WR  NJ ! NJ  Those who cannot tolerate the target dose will be 
withdrawn from study.  Dose assignment (based on weight) will not change during the duration 
of the study even if subject’s weight changes.  Study drug is packaged for taper down in 
decrements of 25 mg/day until off study drug.  See Section 10.5 for direction on administration 
of study drug. 
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 termination procedures. 
Any subject with a new positive response on questions 4 and/or 5 of the Columbia Suicide 
Severity Rating Scale (C-SSRS) will be immediately discontinued and evaluated for risk.   
Any subject with a CDRS-R or PHQ-9 assessment indicative of the onset of a new depressive 
episode at any visit can be discontinued from study participation at the discretion of the 
   
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Confidential 
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Investigator.  The Investigator will perform suicide risk assessment in subjects who respond 
positively to PHQ-9 question 9. 
Subjects will be discontinued due to attempted suicide or suicidal behavior, oculogyric crisis, 
neuroleptic malignant syndrome, new onset seizures, serotonergic syndrome, or tardive 
dyskinesia.  Subjects will also be discontinued if there are any adverse events that are Grade 4 
(life-threatening consequences; urgent intervention indicated) in severity per CTCAE version 5. 
Subjects who discontinue early from the study will be evaluated for one of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, loss of efficacy, 
and administrative/other.  In addition to the primary reason, the subject may have indicated one 
or more of these reasons as secondary reasons for discontinuation.  Study disposition information 
will be collected on the CRF. 
Subjects who discontinue treatment for any reason, other than an SAE (even if the SAE is not 
treatment related) or an AE (unless the AE can be determined to be unrelated to treatment), may 
be replaced only after consultation with Sponsor or its designee  
7.6. 
Criteria for Study Termination 
The Sponsor may suspend or terminate the study, or part of the study, at any time for any reason 
including, but not limited to, safety and lack of efficacy  
If the Sponsor, investigator, or regulatory agency officials discover conditions arising during the 
study that indicates that the study should be halt d or that a study site should be closed, this 
action may be taken after appropriate consul ation between the Sponsor, its designee, and the site 
investigator.  If the study is suspended or terminated, the Sponsor or its designee will ensure that 
applicable sites, regulatory health authorities, and IRBs/ECs are notified as appropriate. 
 
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Table 3: 
Schedule of Assessments 
Visit/TC 
Study Day 
Screening 
Perioda 
Open-Label Stabilization Period 
Double-Blind Randomized Withdrawal Period 
Weeks 12 to 24 
(Days 85 to 169) 
Safety Follow-Up 
(Days 170-199) 
Titration Phase 
Maintenance Phase 
Weeks 4 to 12  
(Day 29 up to 84) 
Screening 
VISIT 1  
Day -28  
to -1 
Baseline 
VISIT 2 
Day 1 
W 2 f 
Day 15 
Telephone 
call only 
(±3d) 
W4 / 
VISIT 
3/ Day 
29 
(±3d) 
W8 / 
VISIT 4 
/ Day 57 
(±3d) 
W 12 
VISIT 
5 
Day 
85 
(±3d) 
W13 / 
VISIT 6 
/ Day 92 
(±3d) 
W14 / 
VISIT 7 
/ Day 99 
(±3d) 
W15 / 
VISIT 8 
/ Day 
106 
(±3d) 
W1  / 
VISIT 9 
/ Day 
113 
(± d) 
W18 / 
VISIT 10 
/ Day 127 
(±3d) 
W20 / 
VISIT 11 
/ Day 141 
(±3d) 
W22 / 
VISIT 
12/ Day 
155 (±3d) 
W 24 
VISIT 
13 
Day 169 
or 
Relapse 
or ET 
(±3d) 
7 Day 
F/U 
VISIT 
14 
(±3d) 
14 
Day 
F/U 
VISIT 
15 
(±3d) 
30 Day  
F/Uf 
Telephone 
call only 
(±3d) 
Informed Consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSM-5-TR Criteria 
for TD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric
/ Medication 
History  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Exam/Vital Signsb 
X 
X 
 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECGb 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
Central Laboratory 
tests (Hematology, 
Chemistry, 
Urinalysis, HbA1c, 
Prolactin)c 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
Central Urine Drug 
Screen 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Local Urine 
Pregnancy Testi 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Yale Global Tic 
Severity Scale 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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Confidential 
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Visit/TC 
Study Day 
Screening 
Perioda 
Open-Label Stabilization Period 
Double-Blind Randomized Withdrawal Period 
Weeks 12 to 24 
(Days 85 to 169) 
Safety Follow-Up 
(Days 170-199) 
Titration Phase 
Maintenance Phase 
Weeks 4 to 12  
(Day 29 up to 84) 
Screening 
VISIT 1  
Day -28  
to -1 
Baseline 
VISIT 2 
Day 1 
W 2 f 
Day 15 
Telephone 
call only 
(±3d) 
W4 / 
VISIT 
3/ Day 
29 
(±3d) 
W8 / 
VISIT 4 
/ Day 57 
(±3d) 
W 12 
VISIT 
5 
Day 
85 
(±3d) 
W13 / 
VISIT 6 
/ Day 92 
(±3d) 
W14 / 
VISIT 7 
/ Day 99 
(±3d) 
W15 / 
VISIT 8 
/ Day 
106 
(±3d) 
W16 / 
VISIT 9 
/ Day 
113 
(±3d) 
W18 / 
VISIT 10 
/ Day 127 
(±3d) 
W20 / 
VISIT 11 
/ Day 141 
(±3d) 
W22 / 
VISIT 
12/ Day 
155 (±3d) 
W 24 
VISIT 
13 
Day 169 
or 
Relapse 
or ET 
(±3d) 
7 Day 
F/U 
VISIT 
14 
(±3d) 
14 
Day 
F/U 
VISIT 
15 
(±3d) 
30 Day  
F/Uf 
Telephone 
call only 
(±3d) 
Clinical Global 
Impression – 
Tourette Syndrome 
Severity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Global 
Impression – 
Tourette Syndrome 
Improvement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Caregiver Global 
Impression of 
Changeh 
X
 
X
X
X
Gilles de la Tourette 
Syndrome – Quality 
of Life Scale for 
Children and 
Adolescentsh 
X
X
X
Gilles de la Tourette 
Syndrome – Quality 
of Life Scaleg  
X
X
X
Premonitory Urge 
for Tics Scale  
X
X
 
X
X
X
Columbia Suicide 
Severity Rating 
Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Children’s 
Depression Rating 
Scale – Revisedh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pediatric Anxiety 
Rating Scaleh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   


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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
Confidential 
Page 41 of 96 
Visit/TC 
Study Day 
Screening 
Perioda 
Open-Label Stabilization Period 
Double-Blind Randomized Withdrawal Period 
Weeks 12 to 24 
(Days 85 to 169) 
Safety Follow-Up 
(Days 170-199) 
Titration Phase 
Maintenance Phase 
Weeks 4 to 12  
(Day 29 up to 84) 
Screening 
VISIT 1  
Day -28  
to -1 
Baseline 
VISIT 2 
Day 1 
W 2 f 
Day 15 
Telephone 
call only 
(±3d) 
W4 / 
VISIT 
3/ Day 
29 
(±3d) 
W8 / 
VISIT 4 
/ Day 57 
(±3d) 
W 12 
VISIT 
5 
Day 
85 
(±3d) 
W13 / 
VISIT 6 
/ Day 92 
(±3d) 
W14 / 
VISIT 7 
/ Day 99 
(±3d) 
W15 / 
VISIT 8 
/ Day 
106 
(±3d) 
W16 / 
VISIT 9 
/ Day 
113 
(±3d) 
W18 / 
VISIT 10 
/ Day 127 
(±3d) 
W20 / 
VISIT 11 
/ Day 141 
(±3d) 
W22 / 
VISIT 
12/ Day 
155 (±3d) 
W 24 
VISIT 
13 
Day 169 
or 
Relapse 
or ET 
(±3d) 
7 Day 
F/U 
VISIT 
14 
(±3d) 
14 
Day 
F/U 
VISIT 
15 
(±3d) 
30 Day  
F/Uf 
Telephone 
call only 
(±3d) 
Extrapyramidal 
Symptom Rating 
Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Swanson, Nolan, 
and Pelham 
Questionnaire-IV-
26h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Children’s Yale-
Brown Obsessive 
Compulsive Scale-
IIh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Health 
Questionnaire-9g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hamilton Rating 
Scale for Anxietyg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conners’ Adult 
ADHD Rating 
Scaleg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Yale-Brown 
Obsessive 
Compulsive Scale-
IIg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Blood Drawsd,e
X 
X 
X
Adverse Events 
X 
X 
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 
X 
   


	
Protocol_9.0_05 Mar 2024 | VV-TMF-38683299 | 1.0
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 42 of 96 
Visit/TC 
Study Day 
Screening 
Perioda 
Open-Label Stabilization Period 
Double-Blind Randomized Withdrawal Period 
Weeks 12 to 24 
(Days 85 to 169) 
Safety Follow-Up 
(Days 170-199) 
Titration Phase 
Maintenance Phase 
Weeks 4 to 12  
(Day 29 up to 84) 
Screening 
VISIT 1  
Day -28  
to -1 
Baseline 
VISIT 2 
Day 1 
W 2 f 
Day 15 
Telephone 
call only 
(±3d) 
W4 / 
VISIT 
3/ Day 
29 
(±3d) 
W8 / 
VISIT 4 
/ Day 57 
(±3d) 
W 12 
VISIT 
5 
Day 
85 
(±3d) 
W13 / 
VISIT 6 
/ Day 92 
(±3d) 
W14 / 
VISIT 7 
/ Day 99 
(±3d) 
W15 / 
VISIT 8 
/ Day 
106 
(±3d) 
W16 / 
VISIT 9 
/ Day 
113 
(±3d) 
W18 / 
VISIT 10 
/ Day 127 
(±3d) 
W20 / 
VISIT 11 
/ Day 141 
(±3d) 
W22 / 
VISIT 
12/ Day 
155 (±3d) 
W 24 
VISIT 
13 
Day 169 
or 
Relapse 
or ET 
(±3d) 
7 Day 
F/U 
VISIT 
14 
(±3d) 
14 
Day 
F/U 
VISIT 
15 
(±3d) 
30 Day  
F/Uf 
Telephone 
call only 
(±3d) 
Dispense Study 
Drug 
 
X 
 
Xd 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Collect Unused 
Study Drug/Assess 
Drug Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abbreviations: ADHD = attention-deficit hyperactivity disorder; AE = adverse event; BP = blood pressure; DSM-5-TR = Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition; ECG = electrocardiogram; F/U = follow up; HR = heart rate; PK = pharmacokinetic(s); TD = Tourette’s Disorder  
a  Informed consent must be obtained prior to any screening procedures.  All screening pr cedures are to occur after confirmation of appropriate timeframe since 
discontinuation of applicable medications.  Rescreening is allowed after approval by the Medical Advisor.    
b  Vital signs will include pulse, BP (done 5 minutes after being supine)  height and weight. 
   Neurological exam should be part of the physical exam. Physical exam t Week 4 visit will include assessment for serotonin syndrome. If serotonin syndrome 
symptoms are present, local laboratory assessment should be performed. 
c  Subjects should be in a fasting state (8 hours) for laboratory t sts. Fas ing at the Screening visit is optional.  HbA1c will be measured only at Baseline, Week 12, and 
Week 24 (completed subjects only).   
d  At Week 4, ecopipam should be administered after the pre-dose blood draw. PK samples will be collected at 1) pre-dose; 2), post-dose between 0.5 and 1.5 hours; and 
3) post-dose between 2 and 4 hours.  Week 12 PK assessment only to be performed if Week 8 assessment is missed. 
e  If visits at Weeks 4, 8 and/or 12 are completed in locations other than study clinic due to restrictions because of the COVID-19 pandemic or other qualifying event, 
then collection of labs for PK assessments are optional. 
f  Week 2 and 30-Day FU visits will be a telephone call.  If there are any abnormal findings, the subject will be brought to the site for full assessment.  Subjects who 
complete the Baseline visit for the EBS-101-TD-391 open label extension study within 30 days of the Week 24 visit are not required to complete the 30-Day FU 
telephone call.   
g  Administration applicable to adult subjects only. 
h  Administration applicable to child and adolescent subjects only (6-17 years of age). 
i  For women of childbearing potential only. If positive, request a serum HCG on the Chemistry blood sample requisition form for confirmation of pregnancy.  
 
