Amendment 1: • Two exclusion criteria were clarified to ensure subject eligibility could be determined accurately; • Secondary efficacy endpoints were specified and prioritized; • Clarified when study appointments were to be made and when blood draws should be conducted for pharmacokinetic (PK) evaluations; • Updates to study procedures and schedule of assessments: 30-day Follow-Up call added, Baseline CGI-I and CGI-C deleted as these were not needed, footnotes added to highlight that laboratory samples should be obtained while subjects were in a fasted state and to include height in vital signs; • Statement added to indicate study drug dosing will not change due to changes in weight during the study; • Added HbA1c as a special laboratory parameter; • Correction made to include reporting of partner pregnancies.

Amendment 2: • Additional assessments added to Week 6 visit to better understand the time course of responses; • Weight bands corrected; • Exclusion on hepatic impairment added to reduce variability in ecopipam exposure • Clarification of pregnancy exclusion criteria; • Clarification of exclusion criteria regarding DSM-5 criteria; • Clarified and specified exclusion criteria regarding the change in YGTSS-TTS score between the Screening and Baseline visits to an absolute percentage change; • Clarified the time period of previous treatments in exclusion criteria; • Added exclusion criteria to exclude subjects who have initiated behavioral therapies; • Added requirement that a subject’s Baseline dose will not be adjusted based on subject weight changes; • Reworded key and other secondary efficacy endpoints in order of importance; • Clarified administration of study drug dose during the Week 4 visit; • Corrected clinical summary from Schering-Plough studies and Psyadon studies to be consistent with the Investigator’s Brochure; • Added text to stipulate the additional requirement for randomization assignment to be based on weight stratification; • Added clarification for subjects who do not tolerate dose titration and dose instructions; • Clarified when safety assessments will be performed; • Clarified the function and responsibilities of the data safety monitoring board (DSMB) charter, the types of DSMB members for the study, as well as clarified recommendations that the DSMB may make for the study.

Amendment 3: • Follow-Up visits and Follow-Up contact amended to be based on the last dose of study drug instead of the date of the visit; • Washout period of medications used to treat motor or vocal tics was reduced from 21 days to 14 days to facilitate subject visit scheduling; • Correction/clarification made to the exclusion criteria regarding mood disorders (DSM-5 criteria) to reflect original intention; • Exclusion criteria text on ECG at Screening was updated to reflect the responsibility of the principal investigator in review of ECG data; • Tetrahydrocannabinol was removed from the urine drug screen exclusion criteria; • Exclusion criterion regarding subjects with a first-degree relative with a major depressive episode was deleted; • Exclusionary previous treatments were reworded to match more realistic pediatric TS population treatment scenarios; • Exclusion criterion for subjects who received psychostimulants for the treatment of attention deficit disorder/ attention deficit/hyperactivity disorder (ADHD) was deleted; • Timing of the PK visit after last dose adjusted and text amended for clarity regarding scheduling of PK visits.

Amendment 4: • Sections 5.2 and 5.3 were created with new subsections for clarity and to provide additional information; • Correction to footnotes in schedule of assessments table; • Inclusion and exclusion criteria were refined for clarity; • Contraception language was revised for consistency with the Clinical Trials Facilitation Group Contraception Guidelines, and the guidelines were added to an appendix; • St. John’s Wort was added as an exclusionary medication; • Text on the removal of subjects from the study was revised to provide additional guidance; • Section added to provide additional information regarding prohibited therapies and a; prohibited medications list was added to an appendix; • Text revised to clarify it was the responsibility of the investigator to determine if the blind must be broken for safety reasons.

Amendment 5: • Alternate remote monitoring procedures were implemented for safety purposes in response to the COVID-19 pandemic; • Inclusion criterion stating the subject has received an adequate trial of nonpharmacological therapy without adequate response was amended to pertain only to subjects enrolled outside of the United States and Canada; • Exclusion criterion regarding subjects who have initiated new behavioral therapies fewer than 10 weeks prior to Baseline was revised to exclude the wording “to treat TS”; • Added an exclusion criterion to provide investigators the ability to ensure that subjects who may not be suitable for the study could be excluded; • Text added to provide investigators guidance to monitor subjects for signs of abuse, and withdrawal or dependence; • Updated information in Sections 5.2 and 5.3; • Updates to schedule of assessments table (urine pregnancy test was added to Day 14 Follow-Up visit and text added to clarify that approval was required for rescreening); • Text added regarding how direct-to-subject shipments of study drug may be necessary as a result of the COVID-19 pandemic; • Efficacy endpoints for change in CGI-TS-I and CaGI-C corrected to begin at Week 4; • Plan for protocol deviations related to the COVID-19 pandemic was specified.