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 43 of 96 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Inclusion Criteria 
 
1) 
If <18 years of age, subject’s parent or legal guardian must sign a written informed 
consent and subject must sign a written informed assent according to the requirements 
RI WKH VLWH¶V ,5%(& ,I  \HDUV RI DJH VXEMHFW PXVW VLJQ D ZULWWHQ LQIRUPHG
consent according to the requirements of the site’s IRB/EC. 
2) 
Subjects must be 6 years of age at time of screening. 
3) 
Subjects must weigh at least 18 kg (39.6 lbs.). 
4) 
Subjects must have TD based on Diagnostic and Statistical Manual for Mental 
Disorders – 5th Edition (DSM-5-TR diagnostic riteria) for TD.  
5) 
Subjects must exhibit both motor and vocal tics that cause impairment with normal 
routines. 
6) 
Subjects must have a minimum score of 20 on the YGTSS-TTS at Screening and at 
Baseline visits with tic symptoms causing impairment in the subject’s normal 
routines, including academic achievement  and/or occupational functioning, and/or 
social activities, and/or relationships r whose symptoms distress the subject to the 
extent that treatment is appropriate  
7) 
Female participants of childbearing potential must agree to use a highly effective 
PHWKRG RI FRQWUDFHSWLRQ LH  SUHJQDQF\ UDWH RI OHVV WKDQ  SHU \HDU GXULQJ WKH
study and for 30 days after the discontinuation of the IMP.  Adequate contraceptive 
methods include combined hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception 
with inhibition of ovulation (oral, injectable, implantable), intrauterine devices 
(IUDs), intrauterine h rmone-releasing system (IUS), true sexual abstinence (when 
this is in line with the preferred and usual lifestyle of the participant), bilateral tubal 
occlusion, vasectomized male partner, or a female participant who is not of 
childbearing potential.  
Female participants and female partners of male study participants using a hormonal 
contraceptive must also use a barrier method (i.e., condom or occlusive cap 
[diaphragm or cervical/vault caps]) and should have been stable on their hormonal 
contraceptive treatment for at least 4 weeks prior to Screening.  
8) 
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.  
9) 
For sites in the EU only, the subject must have received an adequate trial of non-
pharmacological therapy without adequate response prior to study enrollment. 
8.2. 
Exclusion Criteria 
Individuals meeting any of the following criteria at Screening or Baseline are ineligible to 
participate in the study: 
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 44 of 96 
1) 
Subjects with previous exposure to ecopipam (e.g., participated in study PSY301, 
PSY302 or EBS-101-CL-001). 
2) 
Subjects with any unstable mood disorder (DSM-5-TR criteria) at Screening or 
Baseline. 
3) 
Subjects who have unstable medical illness or clinically significant abnormalities on 
laboratory tests, or ECG at Screening as determined by the Principal Investigator.  
4) 
Subjects with a significant risk of attempting suicide based on history (suicide attempt 
in past 1 year or who have had 2 or more lifetime suicide attempts) or who had an 
answer of ‘‘yes’’ on any question other than 1–3 (currently or within the past 30 
days) on the baseline/screening version of the Columbia Suicide Severity Rating 
Scale (C-SSRS). 
5) 
Subjects with a clinical presentation at Screening or Baseline 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). 
6) 
Female subjects who are currently pregnant or lactating or planning to become 
pregnant during the study.  
7) 
Subjects who have moderate to severe renal impairment.   
8) 
Subjects who have hepatic impairment at Screening. 
9) 
Subjects with current or recent (past 3 months) history of DSM-5-TR substance use 
disorder (except for nicotine).  
10) 
Subjects with positive urine drug screen for cocaine, amphetamine, benzodiazepines, 
barbiturates, phencyclidine (PCP), or opiates at Screening, except those receiving 
stable, prescribed treatme t for attention deficit/hyperactivity disorder (ADHD). 
11) 
Subjects with a  GLIIHUHQFH LQ WKH DEVROXWH FKDQJH LQ YGTSS-TTS between the 
Screening visit and the Baseline visit. 
12) 
Subjects with a lifetime history of bipolar disorder type I or II, dementia, 
schizophrenia, or any other psychotic disorder. 
13) 
Subjects with an onset of a major depressive episode in the past 6 months.  
14) 
Subjects with a PHQ-9 score of 10 at Screening or Baseline. 
15) 
Subjects with a history of seizures (excluding febrile seizures that occurred >2 years 
prior to Screening). 
16) 
Subjects with a history of neuroleptic malignant syndrome. 
17) 
Subjects with a myocardial infarction within 6 months prior to Screening.  
18) 
Subjects who have had previous treatment with:  
o investigational medication within 4 weeks prior to Screening  
o oral neuroleptics within 4 weeks prior to Screening  
o depot neuroleptics within 3 months prior to Screening (e.g., risperidone 
microspheres) or 6 months prior to screening (e.g., paliperidone palmitate) 
19) 
Subjects receiving any other medication to treat motor or vocal tics for at least 
14 days prior to Baseline.  
   
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 45 of 96 
20) 
Subjects receiving unstable doses or excluded medications to treat depression, anxiety 
or ADHD for a minimum of 4 weeks prior to Screening.    
21) 
Subjects who have a need for medications which would have unfavorable interactions 
with ecopipam, e.g., CYP2D6, CYP3A4, CYP2C19, P-gp, substrates with a narrow 
therapeutic window (e.g., digoxin), inhibitors of CYP2D6 (e.g., fluoxetine), broad-
spectrum UGT enzyme inhibitors (e.g., valproic acid), dopamine antagonists (e.g., 
neuroleptics) or agonists (including bupropion), tetrabenazine, VMAT-2 inhibiters 
(e.g. tetrabenazine), tricyclics and tetracyclics, monoamine oxidase inhibitors, or St. 
John’s Wort.  See Section 23.  
22) 
Subjects who have initiated new psychological therapies or deep brain stimulation 
within 10 weeks prior to Baseline visit. 
23) 
Initiation or changes in psychological therapies during the study (i.e., Habit Reversal 
Training or Comprehensive Behavioral Intervention for Tics) as well as deep brain 
stimulation. 
24) 
Subjects unable to swallow tablets.  
25) 
Subjects with a known hypersensitivity to any excipients of ecopipam tablets, 
including subjects with confirmed lactose intolerance.   
26) 
Subjects who are employed by the sponsor, vendors working on the study, study site 
personnel or their family members. 
27) 
Siblings or family members of any current subject participating in the study. 
28) 
Subjects deprived of liberty by administrative or judicial decision, patients under 
court protection, guardianship  curatorship or family guardianship.   
29) 
Any subject who in the opinion of the investigator is not a suitable candidate for the 
study.   
8.3. 
Subject Withdrawal, Removal, and Replacement Criteria 
Any subject with a new positive response on questions 4 and/or 5 of the C-SSRS will be 
immediately discontinued and evaluated for risk.   
Any subject with a CDRS-R or a PHQ-9 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.   
Subjects will be discontinued due to attempted suicide or suicidal behavior, oculogyric crisis, 
neuroleptic malignant syndrome, new onset seizures, serotonergic syndrome, or tardive 
dyskinesia.  Subjects will also be discontinued if there are any adverse events that are Grade 4 
(life-threatening consequences; urgent intervention indicated) in severity per CTCAE version 5.  
The Investigator or subject may choose to stop study treatment at any time for safety or personal 
reasons.  Where possible, a subject who discontinues treatment will undergo protocol-specified 
end-of study procedures at the time of discontinuation.  Date and reason(s) of premature 
discontinuation will be described in the CRF.   
Subjects who discontinue treatment for any reason, other than an SAE (even if the SAE is not 
treatment related) or an AE (unless the AE can be determined to be unrelated to treatment), may 
be replaced only after consultation with Sponsor or its representative. 
   

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Protocol_9.0_05 Mar 2024 | VV-TMF-38683299 | 1.0
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 46 of 96 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
Table 4: 
Investigational Product 
 
Investigational product  
Product Name 
Ecopipam 
Placebo 
Dosage Form 
Tablets 
Matching tablets 
Unit Dose of 
Ecopipam  
11.2, 22.4, 33.6, 44.8, 67.2 and 89.6 mg 
Matching unit dose tablets 
Unit Dose of 
Ecopipam HCl 
12.5, 25, 37.5, 50, 75 and 100 mg 
Route of 
Administration 
Oral 
Oral 
Physical 
Description 
Round, biconvex, light blue film-coated 
tablet, plain on both side 
Round, biconvex, light blue 
film-coated tablet, plain on both 
side 
Manufacturer 
Catalent Pharma Solutions, LLC 
Catalent Pharma Solutions, 
LLC 
9.2. 
Concomitant Medications 
For subjects who receive study treatment, any medication (including over-the-counter 
medications) administered to the subject during the study (starting at the date of informed 
consent) will be recorded on the Prior and Concomitant Medication CRF.  Nonpharmacologic 
therapies/procedures will also be captured on the CRF.  The Investigator will record any AE on 
the Adverse Events CRF for which the concomitant medication was administered. 
9.2.1. 
Allowable Medications for Common Comorbid Conditions 
The following medications are allowed for the treatment of subjects with ADHD, anxiety, 
depression, mood disorder, and OCD if doses have been stable for at least 4 weeks prior to 
Screening and the dose is not expected to change and remains stable during the course of the 
study.   
Allowable stimulants for comorbid ADHD 
x Amphetamine 
x Dextroamphetamine 
x Amphetamine and dextroamphetamine (mixed salts) 
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

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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 47 of 96 
x Dexamphetamine 
x Dexmethylphenidate 
x Lisdexamfetamine 
x Methylphenidate 
Allowable medications for anxiety, mood disorders, depression and OCD 
x citalopram  
x desvenlafaxine 
x escitalopram 
x fluvoxamine 
x levomilnacipran 
x milnacipran  
x sertraline 
Anxiolytics 
x lorazepam - Chronic use only 
x hydroxyzine 
 
9.3. 
Prohibited Therapies 
Since ecopipam and its metabolite (EBS-101-40853) may inhibit CYP2D6, OATP1B1, P-gp and 
UGT1A9 and induce CYP3A4 and CYP2C19, for any drug that is a substrate of these enzymes, 
the label for the drug should be co sulted to decide if a dose adjustment is needed.  
Prohibited therapies per the exclusion criteria (Section 8.2) include: 
x Previous treatment with ecopipam 
x Any investigational medication within 1 month prior to Screening 
x Oral neuroleptics within 4 weeks prior to Screening 
x Depot neuroleptics within 3 months prior to Screening (e.g., risperidone 
microspheres) or 6 months prior to screening (e.g., paliperidone palmitate) 
x Any medications for the treatment of tics for at least 14 days prior to Baseline 
x Subjects receiving unstable doses or excluded medications to treat depression, anxiety 
or ADHD for a minimum of 4 weeks prior to Screening. 
x Subjects who have a need for medications which would have unfavorable interactions 
with ecopipam, e.g., CYP2D6, CYP3A4, CYP2C19, P-gp, substrates with a narrow 
therapeutic window (e.g., digoxin), inhibitors of CYP2D6 (e.g., fluoxetine), broad-
spectrum UGT enzyme inhibitors (e.g., valproic acid), dopamine antagonists (e.g., 
   


	
Protocol_9.0_05 Mar 2024 | VV-TMF-38683299 | 1.0
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Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 48 of 96 
neuroleptics) or agonists (including bupropion), tetrabenazine, VMAT-2 inhibiters 
(e.g. tetrabenazine), tricyclics and tetracyclics, monoamine oxidase inhibitors, or St. 
John’s Wort. See Section 23.  
x New psychological therapies that were initiated within 10 weeks prior to the Baseline 
visit 
x Initiation or changes in psychological therapies during the study (i.e., Habit Reversal 
Training or Comprehensive Behavioral Intervention for Tics) as well as deep brain 
stimulation.   
An illustrative, but not complete, list of excluded drugs is provided in the Prohibited Medications 
List in Section 23.  
9.4. 
Treatment Compliance 
During the study period, subject compliance will be monitored by review of the unused tablet 
counts at the study site visits.  /HVV WKDQ  compliance will require evaluation by the 
Investigator and Sponsor or its representative to determine if the subject may continue the study. 
9.5. 
Randomization and Blinding 
Randomization will be stratified by weight band   Throughout the study, subjects, caregivers, and 
all personnel involved with the conduct and interpretation of the study, including the 
investigators, site personnel, and sponsor staff will be blinded to the treatment codes.  
Randomization data will be kept strictly confidential, filed securely by an appropriate group with 
the Sponsor or CRO and accessible only to authorized persons (e.g., Safety) until the time of 
unblinding.  
A master list of all treatments and the subject numbers associated with them will be maintained 
electronically in the Interactive Web Randomization System (IWRS).  The process to request a 
randomization code will be outlined in the IWRS user manual.  The site will be trained in this 
process and should only be used in an emergency.  These codes should only be broken if 
knowledge of the subject’s randomization code will affect his/her medical treatment.  If 
necessary, the Investigator may consult with the sponsor before breaking the blind.  The 
Investigator is to record the date and time of requesting the code and the reason for breaking the 
code.   
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Protocol_9.0_05 Mar 2024 | VV-TMF-38683299 | 1.0
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Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 49 of 96 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Ecopipam tablets and matching placebo tablets. 
10.2. 
Study Drug Packaging and Labeling 
Study drug will be supplied in labeled containers by the Sponsor.  The product release 
certificates for ecopipam tablets will be included in the clinical study report for this protocol.  
Any special storage conditions will be noted on the label and should be followed by the study 
site.  
The labels will be produced by PCI Pharma Services.  Minimally, the labels will contain the 
following information.  This will be adapted for any local laws and regulations:  
1. Name, address, and telephone number of the Sponsor  
2. Pharmaceutical dosage form, route of administration, quantity of dosage units, identifier, 
and dose strength  
3. Lot number  
4. Protocol Number 
5. Study subject identification number  
6. Directions of use  
7. “Caution:  New Drug – Limited by Federal (US) law to investigational use” (or 
equivalent for rest of world) 
8. Storage Conditions  
9. Expiration Date 
10.3. 
Study Drug Storage 
Study drug is to be stored at 59oF to 77oF (15oC to 25oC) protected from light, excessive heat, 
open flame and combustibles, out of direct sunlight, and in a well-ventilated, dry area.   
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.  A daily temperature log for monitoring of proper storage conditions 
must be maintained by the site. 
10.4. 
Study Drug Preparation 
Study drug primary packaging will be in blister packs for ecopipam and matching placebo.  No 
preparation is required. 
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10.5. 
Administration 
During the 4-week titration phase of the open-label Stabilization period, the following ecopipam 
doses will be administered PO for each of the weight bands (see Table 5):  
Table 5: 
Proposed Dosing Regimen 
Weight 
(kg) 
Week 1 
Week 2 
Week 3 
Week 4 
 
ecopipam 
mg/day 
ecopipam 
HCl 
mg/day 
ecopipam 
mg/day 
ecopipam 
HCl 
mg/day 
ecopipam 
mg/day 
ecopipam 
HCl 
mg/day 
ecopipam 
mg/day 
ecopipam 
HCl 
mg/day 
 -  
11.2 
12.5 
22.4 
25 
33.6 
37.5 
33.6 
37.5 
>23 -  
11.2 
12.5 
22.4 
25 
33.6 
37.5 
44.8 
50 
>34 -  
11.2 
12.5 
22.4 
25 
44.8 
50 
67.2 
75 
>44 -  
22.4 
25 
44.8 
50 
67.2 
75 
89.6 
100 
>68 -  
22.4 
25 
44.8 
50 
89.6 
100 
134.41 
1501 
>83 
22.4 
25 
44.8 
50 
89.6 
100 
179.22 
2002 
1 134.4 mg ecopipam dose (150 mg ecopipam HCl) given as two tablets containing 67.2 mg ecopipam (75 mg ecopipam 
HCl) each. 
2 179.2 mg ecopipam dose (200 mg ecopipam HCl) given as two tablets containing 89.6 mg ecopipam (100 mg ecopipam 
HCl) each. 
Subjects who do not tolerate the dose titration up to the full designated dose for their weight 
stratum will be discontinued from the study.  These subjects will be tapered off their current dose 
of study drug according to their weight stratum.   
During Weeks 4 to 12 of the open-label maintenance phase and for Responders in this period 
who are randomized to ecopipam for the 12-week R/WD period, the following ecopipam HCl 
doses will be administered f r each of he weight bands:  
x 7KRVH ZKR ZHLJK  -  NJ ZLOO UHFHLYH  PJ  PJ HFRSLSDP +&O GDLO\ 
x Those who weigh >23 -  ZLOO UHFHLYH  PJ  PJ HFRSLSDP +&O GDLO\ 
x Those who weigh >34 -  ZLOO UHFHLYH  PJ  PJ HFRSLSDP +&O GDLO\ 
x Those who weigh >44 -  NJ ZLOO UHFHLYH  PJ  PJ HFRSLSDP +&O GDLO\ 
x Those who weigh >68 -  NJ ZLOO UHFHLYH  PJ  PJ HFRSLSDP +&O GDLO\ 
x Those who weigh >83 kg will receive 179.2 mg (200 mg ecopipam HCl) daily. 
All doses will be administered PO once daily in the evening without regard to food.  Subjects 
who have changes in weight during the study will not have their doses adjusted for the duration 
of the study.  
Responders who are randomized to placebo for the 12-week R/WD period will taper off 
ecopipam in decrements by 22.4 mg/day (25 mg/day ecopipam HCl) until off study drug.  For 
the remainder of the R/WD period, these patients will receive matching placebo tablets.   
Any subject randomized to placebo who meets Relapse criteria during the R/WD period, or who 
discontinues the study prematurely due to any reason, will receive a taper kit of matching 
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placebo with the same number of tablets as subjects in the same weight band receiving blinded 
ecopipam to preserve the blind.  All subjects will be monitored for signs or symptoms of 
withdrawal, abuse and dependence. 
Non-responders to ecopipam during the Stabilization period, or Responders randomized to 
ecopipam who complete the R/WD period, or who meets Relapse criteria during the R/WD 
period, or who discontinues the study prematurely due to any reason will be tapered off 
ecopipam in decrements of 22.4 mg/day (25 mg/day ecopipam HCl) until off drug.  All subjects 
will be monitored for signs or symptoms of withdrawal, abuse and dependence.  
10.6. 
Dosing Rationale 
A dosage regimen of 1.8 mg/kg/day ecopipam (2 mg/kg/d ecopipam HCl) was chosen based on 
the results of a randomized, double-blind, placebo-controlled, parallel group study (Study  
EBS-101-CL-001) of 153 subjects with TD aged 6-18 years receiving ecopipam at a dose of 
1.8 mg/kg/day (ecopipam HCl 2 mg/kg/day) after a 3- to 4-week titration which demonstrated 
that ecopipam was significantly superior to placebo in reducing tic severity as shown by 
reduction in the YGTSS-TTS) and that the safety profile was acceptable.  
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:  
x Identification (subject number and initials or as allowed per local requirements) of 
subject to whom the study drug was dispensed 
x The dates and lot numbers for the study drug dispensed  
x Initial inventory on receipt of drug at the site  
x 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 made if 
acceptable according to country regulations.  In Germany, these procedures are not possible after 
December 31, 2023.  In these cases, study medication may be transported to the subject by a 
third-party vendor who has systems in place to protect blinding, patient privacy, and data 
integrity.   
On close-out of the site, all used and unused investigational product must be shipped to the 
Emalex-designated location.  The Drug Dispensing Log must be available for monitoring, 
auditing, or inspection. 
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10.8. 
Study Drug Handling and Disposal 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries from 
the sponsor are received by a responsible person (e.g., pharmacist), and that: 
x Such deliveries are recorded; 
x Study drug is handled and stored safely and properly; 
x Study drug is only dispensed to study subjects in accordance with the protocol; 
x Any unused study drug is returned to the sponsor or standard procedures for the 
alternative disposition of unused study drug are followed. 
 
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11. 
ASSESSMENT OF EFFICACY 
All assessment instruments will be administered by raters trained by the rater training group for 
the relevant scale/instrument.  The same rater should conduct the assessment for the same subject 
and as much as possible, the same caregiver(s) should complete the questionnaires and 
interviews.  
Age-appropriate scales/instruments are determined by the subject’s age at the time of Informed 
Consent and will not be adjusted if the subject’s age changes during their participation in the 
study.  
Assessments may be completed in locations other than study clinic and/or via remote 
administration due to restrictions because of the COVID-19 pandemic or other qualifying event 
if acceptable according to country regulations.  In Germany, these procedures are not possible 
after December 31, 2023.   
11.1. 
Primary Efficacy Assessment 
The primary efficacy endpoint for this trial is the time from Randomization (Week 12) to 
Relapse GHILQHG DV WKH ORVV RI  RI WKH LPSURYHPHQW H[SHULHQFHG LQ WKH YGTSS-TTS from 
Baseline (Day 1) to the last visit of the open-label Stabilization period (Week 12), or initiation of 
additional medications to treat symptoms of TD, or requirement of hospitalization for worsening 
symptoms of TD in subjects between the ages of  6 and <18 years for ecopipam compared to 
those receiving placebo during the double-blind, R/WD period.  
11.1.1. 
Yale Global Tic Severity Scale (YGTSS) 
The YGTSS is a clinician-rated, multi dimensional instrument for assessing tic symptom severity 
in children and adults with TD.19  It includes a semi-structured interview with either a caregiver 
(for subjects <18 years of age) or adult subjects (t18 years of age) and clinical observations that 
assess tic and tic-related impairment s verity over the previous week.  Every attempt should be 
made, per subject, to complete interview by the same caregiver or subject and same rater for all 
visits. 
Both motor and vocal tics are assessed for symptom number, frequency, intensity, complexity, 
and interference on a 0–5 Likert scale.  Scores from each dimension are totaled to reflect the 
severity of motor tics (range 0–25), vocal tics (range 0–25) and combined tics, or Total Tic Score 
(-TSS) (range 0–50).  A separate tic-related impairment scale, scored from 0 to 50, is also 
included and calculated for the Global Severity score (-GS).  
The lookback period is over the previous week.  Administration time is approximately 
15 minutes. 
11.2. 
Secondary Efficacy Assessment 
The secondary efficacy endpoint in this trial is the time from Randomization (Week 12) to 
Relapse in all subjects irrespective of age for ecopipam compared to those receiving placebo 
during the double-blind, R/WD period. 
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11.3. 
Exploratory Efficacy Assessments  
 
x Time from Randomization (Week 12) to a worsening by at least one category of the CGI-
TS-S in subjects > 6 and < 18 years for ecopipam compared to those receiving placebo 
during the double-blind, R/WD period.  If there is a strong correlation of this endpoint 
with Relapse criteria based on the YGTSS-TTS, it may be considered as another 
secondary endpoint with agreement from Health Authorities.    
x Time from Randomization (Week 12) to a worsening by at least one category of the CGI-
TS-S in all subjects for ecopipam compared to those receiving placebo irrespective of 
age.  If there is a strong correlation of this endpoint with Relapse criteria based on the 
YGTSS-TTS, it may be considered as another secondary endpoint with agreement from 
Health Authorities.    
x Mean change from Randomization (Week 12) to Week 24 in the YGTSS-TTS for 
ecopipam compared to placebo. 
x Mean change from Randomization (Week 12) to Week 24 in the Clinical Global 
Impression of Tourette Syndrome Severity (CGI-TS-S) for ecopipam compared to 
placebo. 
x Mean change from Randomization (Week 12) to Week 24 in the YGTSS-Global Severity 
(GS) score for ecopipam compared to placebo. 
x Mean change from Randomization (W ek 12) to Week 24 in the Caregiver Global 
Impression of Change (CaGI-C) for ecopipam compared to placebo. 
x 7LPH IURP 5DQGRPL]DWLRQ :HHN  WR D ORVV RI   RI WKH LPSURYHPHQW IURP
Baseline (Day 1) experienced on the Yale Global Tic Severity Scale-Total Tic Score 
(YGTSS-TTS) at the last visit (Week 12) in the open-label Stabilization period. 
x Mean change from Randomization (Week 12) to Week 24 in the Clinical Global 
Impression of Tourette Syndrome Improvement (CGI-TS-I) for ecopipam compared to 
placebo. 
x Mean change from Randomization (Week 12) to Week 24 in the Premonitory Urge for 
Tics Scale (PUTS) for ecopipam compared to placebo. 
x Mean change from Baseline (Day 1) to Week 24 in Gilles de la Tourette Syndrome–
Quality of Life Scale for Children and Adolescents (C&A-GTS-QOL) score for 
ecopipam compared to placebo.  
x Mean change from Baseline (Day 1) to Week 24 in Gilles de la Tourette Syndrome–
Quality of Life Scale (GTS-QOL) score in adults for ecopipam compared to placebo.  
x Mean change from Baseline (Day 1) to Week 12 in the YGTSS-TTS. 
x Percentage of subjects with a decrease in their YGTSS-776 E\  RU JUHDWHU DW DQ\
time point from Baseline (Day 1) to Week 12. 
x Mean change from Baseline (Day 1) to Week 24 in the YGTSS-TTS for ecopipam 
compared to placebo. 
x Mean change from Baseline (Day 1) to Week 24 in the YGTSS-GS score for ecopipam 
compared to placebo. 
x Mean change from Baseline (Day 1) to Week 24 in the Clinical Global Impression of 
Tourette Syndrome Severity (CGI-TS-S) for ecopipam compared to placebo. 
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x Caregiver Global Impression of Change (CaGI-C) through Week 24 for ecopipam 
compared to placebo.   
x Mean change from Randomization (Week 12) to Week 24 in Gilles de la Tourette 
Syndrome–Quality of Life Scale for Children and Adolescents (C&A-GTS-QOL) for 
ecopipam compared to placebo.  
x Mean change from Baseline (Day 1) to Week 24 in the Clinical Global Impression of 
Tourette Syndrome Improvement (CGI-TS-I) for ecopipam compared to placebo. 
x Time from Randomization (Week 12) to treatment discontinuation during the double-
blind R/WD period for ecopipam compared to placebo.  
x 7LPH IURP 5DQGRPL]DWLRQ :HHN  WR ORVV RI   RI WKH LPSURYHPHQW H[SHULHQFHG
on the Yale Global Tic Severity Scale- Total Tic Score (YGTSS-TTS) from Baseline 
(Day 1) to the last visit (Week 12) in the open-label Stabilization period for ecopipam 
compared to placebo. 
x To evaluate the population PK/pharmacodynamic (PD) relationships with ecopipam 
during the open-label Stabilization period of the study. 
Additional analyses will include efficacy endpoints listed above at all earlier timepoints and the 
YGTSS subscales individually (Motor, Vocal, and Impairment).  The correlation between 
subjects meeting Relapse criteria based on YGTSS-TTS and those who also had at least a 1-point 
reduction on CGI-TS-S will also be investigated   If there is a strong correlation between subjects 
 DQG  \HDUV ZKR meet Relapse criteria based on the YGTSS-TTS and have a worsening by 
at least one category of the CGI-TS-S, Relapse will not be a competing risk, and therefore the 
time to worsening of the CGI-TS-6 IRU VXEMHFWV  DQG  \HDUV ZLOO EH FRQVLGHUHG D
secondary endpoint.  Similarly, if there is a strong correlation between all subjects irrespective of 
age who meet Relapse criteria based on the YGTSS-TTS and have a worsening by at least one 
category of the CGI-TS-S, Relapse will not be a competing risk, and therefore the time to 
worsening of the CGI-TS-S for all subjects irrespective of age will be considered a secondary 
endpoint. 
 
Subgroup analyses will also be conducted on all efficacy endpoints listed above for the following 
populations: 
x &KLOGUHQ   DQG   \HDUV RI DJH $GROHVFHQWV   DQG   \HDUV RI DJH DQG
$GXOWV   \HDUV RI DJH 
x Subjects per region 
x Males and Females 
x Ethnicity  
 
$GGLWLRQDOO\ 7LPH IURP 5DQGRPL]DWLRQ WR D ORVV RI   LPSURYHPHQW RQ WKH <*766-TTS 
will also be analyzed using the following subgroups: 
x Early Responders (at Week 4) and Later Responders (at Week 8) 
Rank order of hierarchy of the secondary and exploratory endpoints will be outlined in the 
statistical analysis plan.  
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11.3.1. 
Clinical Global Impression Tourette Syndrome (CGI-TS)20,12 
The CGI-TS provides an overall clinician-determined summary assessment that takes into 
account all available information, including a knowledge of the patient's history, psychosocial 
circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to 
function.  
Administered by an experienced clinician familiar with the disease under study and the likely 
progression of treatment, the CGI rater can make an expert clinical global judgment about the 
severity of the illness across various time points within the context of that clinical experience.  
The clinician makes a judgment about the total health of the subject at each visit: the illness 
severity, the subject’s level of distress and other aspects of impairment, and the impact of the 
illness on functioning.  The CGI is rated without regard to the clinician's belief that any clinical 
changes are or are not due to medication and without consideration of the etiology of the 
symptoms. 
The CGI consists of two reliable and valid 7-item Likert scales used to assess severity and 
change in clinical symptoms.  The severity scale (CGI-S) ranges from 1 (Normal, not ill) to 7 
(extremely ill).  The improvement scale (CGI-I) ranges from 1 (very much improved) to 7 (very 
much worse) with a score of 1 or 2 defining positive resp nse.  Pediatric and adult versions of 
the CGI-TS-S and CGI-TS-I scales are available and will be administered according to the age of 
the subject at the time of Informed Consent.   
The severity rating is based upon observed and reported symptoms, behavior, and function in the 
past seven days with the score reflecting the average severity level across the seven days.  The 
efforts of peers, teachers and parents to as ist, accommodate, or support the subject should be 
considered in overall severity in the case of pediatric subjects.  
The improvement rating compares the subject’s overall clinical condition to the Baseline visit 
and the rater should consider the following question: “Compared to tic severity at baseline, how 
much has the subject changed?”  The two CGI-TS scores can occasionally be dissociated such 
that a clinician may notice changes in the CGI-I relative to baseline despite no recent changes in 
the overall CGI-S score or vice versa.21 
The look back period is past 7 days.  Administration time is approximately 5 minutes. 
11.3.2. 
Caregiver Global Impression of Change (CaGI-C)12 
The CaGI-C is a short scale completed by the caregiver(s) of subjects <18 years old.  It consists 
of an 8-item Likert scale ranging from 0 (Not rated) to 7 (Very much worse). 
The caregiver will rate whether the subject’s overall TD symptoms change since the beginning of 
the study (prior to starting study drug).  Completion time is approximately 5 minutes. 
11.3.3. 
Premonitory Urge for Tics Scale (PUTS)22 
The PUTS is designed as a self-reported scale to measure tic-related premonitory urges.  In this 
study, the rater will read the questions to 6-17 year-old subjects and record their responses.  The 
PUTS consists of a 9-item Likert scale with each item ranging from 1 (Not at all true) to 4 (very 
much true).  Total scores range from 9 to 36 with higher scores indicative of worse severity. 
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The lookback period is over the past week.  Administration time is under 5 minutes. 
11.3.4. 
Gilles de la Tourette Syndrome – Quality of Life scale for Children aged 
6-12 years and Adolescents aged 13-18 years (C&A GTS-QOL)16  
The C&A GTS-QOL is a 27-item questionnaire completed through a clinician-rated interview 
for subjects aged 6-12 years and a self-report questionnaire for subjects aged 13-18 years.  In this 
study, 18-year-olds are defined as adults and will complete the adult version (GTS-QOL).  The 
instrument assesses 4 areas of health-related quality of life: psychological, physical/activities of 
daily living, obsessive–compulsive, and cognitive domains.  Each item is rated on a 5-point 
Likert-type scale.  Higher scores indicate worse symptom severity.  The instrument includes a 
visual analogue scale used to express the extent of self-satisfaction about life.  Higher scores 
indicate greater satisfaction.   
The lookback period is 4 weeks.  Administration time is approximately 15 minutes. 
11.3.5. 
Gilles de la Tourette Syndrome – Quality of Life Scale (GTS-QOL)23 
The GTS-QOL is a 27-item questionnaire completed by adult subjects aged !18 years.  In this 
study, 18-year-olds are defined as adults and will complete this adult version.  The instrument 
assesses 4 areas of health-related quality of life: psychological, physical/activities of daily living, 
obsessive–compulsive, and cognitive domains.  Each item is rated on a 5-point Likert-type scale.  
Higher scores indicate worse symptom severity.  The instrument includes a visual analogue scale 
used to express the extent of self-satisfaction about life.  Higher scores indicate greater 
satisfaction.   
The lookback period is 4 weeks.  Completion time is approximately 10 minutes. 
11.4. 
Pharmacokinetics Assessments 
Blood samples will be collected to measure concentrations of ecopipam and its major (active) 
metabolites at Weeks 4 and 8.  If the Week 8 PK assessment is missed, samples may be drawn at 
Week 12 during the open-label Stabilization period.  
Subjects and parents/caregivers (as applicable) will be instructed to skip their at-home 
administration of study medication on the evening prior to the Week 4 visit and to record the 
date and time the last dose of study medication was taken.  The study drug administration will 
occur on the day of the Week 4 visit at the site under the supervision of the study investigator.  
An intravenous catheter will be placed and the subject will have samples collected at the 
following three time windows: predose (34 to 44 hours since the last dose), between 0.5 and 
1.5 hours after administration of study medication, and between 2 and 4 hours after study drug 
administration.  Any samples should be collected at least 30 min apart.  
At Weeks 8 or 12 visit, subjects and parents/caregivers (as applicable) will be asked to record the 
date and time of the last dose of study medication taken.  The time of blood sample collection 
will be recorded.  Blood samples will be processed as outlined in the laboratory manual and 
analyzed for ecopipam and its major metabolite EBS-101-40853. 
 
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Page 58 of 96 
12. 
ASSESSMENTS OF SAFETY 
All assessment instruments will be administered by raters trained by the rater training group for 
the relevant scale/instrument.  The same rater should conduct the assessment for the same subject 
and as much as possible, the same caregiver(s) should complete the questionnaires and 
interviews.  
Age-appropriate scales/instruments are determined by the subject’s age at the Baseline visit and 
will not be adjusted if the subject’s age changes during their participation in the study.  
Assessments may be completed in locations other than study clinic and/or via remote 
administration due to restrictions because of the COVID-19 pandemic or other qualifying event 
if acceptable according to country regulations.  In Germany, these procedures are not possible 
after December 31, 2023.   
12.1. 
Safety Parameters 
Safety will be assessed by monitoring and recording all adverse events (AEs) and Serious 
Adverse Events (SAEs) at all Visits, regular monitoring of hematology, blood chemistry, 
urinalysis, and prolactin (Screening, Baseline, Week 12, Week 18 and Week 24 Completion or 
Relapse/Early Termination, and 7- and 14-day Follow Up visits).  HbA1c will be measured at 
Baseline, Week 12 and at Week 24 Completion or Early Termination visits.  Regular 
measurement of vital signs and the performance of a physical examination will occur at every 
visit.  An ECG will be performed at Screening, Baseline and Weeks 4, 12, 18, and 24 after 
supine BP is collected and at the 7-day and 14-day Follow Up visits.  All subjects will be 
monitored for signs or symptoms signs or symptoms of withdrawal, abuse and dependence.  
12.1.1. 
Columbia Suicide Severity Rating Scale (C-SSRS)10 
The C-SSRS10 is a low burden instrument to assess both suicidal behavior and ideation.  
Questions are phrased for use in an interview format.  The Screening/Baseline version will be 
administered at Screening and the Since Last Visit version of the scale will be administered at all 
subsequent visits.  The scale is appropriate for subjects from age 6 through to an elderly 
population.  
The clinician interview time is approximately 10 minutes. 
12.1.2. 
Children’s Depression Rating Scale-Revised (CDRS-R) 
The CDRS-R15 is a semi-structured clinician interview-based instrument.  Originally designed 
for 6-12 years old, it is the most commonly used scale in adolescent depression research.24  In 
this study, children and adolescents aged 6-17 will be interviewed by the clinician.  Seventeen 
symptom areas are assessed during the interview.  Each item is rated on a scale of 1 to a 
maximum of either 5 or 7, with 1 being least severe (no difficulties) and 5 or 7 being most severe 
(severe clinical difficulties). 
The domains include: social withdrawal, sleep disturbance, excessive fatigue, suicide ideation 
etc., aligned with the DSM-IV criteria for childhood depression. 
The symptoms being evaluated by this scale are rated by the clinician as present or absent at the 
time of evaluation.  Administration time is approximately 15 minutes. 
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12.1.3. 
Patient Health Questionnaire-9 (PHQ-9)25 
The PHQ-9 is a validated, 9-question instrument to assess the degree of depression present in 
adults (18 years of age and older).  The PHQ-9 incorporates DSM-4 depression diagnostic 
criteria with other leading major depressive symptoms into a brief, self-report questionnaire.  
The questionnaire rates the frequency of the symptoms which factors into the scoring severity 
index.  Question 9 on the PHQ-9 screens for the presence and duration of suicide ideation.  The 
clinician will perform suicide risk assessment in subjects who respond positively to question 9.  
A follow-up, non-scored question screens and assigns weight to the degree to which depressive 
problems have affected the subject’s level of function.  
As a severity measure, the PHQ-9 scores 9 items from 0 (not at all) to 3 (nearly every day) with 
total score range from 0 to 27.   
The lookback period is 2 weeks.  Completion time is less than 5 minutes. 
12.1.4. 
Pediatric Anxiety Rating Scale (PARS)17 
The PARS is a clinician-rated instrument for assessing the se erity of anxiety symptoms 
associated with common anxiety disorders and generalized anxiety in children and adolescents 
6-17 years of age.  The PARS is comprised of 2 sections: a 50-item symptom checklist grouped 
into 6 categories and 7 severity items.  For the sympt ms checklist, the clinician interviews the 
caregiver(s) and child (separately or together) and rates each item as present (1=yes) or absent 
(2=no) during the previous week.  The clinician will integrate the child and caregiver’s endorsed 
symptoms to make severity ratings on 7 dimensions using a 6-point scale 0-5.  Higher ratings 
indicate greater severity.  
The lookback period is the past week.  Administration time is approximately 30 minutes. 
12.1.5. 
Hamilton Rating Scal  for Anxiety (HAM-A)26 
The HAM-A is a clinician rated instrument for assessing the severity of anxiety symptoms in 
adults.  The HAM-A consists of 14 items, each defined by a series of symptoms, and measures 
both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety).  Each item is scored on a scale of 0 (not present) to 4 (severe).  
Total scores range from 0 to 56 with higher scores indicating more severity.  
The lookback period is 1 week.  Administration time is approximately 15 minutes.  
12.1.6. 
Extrapyramidal Symptom Rating Scale (ESRS)27 
The ESRS is a clinician-reported instrument developed to assess four types of drug-induced 
movement disorders (DIMD): Parkinsonism, akathisia, dystonia, and tardive dyskinesia.  The 
ESRS consists of 2 parts: 
Part A: 4 subscales: 
Part B: 4 CGI-S scales assessing: 
x A questionnaire of EPS or DIMD 
x An examination of Parkinsonism and akathisia 
x Tardive dyskinesia 
x Parkinsonism 
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x An examination of dystonia 
x An examination of dyskinesia 
x Dystonia 
x Akathisia 
The lookback period is 7 days.  Administration time is approximately 15 minutes. 
12.1.7. 
Children’s Yale-Brown Obsessive-Compulsive Scale-II (CY-BOCS-II)28,29 
The CY-BOCS-II is a reliable and valid scale14 to both determine severity of OCD and to monitor 
improvement during treatment.  The scale is a clinician-rated, 10-item scale (5 items regarding 
severity and 5 items regarding obsessions) that includes questions about the amount of time spent 
on obsessions/compulsions, level of impairment or distress, and how much resistance and control 
subjects have over these thoughts.  The 10 items are assessed on a 6-point scale with an overall 
score. 
The lookback period for each item is dichotomously rated.  Administration time is approximately 
10 minutes. 
12.1.8. 
Yale-Brown Obsessive-Compulsive Scale-II (Y-BOCS-II)30 
The Y-BOCS-II is a 10-item clinician-rated measure of OCD symptom severity.  Raters assess 
obsessions and compulsions separately in five domains: time spent, interference, distress, 
resistance, and control.  Each domain is rated on a scale from 0 to 4.  Total scores range from 0 
to 40, with higher scores indicating greater symptom severity. 
The lookback period for each item is dichotomously rated.  Administration time is approximately 
10 minutes. 
12.1.9. 
Swanson, Nolan and Pelham SNAP-IV-26)13  
The SNAP-IV-26 questionnaire is designed to assess ADHD core symptoms of inattention (items 
1-9), hyperactivity/impulsivity (items 10 18), and symptoms of oppositional defiant disorder 
(ODD) (items 19-26) in children and adolescents 6-18 years of age.  In this study, 18-year-olds 
are defined as adults and will complete the CAARS-S:S adult scale. 
All 26 items are rated on 4-point scale and the total score ranges from 0-78, with higher scores 
indicating greater severity.  
It is rated by the caregiver(s) as present or absent at the time of evaluation on a 0-3-point scale.  
Completion time is approximately 10 minutes. 
12.1.10. 
Conners Adult ADHD Rating Scale – Self Report, Short Version (CAARS-S:S) 
The CAARS31 is a 26-item self-report questionnaire assessing ADHD symptoms in adults (ages 
18 and older).  Subjects are asked to rate themselves on a range of symptoms and behaviors 
associated with ADHD in adults, using a 4-point scale and the total score ranges from 0-78 with 
higher scores indicating greater severity. 
It is rated by the subject as present or absent at the time of evaluation on a 0-3-point scale.  
Completion time is approximately 5 minutes. 
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12.1.11. 
Vital Signs 
Vital signs [blood pressure (after being supine for 5 minutes), pulse, height (children and 
adolescents only) and weight] will be collected at each clinic visit per Table 3.  
12.1.12. 
Electrocardiogram (ECG) 
Sites will be provided with a 12-lead ECG device to complete assessments per Table 3.  
Clinicians will instruct subjects to follow-up with care as appropriate upon evidence of new or 
worsening abnormal ECG readings. 
12.1.13. 
Central Laboratory Tests: 
Subjects should be in fasting state (minimum of 8 hours) for all blood laboratory tests collected 
at study visits after the Screening visit, per Table 3.  
Category 
Test names 
Hematology 
Red blood cell (RBC) count, hemoglobin (Hb), hematocrit (Hct), 
platelets, and white blood cell (WBC) count with differential 
(neutrophils, bands lymphocytes, monocytes, eosinophils, basophils, 
immature granulocyte) Mean Corpuscular Hemoglobin (MCH), 
Mean Corpuscular Hemoglobin Concentration (MCHC), Mean 
Corpuscular Volume (MCV), Mean Platelet Volume (MPV), Red 
Cell Distribution Width (RDW), CBC, Nucleated Red Blood Cell 
 
Chemistry 
Glucose, calcium, albumin, cholesterol, triglycerides, phosphorus, 
lactate dehydrogenase (LDH), total protein, globulin, prolactin;  
Liver function tests: albumin, alkaline phosphatase (ALP), aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase 
(ALT/SGPT), total bilirubin, direct bilirubin, Calcium (Ca), Total 
cholest rol, glucose, lactate dehydrogenase (LDH), phosphorous, 
total protein, triglycerides;  
Electrolytes: sodium (Na), potassium (K), chloride (Cl), bicarbonate; 
Renal function tests: Blood urea/blood urea nitrogen (BUN), 
creatinine 
 
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 
A local urine test (for women of childbearing potential only) and 
central laboratory serum test to confirm a positive urine result 
 
Urine Drug Screen 
Central laboratory test to detect the presence of cocaine, 
amphetamine, benzodiazepines, barbiturates, phencyclidine (PCP), 
opiates 
 
Special Test 
Hemoglobin A1c (HbA1c) at Baseline, Week 12 and Week 24 
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Maximum blood volume to be drawn at each visit is noted below.   
 
Visit 
 
 
 
 
      
Maximum Blood Volume (mL) 
Visit 1 – Screening 
 
 
 
 
 
6  
Visit 2 – Baseline  
 
 
 
 
 
8   
Visit 3 – Week 4   
 
 
 
 
 
14  
Visit 4 – Week 8  
 
 
 
 
 
6   
Visit 5 – Week 12  
 
 
 
 
 
12  
Visit 10 – Week 18 
 
 
 
 
 
6  
Visit 13 – Week 24/Relapse/ET  
 
8  
Visit 14 – 7 Day Follow Up  
 
 
6  
Visit 15 – 14 Day Follow Up  
 
 
6  
 
7RWDO YROXPH DW HDFK YLVLW GRHV QRW H[FHHG  RI WKH WRWDO EORRG YROXPH DQG WKH WRWDO YROXPH RI
DOO EORRG VDPSOHV GRHV QRW H[FHHG  RI WKH WRWDO EORRG YROXPH  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Event  
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered 
a study drug and which does not necessarily have a causal relationship with this treatment.  An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or diseas  temporally associated with the use of a study drug, whether related 
to the study drug or not. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, 
physical exam) should be defined as an AE only if the abnormality meets one of the following 
criteria: 
x Induces clinical signs or symptoms 
x Requires active intervention 
x Requires interruption or discontinuation of study medication 
x The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
12.2.1.1. Adverse Event (AE) 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition including worsening of TD following or during exposure to a 
pharmaceutical product, whether or not considered casually related to the product.  In clinical 
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studies, an AE can include an undesirable medical condition occurring at any time, including 
baseline or washout periods, even if no study treatment has been administered. 
All AEs that occur after any subject has been screened, enrolled, before treatment, during 
treatment, or within 30 days following the cessation of treatment, whether they are related to the 
study or not, must be recorded on forms provided by Sponsor or its representatives. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during any study phase (i.e., baseline, treatment, 
washout, or follow-up), and at any dose of the investigational product, comparator, or placebo, 
that fulfills one or more of the following: 
x Results in death. 
x It is immediately life-threatening. 
x It requires in-subject hospitalization or prolongation of existing hospitalization. 
x It results in persistent or significant disability or incapacity. 
x Results in a congenital abnormality or birth defect  
x It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
All SAEs that occur after any subject/subject h s been enrolled, before treatment, during 
treatment, or within 30 days following the cessation of treatment, whether they are related to the 
study, must be recorded on forms provided by the Sponsor or its representatives. 
12.2.1.3. Other Adverse Event (OAE) 
OAEs will be identified by the Drug Safety Physician and if applicable also by the Clinical Study 
Team Physician during the eval ation of safety data for the Clinical Study Report.  Significant 
adverse events of clinical importance, other than SAEs and those AEs leading to discontinuation 
of the subject/subject from the study, will be classified as OAEs.  For each OAE, a narrative may 
be written and included in the Clinical Study Report.  Adverse events of special interest (AESI) 
to characterize ecopipam are programmatically listed for review and will be identified by the 
Medical Director(s) and Drug Safety Physician.  The AEs include weight gain, extra-pyramidal 
reactions and suicidal ideations and behavior. 
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.” 
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If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered related to the Investigational Product for 
the purposes of expedited regulatory reporting. 
12.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site.  Clinically significant changes in laboratory values, blood pressure, and 
pulse can be reported as AEs per the investigator’s judgement.  However, abnormal values that 
constitute an SAE or lead to discontinuation of administration of study drug must be reported 
and recorded as an AE.  Information about AEs will be collected from the signing of consent 
form until the end of the study.  SAE information will be collected from signing of consent form 
until 30 days following the last dose of study drug.  The AE term should be reported in standard 
medical terminology when possible.  For each AE, the investigator will evaluate and report the 
onset (date and time), resolution (date and time), intensity, causality, action taken, serious 
outcome (if applicable), and whether it caused the subject to discontinue the study. 
Intensity will be assessed according to the following scale: 
x Mild (awareness of sign or symptom, but easily tolerated) 
x Moderate (discomfort sufficient to cause interference with normal activities) 
x Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2.  An AE of severe intensity 
may not be considered serious. 
Should a pregnancy of a subject or partner occur, it must be reported and recorded on Sponsor’s 
or Sponsor approved pregnancy form.  Pregnancy is not regarded as an AE unless there is a 
suspicion that an investigational product may have interfered with the effectiveness of a 
contraceptive medication.  Reports of pregnancy must be submitted without undue delay and no 
longer than 24 hours of awareness of the event:  
Email Address: safetyreporting@syneoshealth.com    
Fax no. Americas: +1 877 464 7787 
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 Serious 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 SAE considered possibly or probably related to 
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the investigational product and discovered by the Investigator at any time after the study should 
be reported.  All SAEs must be reported without undue delay and no longer than 24 hours of 
awareness of the event :   
Email Address: safetyreporting@syneoshealth.com    
Fax no. USA: +1 877 464 7787 
Fax no. outside USA +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 without undue delay and no longer than 24 hours of awareness of the event  and 
this should be completed on a follow-up SAE form and placed with the original SAE information 
and kept with the appropriate section of the CRF and/or study file. 
The Sponsor and its representatives are responsible for notifying the relevant regulatory 
authorities of certain events.  It is the Principal Investigator’s responsibility to notify the IRB or 
IEC of all SAEs that occur at his or her site.  Investigators will also be notified of all unexpected, 
serious, drug-related events (7/15 Day Safety Reports) that occur during the clinical study.  Each 
site is responsible for notifying its IRB or IEC of these additional SAEs. 
 
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13. 
STATISTICS 
All data analyses will be performed by the Sponsor or its representatives after the study is 
completed, and the database is finalized and released.  The statistical analyses described in this 
section will be performed using SAS 9.4.  All collected data will be listed.  Additional analyses 
may need to be conducted for data not collected at sites and/or via remote administration due to 
restrictions because of the COVID-19 pandemic or other qualifying event, details of these 
additional analyses will be specified in the SAP.  
13.1. 
Analysis Population  
The Modified Intention-to-Treat (mITT) population will include all randomized subjects who 
received at least one dose of study drug post randomization.  The mITT population will be used 
for the analysis of primary, secondary and exploratory efficacy endpoints.  All analyses 
performed for the mITT population will also be performed for the Intent-to-Treat (ITT) 
population defined as all randomized subjects.   
The Per-Protocol (PP) population will include subjects from the mITT population who have no 
major protocol deviations that may adversely impact assessment of efficacy.  Before data are 
released for statistical analysis, a blinded review of all data will be performed by the Sponsor’s 
clinical team to identify protocol deviations that may potentially affect the results.  At this time, 
it will be determined if subjects and/or data should be excluded from the PP Population.  The list 
of subjects or observations to be excluded from the PP Population, along with the reason for 
exclusion, will be finalized prior to database unblinding.  Protocol deviations that occur due to 
COVID-19 related issues or other qualifying vents will be categorized separately as applicable.    
The Safety population will include all subjects who received at least one dose of study drug.  The 
safety population will be used for the analysis of the safety endpoints. 
The Pharmacokinetics (PK) population will include all subjects from safety population who have 
a valid concentration measurem nt   
13.2. 
Data Safety Monitoring Board 
An independent data safety and monitoring board (DSMB) consisting of a physician experienced 
in the conduct of clinical studies (Chairman with TD experience), one clinician and one 
statistician experienced in TD will review the data at the interim analysis.  The data will be 
cleaned by the data management group, and the analysis and reporting of the interim data to the 
DSMB will be the responsibility of an independent statistical group (which will not be directly 
involved in the conduct of the study).  The DSMB will meet after the data presentation and issue 
recommendations.  Minutes of the DSMB will be submitted to the sponsor after the study has 
been unblinded and will be appended to the final study report. 
Full details of the DSMB procedures including primary responsibilities of the DSMB, its 
relationship with other study components, its membership, and the purpose and timings of its 
meetings will be documented in a DSMB charter.  These details will also include procedures to 
ensure confidentiality and proper communication, the guidelines to be implemented by the 
DSMB and an outline of the content of the closed reports (unblinded) and open reports (blinded) 
that will be provided to the DSMB.   
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13.3. 
Interim Analysis 
An interim analysis (IA) will be conducted by an independent data safety monitoring board 
'60% DIWHU DSSUR[LPDWHO\  RI 5HODSVH HYHQWV KDYH DFFUXHG  5HODSVH HYHQWV  The 
2-sided alpha level for the IA is 0.005.  If statistical significance is reached at the IA, the DSMB 
can recommend stopping the study for overwhelming efficacy.  If the study proceeds to the 
planned completion, the final 2-sided alpha level will be 0.0492.  In addition to the possibility of 
stopping early for efficacy, a conditional power analysis will be performed to assess whether the 
total number of relapse events should be increased beyond 49 in order to increase statistical 
power at the final analysis.  If the probability based on conditional power of a successful study is 
too small and does meet pre-specified criteria, the DSMB can recommend stopping the study for 
futility.  If the probability of a successful study is reasonable, the DSMB can recommend 
continuing the trial as planned or can also recommend continuation of the trial with a sample size 
adjustment based on conditional power.  Interpretation of conditional power will be guided by 
the promising zone approach. 32  One consequence of this approach is that no adjustment of the 
final alpha level will be required (other than the alpha spending of the IA).  Full details will be 
provided in the Statistical Analysis Plan (SAP). 
13.4. 
Planned Analysis 
13.4.1. 
Efficacy Analysis 
The primary efficacy endpoint is time from Randomization to Relapse defined as a loss of  
of the improvement experienced on the YGTSS-TTS at the last visit in the open-label 
Stabilization period (Week 12), or initiation of additional medications to treat symptoms of TD, 
or requirement of hospitalization for w rsening symptoms of TD in subjects   DQG  18 years 
during the double-blind R/WD period for ecopipam compared to placebo.  Data from subjects 
who complete or discontinue from the double-blind R/WD period without Relapse will be 
considered as censored obs rvations.  The log rank test will be the primary test of statistical 
significance.  Kaplan-Meier curves will be used to compare the times to relapse between the 
treatment groups.  7KH KD]DUG UDWLR DQG LWV  FRQILGHQFH LQWHUYDO &, ZLOO EH HVWLPDWHG IURP
the Cox proportional hazard model with treatment as a factor.  The proportional hazards 
assumption will be evaluated graphically and analytically, for example by assessing martingale 
and Schoenfeld residuals and by modeling time-dependent covariates.  The analysis of the 
primary efficacy endpoint will be performed in the mITT and PP populations according to the 
randomized treatment.  Details will be provided in the Statistical Analysis Plan. 
The time-to-event secondary and exploratory endpoints related to Relapse will be analyzed in a 
similar manner as the primary endpoint.  The exploratory endpoints of mean change will be 
assessed with a Mixed Model for Repeated Measures (MMRM) model using the SAS MIXED 
procedure, with a REPEATED statement, with no imputation.  The model will include fixed 
effects for treatment, visit, the interaction between treatment and visit, and a covariate for 
baseline score for the given assessment and other covariates such as gender, age group, 
race/ethnicity, and region.  All secondary and exploratory endpoints will be analyzed in the 
mITT population according to randomized treatment.  Details will be provided in the Statistical 
Analysis Plan. 
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The CGI-TS-S endpoints currently listed as time-to-event exploratory endpoints may be 
considered as secondary endpoints, if there is a strong correlation between subjects meeting 
Relapse criteria based on YGTSS-TTS and those who also had at least a 1-point reduction on 
CGI-TS-S. The strong correlation would suggest Relapse is not a competing risk.  Details will be 
provided in the Statistical Analysis Plan. 
The time-to-event estimand for the primary endpoint, which uses the mITT study population, and 
for the time-to-event secondary and exploratory endpoints related to Relapse will rely on a 
treatment policy strategy (which also has elements of a composite strategy, in that three 
intercurrent events, initiation of additional medications and hospitalization for worsening 
symptoms  are incorporated as part of the definition of the primary endpoint).  The intercurrent 
events of loss to follow-up will be assumed unrelated to treatment and treated in estimation as 
censored observations.  Sensitivity analyses for the primary endpoint may assess alternate 
treatment of such missing data; details will be provided in the Statistical Analysis Plan. 
The time-to-event endpoints not related to Relapse will rely on a treatment policy strategy.  A 
cumulative incidence approach will be used to account for the competing risk of study 
discontinuation due to Relapse.  Cause-specific Cox models will be used to obtain the hazard 
UDWLR DQG LWV  &, IRU WLPH WR ZRUVHQLQJ  In this model, subjects who complete or discontinue 
from the double-blind randomized withdrawal period before meeting endpoint criteria and for 
reasons not related to Relapse will be censored at the time of discontinuation.  In addition, we 
will consider graphical and descriptive approaches in correlating the YGTSS with other scores 
(e.g., CGI-TS-S) in the study subjects acros  time points. 
For exploratory endpoints of mean change, the difference in means between treatment arms in 
change from Randomization (Week 12) to Week 24 or from Baseline (Day 1) to Week 24, a 
sensitivity analysis may be performed.  For the intercurrent events of study treatment 
discontinuation due to lack of efficacy, treatment related adverse events, death prior to Week 24 
and Relapse for subjects with no assessment at Week 24, the non-collected data of assessment at 
Week 24 will be multiple imput d using similar subjects (relevant demographic/baseline 
characteristics) from the placebo arm.  For exploratory endpoints of mean change to fixed time 
point, additional analyses will be performed by time point. 
In consideration of missing data, additional multiple imputation or tipping point methods may be 
used as a sensitivity analysis, such as: 
x Missing at Random (MAR) predictive mean matching multiple imputation method 
x Missing not at Random (MNAR) “jump to reference” multiple imputation method 
x Tipping point analysis under MNAR assumption 
x The mean change from Baseline (Day 1) to Week 12 (open-label) in YGTSS-TTS will be 
calculated. The paired t-test will be used for analyzing the change from baseline within 
treatment. 
x 7KH SHUFHQWDJH RI VXEMHFWV ZLWK D  RU JUHDWHU GHFUHDVH LQ WKHLU <*766-TS will be 
analyzed using Fisher Exact test.  
x A fixed-sequence statistical strategy will be used to test selected efficacy endpoints in a 
predefined rank order hierarchy which will be outlined in the SAP. 
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The full details will be specified in the SAP. 
 
Subgroup analyses will be conducted on all efficacy endpoints for the following populations:  
x &KLOGUHQ   DQG   \HDUV RI DJH $GROHVFHQWV   DQG   \HDUV RI DJH DQG
$GXOWV  18 years of age). 
x Subjects per region 
x Males and Females 
x Ethnicity and Race 
 
$GGLWLRQDOO\ 7LPH IURP 5DQGRPL]DWLRQ WR D ORVV RI   LPSURYHPHQW RQ WKH <*766-TTS 
will also be analyzed using the following subgroups: 
x Early Responders (at Week 4) and Later Responders (at Week 8) 
The treatment of missing data and sensitivity analyses for the endpoints will be specified in the 
Statistical Analysis Plan. 
13.4.2. 
Safety Analysis 
All safety data will be summarized in Safety population according to the actual treatment. 
Treatment-emergent adverse events (TEAEs) are defined as adverse events that are newly 
occurring or worsening after the first dose of study medication.  The incidence of TEAEs will be 
summarized by treatment group, by severity and by relationship to study medication.  Serious 
TEAEs and TEAEs leading to the study termination will be summarized by treatment group.  
Laboratory, vital signs, physical examination, and ECG data will be summarized by treatment 
and visit. 
The Columbia-Suicide Severity Rating Scale (C-SSRS), the Children’s Depression Rating Scale-
Revised (CDRS-R), the Pediatric Anxiety Rating Scale (PARS), the Extrapyramidal Symptom 
Rating Scale (ESRS), the Swanson, Nolan, and Pelham (SNAP-IV-26) questionnaire, the 
Children’s Yale-Brown Obsessive-Compulsive Scale-II (CY-BOCS-II), the Patient Health 
Questionnaire-9 (PHQ-9), the Hamilton Rating Scale for Anxiety (HAM-A), the Conners Adult 
ADHD Rating Scale Self Report: Short Version (CAARS-S:S) and the Yale-Brown Obsessive-
Compulsive Scale-II (Y-BOCS-II) will also be summarized descriptively.  
13.4.3. 
Pharmacokinetics Analysis 
Plasma concentration-time data will be summarized in the Clinical Study Report (CSR).  
Population pharmacokinetic and pharmacodynamic analyses will be conducted and summarized 
separately, using data from this study along with data from other studies.  The methodology for 
analyses will be reported in a separate analysis plan.  
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13.5. 
Sample Size Justifications  
The planned number of Relapse events for the double-blind R/WD Phase is 49 children and 
adolescents.  This number of events will provide 85 SRZHU WR GHWHFW D GLIIHUHQFH EHWZHHQ
treatment groups, assuming a hazard ratio of 0.4 for Relapse and statistical testing at alpha level 
0.05 (2-sided).  Subject enrollment will stop around the time that 49 Relapse events among 
children and adolescents are expected to have occurred.  The number of Relapses among adults 
will not determine study completion.  
$VVXPLQJ WKH SURSRUWLRQ RI VXEMHFWV ZKR 5HODSVH LQ WKH '% UDQGRPL]DWLRQ SKDVH LV  LQ WKH
SODFHER JURXS DQG  LQ WKH HFRSLSDP JURXS DSSUR[LPDWHO\ 98 subjects (49 subjects per 
group) will be required to achieve this number of events.   
Total Number of Subjects: 
Approximately 196 subjects (children and adolescents) will be enrolled into the open-label 
Stabilization Period in order to randomize 98 subjects age   WR   \HDUV RI DJH assuming the 
stabilization rate in the open-ODEHO 6WDELOL]DWLRQ 3HULRG LV 
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40 adult subjects are also expected to be enrolled.   
 
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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The sponsor should ensure that it is specified in the protocol or other written agreement that the 
investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC review, and 
regulatory inspection(s) by providing direct access to source data/documents. 
14.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, the Sponsor or its representatives 
will visit the investigational study site to: 
x Determine the adequacy of the facilities. 
x Discuss with the investigator(s) and other personnel their responsibilities about protocol 
adherence, and the responsibilities of Emalex or its representatives.  This will be 
documented in a Clinical Study Agreement between Emalex and the investigator. 
During the study, a monitor from the Sponsor or its representatives will have regular contacts 
with the investigational site, for the following: 
x Provide information and support to the investigator(s). 
x Confirm that facilities remain acceptable. 
x Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report f rms, and that investigational product 
accountability checks are being performed. 
x Perform source data verification.  This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, and other 
records relevant to the study.  This will require direct access to all original records for 
each subject (e.g., clinic charts). 
x Record and report any protocol deviations not previously sent to Emalex. 
x Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to the Sponsor or its representatives and those SAEs that met 
criteria for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Authorized representatives of the Sponsor or its representatives, a regulatory authority, an 
Independent Ethics Committee, or an Institutional Review Board may visit the site to perform 
audits or inspections, including source data verification.  The purpose of an Emalex audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice guidelines of 
the International Conference on Harmonization, and any applicable regulatory requirements.  
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The investigator should contact the Sponsor or its representatives immediately if contacted by a 
regulatory agency about an inspection. 
14.3. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) 
IRB/IEC approval for the investigation must be obtained prior to initial dosing of any subjects.  
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
subject consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
The Investigator shall make accurate and adequate written progress reports to the IRB/IEC at 
appropriate intervals, not exceeding one year.  The Investigator shall make an accurate and 
adequate final report to the IRB/IEC within 90 days after the close-out visit within one year after 
last subject out (LPO) or termination of the study. 
 
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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
the Sponsor or its designee may conduct a quality assurance audit.  Please see Section 14.2 for 
more details regarding the audit process. 
The Sponsor or its designee will implement and maintain quality assurance and quality control 
systems with written SOPs to ensure that studies are conducted, and data are generated, 
documented (record), and reported in compliance with the Protocol, GCP, and applicable 
regulatory requirement(s). 
 
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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Forms, must be 
approved, or given a favorable opinion in writing by an IRB or IEC as appropriate.  The 
investigator must submit written approval to the Sponsor or its representatives before he or she 
can enroll any subject/subject into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the Protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all advertising 
and materials used to recruit and retain subjects for the study.  The protocol must be re-approved 
by the IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  The Sponsor or its designee will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines  
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (please see Appendices) and are consistent with ICH/Good Clinical 
Practice and applicable regulatory requirements. 
16.3. 
Written Informed Consent 
The Principal Investigator(s) at ea h center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study.  
Subjects must also be notified that hey are free to discontinue from the study at any time.  The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
For subjects <18 years of age at Baseline, the parents’, or legal guardian’s signed and dated 
informed consent and the subject’s signed and dated assent form must be obtained before 
conducting any study procedures.  Subject assents will be administered according to the 
requirements of the site’s IRB/IEC.  6XEMHFWV  \HDUV RI DJH PXVW H[HFXWH D ZULWWHQ LQIRUPHG
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 Diversity  
Study centers will be selected in support of recruitment of an ethnically diverse group of study 
participants. 
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A review of the published literature indicated that while the prevalence of TD is greater in males 
as compared to females (Section 5.1) it does not show any disproportionate impact on specific 
ethnic groups.  Hence the goal of participant recruitment would be to enroll a study population 
similar to the general population. 
Study design, protocol inclusion/exclusion criteria and prohibited medications have been 
reviewed to ensure that they do not unduly restrict inclusion of any ethnic group.  Study sites will 
be selected to ensure that sites are distributed across regions and are not confined to some 
regions of the country. 
Sites that indicate potential to enroll a diverse population will be recruited for participation in the 
trial.  Support for enrollment of disadvantaged population such as reimbursement for travel, 
parking assistance and other assistance as needed will be provided.  Recruitment plans will 
include focus on enrolling study participants similar to the general population.  Enrollment will 
be actively monitored so adjustments may be made on ongoing basis to assist in achieving the 
goal of subject diversity. 
16.5. 
Subject Confidentiality and Data Security  
The safety of the persons participating in the clinical trial and the validity of the data collected in 
the clinical trial are of the highest priority.  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 permission, medical information may be given to his or 
her personal physician or other appropriate medical personnel responsible for his or her medical 
welfare.  
The Sponsor will use the information obtained during the conduct of this study for the 
development of ecopipam.  The study Investigator is obliged to provide the Sponsor with 
complete test results and all data developed in this study.   
In the event of a data security breach, Emalex as a data controller has implemented privacy and 
security controls designed to help protect subject personal data; including information security 
controls, firewalls, incident detection, and secure transfer measures.  In the event of any 
accidental or unlawful destruction, loss, alteration, unauthorized disclosure of, or access to, 
personal data (“breach”), the controller has implemented procedures and measures to promptly 
address and mitigate any risk to the data.  Emalex uses proactive and reactive detection channels 
to identify potential breaches. In the event of a breach, the data controller will notify the 
appropriate regulatory authorities and/or the subject in accordance with applicable data 
protection law.   
Collected study data will be pseudonymized and maintained in a secure system.  Such data will 
be processed and transferred using systems with proper certification and validation to ensure data 
security, privacy and quality management are in place.  Technical and organizational measures to 
safeguard data include antivirus protection, encryption, data loss prevention practices, data 
privacy policy, password management policies, and access control.  Additionally, a data 
protection officer (DPO) has been appointed by the Sponsor.  Appropriate records of data 
processing activity are to be kept and the DPO will assist in case of a data breach, in which case 
the incident will be recorded, and notification will be made to the relevant Supervisory 
Authorities and data subjects, as applicable. 
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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. 
16.6. 
Ethnicity Data Collection  
Ethnicity data will be collected for all subjects.  In vitro metabolism studies with ecopipam and 
its active metabolite, N-desmethylecopipam revealed the primary route of metabolism to be 
through UGT and CYP enzymes, specifically UGT1A9 and CYP3A4.  Ethnicity information 
collected in patients along with the pharmacokinetic sampling and analyses may help describe 
variability in exposures and response to ecopipam.  Data from the Phase 2b EBS-101-CL-001 
study along with Phase 3 study data across all ethnicities will pr vide information to support the 
exploration of exposure-response relationships and modeling and eventual dosing 
recommendations.   
 
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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sponsor or its designee will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor to 
inspect the drug storage area, study drug stocks, drug accountability records, subject charts and 
study source documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of time after 
the last marketing application approval, or if not approved period of time following the 
discontinuance of the test article for investigation based on country and local regulations.  If it 
becomes necessary for Emalex or the Regulatory Authority to review any documentation relating 
to the study, the Investigator must permit access to such records  
 
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18. 
PUBLICATION POLICY 
The Principal Investigator is obliged to provide the sponsor with complete data derived from the 
program.  During the program, only Emalex Biosciences may make information available to 
other participating physicians or to regulatory agencies, except as required by law or regulation.  
Except as otherwise allowable in the Clinical Site Agreement, any public disclosure (including 
publicly accessible websites) related to the protocol or program results, is the sole responsibility 
of Emalex Biosciences. 
Emalex Biosciences may publish any data and information from the program (including data and 
information generated by the physicians) without the consent of the treating physician.  
Manuscript authorship for any peer-reviewed publication will appropriately reflect contributions 
to the production and review of the document.  All publications and presentations must be 
prepared in accordance with this section and the Clinical Site Agreement.  In the event of any 
discrepancy between the protocol and the Clinical Site Agreement, the Clinical Site Agreement 
will prevail.  All scientific publications generated by Emalex Biosciences and its agents will be 
consistent with the principals outlined in Good Publication Practices. 
Data from all sites participating in the program will be pooled and analyzed by Emalex 
Biosciences or its designees.  The first publication of the results shall be made in conjunction 
with the results from other sites as a multicenter publication.  If a multicenter publication is not 
forthcoming within 24 months of completion of the program at all sites, the treating physician 
may publish or present the results generated at his or her site. 
The treating physician will provide Emalex Biosciences with a copy of any proposed publication 
or presentation for review and comment at least 60 days prior to such presentation or submission 
for publication.  Emalex Biosciences shall inform the investigator in writing of any changes or 
deletions in such presentation or publi ation required to protect Emalex Biosciences’ 
confidential and proprietary techni al 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. 
8. 
Robertson MM, Banerjee S, Kurlan R, Cohen DJ, Leckman JF, McMahon W, et al. The 
Tourette Syndrome Diagnostic Confidence Index: Development and Clinical Associations. 
Neurology. 1999;53(9):2108-2112. 
9. 
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. 
10. Posner K, Brown GK, Sta ley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168(12):1266-77.  
11. 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. 
12. 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. 
13. Swanson JM, Kraemer HC, Hinshaw SP, Arnold LE, Conners CK, Abikoff HB, et al. 
Clinical relevance of the primary findings of the MTA: success rates based on severity of 
ADHD and ODD symptoms at the end of treatment. J Am Acad Child Adolesc Psychiatry. 
2001;40(2):168-179. 
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14. Scahill L, Riddle MA, McSwiggin-Hardin M, Ort SI, King RA, Goodman WK, et al. 
Children's Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad 
Child Adolesc Psychiatry. 1997;36(6):844-52. 
15. Poznanski EO, Freeman LN, Mokros HB. Children's Depression Rating Scale Revised 
(September 1984). Psychopharmacol Bull. 1985; 21:979-989. 
16. 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. 
17. 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. 
18. American Psychiatric Association (Ed.). (2022). Diagnostic and statistical manual of 
mental disorders: DSM-5-TR (Fifth edition, text revision). American Psychiatric 
Association Publishing. 
19. Haas M, Jakubovski E, Fremer C, Dietrich A, Hoekstra PJ, Jäger B, et al. Yale Global Tic 
Severity Scale (YGTSS): Psychometric Quality of the Gold Standard for Tic Assessment 
Based on the Large-Scale EMTICS Study. Front Psychiatry. 2021;12:626459. 
20. Sukhodolsky DG, Gladstone TR, Kaushal SA, Piasecka JB, Leckman JF (2017). "Tics 
and Tourette Syndrome". In Matson JL (ed.). Handbook of Childhood Psychopathology 
and Developmental Disabilities Treatment. Autism and Child Psychopathology Series. 
p. 248. 
21. Busner J, Targum SD. The clinical global impressions scale: applying a research tool in 
clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37. 
22. Woods DW, Piacentini J, Himle MB, Chang S (2005). Premonitory Urge for Tics Scale 
(PUTS): initial psychometric results and examination of the premonitory urge 
phenomenon in youths with tic disorders. J Dev Behav Pediatr. 26:397–403. 
23. Cavanna AE, Schrag A, Morley D, Orth M, Robertson MM, Joyce E, et al. The Gilles de 
la Tourette Syndrome-Quality of Life Scale (GTS-QOL). Neurology. 2008;71:1410-1416. 
24. Poznanski EO, Cook SC, Carroll B.J. A depression rating scale for children. Pediatrics. 
1979;64(4):442-50. 
25. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
measure. J Gen Intern Med. 2001;16(9):606-13. 
26. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50-
5. 
27. Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale 
(ESRS). Schizophr Res. 2005;76(2-3):247-65. Epub 2005 Apr 18. 
28. Storch EA, Rasmussen SA, Price LH, Larson MJ, Murphy TK, Goodman WK. 
Development and psychometric evaluation of the Yale-Brown Obsessive-Compulsive 
Scale--Second Edition. Psychol Assess. 2010;22(2):223-32. https://doi.org/00012030-
201006000-00003 
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29. Storch EA, McGuire JF, Wu MS , Hamblin R, McIngvale E, Cepeda SL, et al. 
Development and Psychometric Evaluation of the Children’s Yale-Brown Obsessive-
Compulsive Scale Second Edition. J Am Acad Child Adolesc Psychiatry. 2019;58(1):92-
9. DOI: HTTPS://DOI.ORG/10.1016/J.JAAC.2018.05.029 
30. Storch EA, Rasmussen SA, Price LH, Larson MJ, Murphy TK, Goodman WK. (2010). 
Development and psychometric evaluation of the Yale–Brown Obsessive-Compulsive 
Scale—Second Edition. Psychological Assessment. 22(2), 223–232. 
31. Conners CK, Erhardt D, Sparrow E. (1999). Conners’ adult ADHD rating scales 
(CAARS). Multi-Health Systems, Inc. 
32. Mehta C, Pocock S. Adaptive increase in sample size when interim results are promising: 
a practical guide with examples. Stat Med. 2011;30:3267–84.  
 
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20. 
WMA DECLARATION OF HELSINKI – ETHICAL PRINCIPLES 
FOR MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
be applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles. 
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my subject will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the subject s best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights 
of subjects, including those who are involved in medical research. The physician’s knowledge 
and conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6.         The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility 
and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects must 
always rest with the physician or other health care professionals and never with the research 
subjects, even though they have given consent. 
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10.       Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement should 
reduce or eliminate any of the protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12.       Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on subjects 
or healthy volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14.       Physicians who combine medical research with medical care should involve their 
subjects in research only to the extent that this is justified by its potential preventive, diagnostic 
or therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the subjects who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits 
16.       In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by the 
condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18.       Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed. 
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. 
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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 Declara ion have been addressed. The protocol should include 
information regarding funding, sponsors, insti utional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a conseq enc  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 
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. 
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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 
assent in addition to the consent of the legally authorised representative. The potential subject’s 
dissent should be respected. 
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30.       Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious subjects, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. Consent 
to remain in the research must be obtained as soon as possible from the subject or a legally 
authorised representative. 
31.       The physician must fully inform the subject which aspects of their care are related to the 
research. The refusal of a subject to participate in a study or the subject’s decision to withdraw 
from the study must never adversely affect the subject-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 
consent for its collection, storage and/or reuse. There may be exceptional situations where 
consent would be impossible or impracticable to obtain for such research. In such situations the 
research may be done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the us  of placebo, or no intervention, is acceptable; or 
Where for compelling and sci ntifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention 
and the subjects who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a result of 
not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention identified 
as beneficial in the trial. This information must also be disclosed to participants during the 
informed consent process. 
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Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable for 
the completeness and accuracy of their reports. All parties should adhere to accepted guidelines 
for ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual subject, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the subject or a legally authorised representative, may use an unproven 
intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all ases, new information must be recorded and, 
where appropriate, made publicly available  
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21. 
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: 
x Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
x Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
x Intrauterine device (IUD) 
x Intrauterine hormone-releasing system (IUS) 
x Bilateral tubal occlusion 
x 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. 
x Sexual abstinence (defined as r fraining 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 need  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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22. 
ALLOWABLE MEDICATIONS LIST FOR COMORBID 
CONDITIONS 
 
The following medications are allowed for the treatment of subjects with ADHD, anxiety, 
depression, and OCD if doses have been stable for at least 4 weeks prior to Screening and the 
dose is constant during the study:   
 
Stimulants for ADHD 
x Amphetamine 
x Amphetamine and dextroamphetamine 
x Dexamphetamine 
x Dexmethylphenidate 
x Lisdexamfetamine 
x Methylphenidate 
 
Anti-Depressants 
x Citalopram 
x Desvenlafaxine 
x Escitalopram 
x Fluvoxamine 
x Levomilnacipran 
x Milnacipran 
x Sertraline 
 
Anxiolytics 
x Lorazepam- Chronic use only 
x Hydroxyzine 
 
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23. 
PROHIBITED MEDICATIONS LIST 
 
Examples of prohibited medications in this section are provided below.   
This is not a complete list.  Please contact the Medical Monitor if you have questions about 
prohibited medications. 
In general, medications that are prohibited fall into the following categories:  
x Other medications used to treat tics associated with Tourette’s disorder are prohibited. 
x Medications that deplete dopamine to a significant extent (i.e., D2 receptor antagonists) or  
increase dopamine (i.e., dopamine agonists) to a significant extent are prohibited. 
x Medications that have unfavorable drug-drug interactions with ecopipam that could have 
safety implications due to:  
o Increased exposure to the concomitant drug (i.e  ecopipam is a strong inhibitor of 
CYP2D6 and substantially increases plasma levels of drugs that are metabolized by 
this system). 
o Increased exposure to ecopipam (i.e., ecopipam is primarily metabolized by UGT1A9 
and inhibitors of this system and other UGT enzymes increases plasma levels of 
ecopipam up to 2x normal levels). 
o Decreased exposure to concomitant drugs with narrow therapeutic indices, anticancer 
drugs, anticoagulants, and/or antibiotic or antiviral drugs that require a minimum 
plasma level to mitigate dr g resistance unless routine monitoring of serum drug 
levels is performed (i.e.  ecopipam moderately induces the metabolism of drugs 
metabolized by CYP2C  CYP3A4, and or PGP substrates resulting in lower plasma 
levels of drugs that are metabolized by these systems).   
o Decreased exposure to ecopipam due to co-administration with strong inducers, 
leading to sub-therapeutic effect.   
x Medications that are not appropriate for the pediatric population based on safety 
considerations. 
x Investigational medications. 
Some of the medications prohibited in this double-blind study may be allowed with dose 
adjustments in the open-label safety extension.  Refer to Protocol EBS-101-TD-391. 
 
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Prohibited: Medications for the Treatment of Tics  
Amisulpride 
Olanzapine 
Aripiprazole 
Pimozide 
Asenapine 
Quetiapine 
Baclofen 
Reserpine 
Botulinum toxin 
Risperidone 
Clonazepam 
Sulpiride 
Clonidine 
Tiapride 
Duetetrabenazine 
Tetrabenazine 
Fluphenazine 
Topiramate 
Guanfacine 
Valbenazine 
Haloperidol 
Ziprasidone 
 
 
Prohibited: Anti-ADHD, Anti-Anxiety, Anti Depressant, and Anti-Psychotic Medications  
(not appearing on previous list) 
Alprazolam 
Imipramine 
Amoxapine 
Loxapine 
Amitriptyline 
Maprotiline 
Atomoxetine 
Nortriptyline 
Bupropion 
Paliperidone 
Chlorpromazine 
Paroxetine 
Clomipramine 
Perphenazine  
Desipramine 
Propranolol 
Doxepin 
Protriptyline 
Dronedarone 
Thioridazine 
Droperidol 
Trimipramine 
Duloxetine 
Venlafaxine 
Fluoxetine 
Viloxazine 
 
 
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Prohibited: Medications that Significantly Decrease Dopamine Levels  
(not appearing on previous lists) 
 
Chloroethylnorapomorphine 
Domperidone 
Cinnarizine 
Metoclopramide 
 
 
Prohibited: Medications that Significantly Increase Dopamine Levels  
(not appearing on previous lists) 
 
Apomorphine 
Pramipexole 
Bromocriptine 
Ropinirole 
Cabergoline 
Rotigotine 
 
 
Prohibited: Sensitive CYP2D6 Substrates  
(not appearing on previous lists) 
 
Codeine 
Prajmaline 
Dextromethorphan 
Propafenone 
Eliglustat 
Repinotan (IV) 
Encainide 
Tamoxifen 
Enclomiphene 
Tolperisone 
Ibogaine 
Tolterodine 
Metoprolol 
Tramadol 
Methoxyphenamine 
Traxoprodil 
Nebivolol 
Trimipramine 
Nicergoline 
Tropisetron 
Perhexiline 
Vernakalant 
 
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Prohibited: UGT Inhibitors 
(not appearing on previous lists) 
 
Mefanamic acid 
Propofol 
Mycophenolic acid 
Valproic acid 
 
 
Prohibited: Sensitive CYP3A4 and CYP2C19 Substrates- Prohibited unless routine 
monitoring of serum drug levels is performed 
(not appearing on previous lists) 
 
Amiodarone 
Macrolide antibiotics (Azithromycin, 
Erythromycin, Clarithromycin, etc.) for long term 
use 
Anticoagulants (Apixaban, Rivaroxaban, 
Warfarin)  
Paclitaxel 
Antiretrovirals (Etravirine, Nelfinavir, Protease 
inhibitors) 
Quinidine 
Bortezomib 
Sirolimus 
Clopidogrel 
Tacrolimus 
Copanlisib 
Thalidomide 
Cyclophosphamide  
Ticagrelor 
Cyclosporine  
Tyrosine kinase inhibitors (Ivosidenib,  
Lapatinib, Larotrectinib Nintedanib, etc.) 
Docetaxel 
Vinblastine 
Dronedarone 
Vincristine 
Lidocaine (IV only, topical allowed) 
 
 
 
Prohibited: PGP Substrates- Prohibited unless routine monitoring of serum drug levels is 
performed 
(not appearing on previous lists) 
 
Acalabrutinib 
Edoxaban 
Irinotecan 
Rivaroxaban 
Albendazole 
Elbasvir 
Ledipasvir 
Proguanil 
Apixaban 
Emtricitabine 
Linezolid 
Saquinavir 
Bictegravir 
Erlotinib 
Maraviroc 
Simeprevir 
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Prohibited: PGP Substrates- Prohibited unless routine monitoring of serum drug levels is 
performed 
(not appearing on previous lists) 
 
Dabigatran 
Etoposide 
Mitoxantrone 
Sofosbuvir 
Dicloxacillin 
Everolimus 
Nevirapine 
Tenofovir 
Digoxin 
Glecaprevir 
Paritaprevir 
Velpatasvir 
Doravirine 
Idarubicin 
Pazopanib 
Venetoclax 
Doxorubicin 
Indinavir 
Pibrentasvir 
 
 
 
Prohibited: Strong Inducers of Drug Metabolism 
(not appearing on previous lists) 
 
Apalutamide 
Mitotan  
Avasimibe 
Rifampin 
Enzalutamide 
Rifapentine 
Ivosidenib 
St John's Wort extract 
Lumacaftor 
 
 
 
Prohibited: Not Appropriate for Pediatric Patient Population 
(not appearing on previous lists  
 
Monoamine oxidase inhibitors (MAOIs) 
 
 
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24. 
DISALLOWED CONCOMITANT MEDICATION TIME-FRAMES  
 
Disallowed for 6 Months Prior to Screening  
 
Abilify Maintena 
Haloperidol decanoate 
Aristada 
Paliperidone palmitate 
Botulinum toxin 
 
 
Disallowed for 3 Months Prior to Screening 
 
Fluphenazine decanoate 
Zuclopenthixol decanoate 
Risperidone microspheres 
Zyprexa Relprevv 
 
Disallowed for 4 Weeks Prior to Screening 
 
All Investigational Medications 
Risperidone 
Aripiprazole  
Itopride 
Chloroethylnorapomorphine  
Loxapine  
Chlorpromazine 
Metoclopramide  
Cinnarizine 
Paliperidone  
Desmethoxyfallypride   
Perphenazine 
Domperidone  
Pimozide 
Eticlopride  
Quetiapine 
Fallypride  
Reserpine 
Fluoxetine  
Thioridazine  
Haloperidol 
Ziprasidone 
 
   


	
Protocol_9.0_05 Mar 2024 | VV-TMF-38683299 | 1.0
Approved
Downloaded by 
 on 12 Sep 2024

Emalex Biosciences, Inc. 
Protocol EBS-101-TD-301 
Ecopipam 
Version 9.0, 05 March 2024 
 
Confidential 
Page 96 of 96 
Disallowed for 14 Days Prior to Baseline 
Baclofen 
Guanfacine  
Clonazepam  
Tetrabenazine 
Clonidine  
Valbenazine 
Duetetrabenazine 
 
 
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

	
Protocol_9.0_05 Mar 2024 | VV-TMF-38683299 | 1.0
Approved
Downloaded by 
 on 12 Sep 2024